Mitchel L. Zoler, PhD

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

McMurray_John_Glasgow2_web.jpg

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Bozkurt_Biykem_TEX_web.JPG

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

Itchhaporia_Dipti_CA_web.jpg

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

McMurray_John_Glasgow2_web.jpg

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Bozkurt_Biykem_TEX_web.JPG

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

Itchhaporia_Dipti_CA_web.jpg

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

BARCELONA – Treatment of patients with chronic heart failure with sacubitril/valsartan (Entresto), a mainstay agent for people with this disorder, produced no hint of incremental adverse cognitive effects during 3 years of treatment in a prospective, controlled, multicenter study with nearly 600 patients, although some experts note that possible adverse cognitive effects of sacubitril were not an issue for many heart failure clinicians, even before the study ran.

The potential for an adverse effect of sacubitril on cognition had arisen as a hypothetical concern because sacubitril inhibits the human enzyme neprilysin. This activity results in beneficial effects for patients with heart failure by increasing levels of several endogenous vasoactive peptides. But neprilysin also degrades amyloid beta peptides and so inhibition of this enzyme could possibly result in accumulation of amyloid peptides in the brain with potential neurotoxic effects, which raised concern among some cardiologists and patients that sacubitril/valsartan could hasten cognitive decline.

McMurray_John_Glasgow2_web.jpg

Results from the new study, PERSPECTIVE, showed “no evidence that neprilysin inhibition increased the risk of cognitive impairment due to the accumulation of beta amyloid” in patients with heart failure with either mid-range or preserved ejection fraction,” John McMurray, MD, said at the annual congress of the European Society of Cardiology.

Dr. McMurray, professor of medical cardiology at the University of Glasgow, highlighted that the study enrolled only patients with heart failure with a left ventricular ejection fraction of greater than 40% because the study designers considered it “unethical” to withhold treatment with sacubitril/valsartan from patients with an ejection fraction of 40% or less (heart failure with reduced ejection fraction, HFrEF), whereas “no mandate” exists in current treatment guidelines for using sacubitril/valsartan in patients with heart failure and higher ejection fractions. He added that he could see no reason why the results seen in patients with higher ejection fractions would not also apply to those with HFrEF.
 

Reassuring results, but cost still a drag on uptake

“This was a well-designed trial” with results that are “very reassuring” for a lack of harm from sacubitril/valsartan, commented Biykem Bozkurt, MD, PhD, the study’s designated discussant and professor of medicine at Baylor College of Medicine, Houston. The findings “solidify the lack of risk and are very exciting for the heart failure community because the question has bothered a large number of people, especially older patients” with heart failure.

Bozkurt_Biykem_TEX_web.JPG

Following these results, “hopefully more patients with heart failure will receive” sacubitril/valsartan, agreed Dr. McMurray, but he added the caveat that the relatively high cost of the agent (which has a U.S. list price of roughly $6,000/year) has been the primary barrier to wider uptake of the drug for patients with heart failure. Treatment with sacubitril/valsartan is recommended in several society guidelines as a core intervention for patients with HFrEF and as a treatment option for patients with heart failure and higher ejection fractions.

“Cost remains the single biggest deterrent for use” of sacubitril/valsartan, agreed Dipti N. Itchhaporia, MD, director of disease management at the Hoag Heart and Vascular Institute in Newport Beach, Calif. “Concerns about cognitive impairment has not been why people have not been using sacubitril/valsartan,” Dr. Itchhaporia commented in an interview.

Itchhaporia_Dipti_CA_web.jpg

PERSPECTIVE enrolled patients with heart failure with an ejection fraction greater than 40% and at least 60 years old at any of 137 sites in 20 countries, with about a third of enrolled patients coming from U.S. centers. The study, which ran enrollment during January 2017–May 2019, excluded people with clinically discernible cognitive impairment at the time of entry.

Researchers randomized patients to either a standard regimen of sacubitril/valsartan (295) or valsartan (297) on top of their background treatment, with most patients also receiving a beta-blocker, a diuretic, and a statin. The enrolled patients averaged about 72 years of age, and more than one-third were at least 75 years old.

The study’s primary endpoint was the performance of these patients in seven different tests of cognitive function using a proprietary metric, the CogState Global Cognitive Composite Score, measured at baseline and then every 6 months during follow-up designed to run for 3 years on treatment (the researchers collected data for at least 30 months of follow-up from 71%-73% of enrolled patients). Average changes in these scores over time tracked nearly the same in both treatment arms and met the study’s prespecified criteria for noninferiority of the sacubitril valsartan treatment, Dr. McMurray reported. The results also showed that roughly 60% of patients in both arms had “some degree of cognitive impairment” during follow-up.

A secondary outcome measure used PET imaging to quantify cerebral accumulation of beta amyloid, and again the results met the study’s prespecified threshold for noninferiority for the patients treated with sacubitril/valsartan, said Dr. McMurray.

Another concern raised by some experts was the relatively brief follow-up of 3 years, and the complexity of heart failure patients who could face several other causes of cognitive decline. The findings “help reassure, but 3 years is not long enough, and I’m not sure the study eliminated all the other possible variables,” commented Dr. Itchhaporia.

But Dr. McMurray contended that 3 years represents robust follow-up in patients with heart failure who notoriously have limited life expectancy following their diagnosis. “Three years is a long time for patients with heart failure.”

The findings also raise the prospect of developing sacubitril/valsartan as an antihypertensive treatment, an indication that has been avoided until now because of the uncertain cognitive effects of the agent and the need for prolonged use when the treated disorder is hypertension instead of heart failure.

PERSPECTIVE was funded by Novartis, the company that markets sacubitril/valsartan (Entresto). Dr. McMurray has received consulting and lecture fees from Novartis and he and his institution have received research funding from Novartis. Dr. Bozkurt has been a consultant to numerous companies but has no relationship with Novartis. Dr. Itchhaporia had no disclosures.

The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers. 

The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.

But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.

A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
 

‘Unprecedented demand’ for Wegovy derailed when plant went offline

The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.

Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”

A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.

“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.

“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.

“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.

“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
 

The liraglutide/Saxenda workaround

The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.

Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).

Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.

Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
 

A ‘reasonable’ evidence base, but more work

Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.

“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.

Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.

Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.

“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”

The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
 

The tirzepatide coupon program works ‘off label’ for obesity

Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.

Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.

Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.

Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.

“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.

But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.

“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.

Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.

Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.

Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
 

Even more workarounds

Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.

Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”

Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.

“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.

“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.

Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.

“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.

Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.

A version of this article first appeared on Medscape.com.

The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers. 

The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.

But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.

A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
 

‘Unprecedented demand’ for Wegovy derailed when plant went offline

The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.

Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”

A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.

“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.

“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.

“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.

“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
 

The liraglutide/Saxenda workaround

The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.

Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).

Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.

Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
 

A ‘reasonable’ evidence base, but more work

Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.

“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.

Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.

Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.

“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”

The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
 

The tirzepatide coupon program works ‘off label’ for obesity

Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.

Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.

Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.

Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.

“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.

But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.

“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.

Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.

Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.

Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
 

Even more workarounds

Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.

Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”

Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.

“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.

“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.

Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.

“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.

Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.

A version of this article first appeared on Medscape.com.

The glucagon-like peptide-1 (GLP-1) agonist semaglutide formulated for treating obesity (Wegovy) had a roaring takeoff a little more than a year ago, with surging patient demand after the U.S. Food and Drug Administration approved it in June 2021. But starting doses of the Wegovy form of semaglutide went missing in action starting late 2021 and continue to date, frustrating patients and their health care providers. 

The arrival of Wegovy last year was hailed by obesity medicine specialists and others as a “game changer” for treating people with obesity because of semaglutide’s proven safety and efficacy at the subcutaneous dose of 2.4 mg delivered once a week to produce at least 15% weight loss in half the people who received it, as documented last year in results from one of the drug’s pivotal clinical trials.

But during the months following semaglutide’s approval for treating obesity (it also received an FDA marketing nod in late 2017 as Ozempic for treating type 2 diabetes), a worldwide shortage of Wegovy, including in the United States, emerged.

A manufacturing glitch shut down the primary location for production of U.S.-bound Wegovy injector pens for several months starting in late 2021, according to a December report from Novo Nordisk, the company that makes and markets the agent. (The Wegovy production issue appears to have had a very modest impact, especially in U.S. pharmacies, on the supply of semaglutide formulated as Ozempic, also marketed by Novo Nordisk, although Wegovy supply and demand have dramatically limited Ozempic availability in Australia.)
 

‘Unprecedented demand’ for Wegovy derailed when plant went offline

The supply side for Wegovy became so hopelessly broken that just months after U.S. sales began and immediately skyrocketed, Novo Nordisk made the remarkable decision to pull starting doses of Wegovy from the market to make it much harder to initiate patients (semaglutide and other GLP-1 agonists require gradual dose ramp-up to avoid gastrointestinal side effects), and the company publicly implored clinicians to not start new patients on the agent, which is where the status remains as of early August 2022.

Novo Nordisk’s financial report for the second quarter of 2022, released on Aug. 3, said the company “expects to make all Wegovy dose strengths available in the United States towards the end of 2022.”

A Dear Health Care Provider letter that Novo Nordisk posted on its U.S. Wegovy website last spring cited “unprecedented demand” that exceeded every prior product launch in the company’s history. It forced Novo Nordisk to pull the plug on all U.S. promotion of Wegovy and compelled the company to ask U.S. clinicians to halt new patient starts.

“I stopped offering Wegovy to new patients” since about the beginning of 2022, says Lauren D. Oshman, MD, a family and obesity medicine specialist at the University of Michigan, Ann Arbor. “It’s very frustrating to not have patients [with obesity] receive the optimal treatment available.” Although she adds that she tries to match obesity treatments to each patient’s clinical needs, and a GLP-1 agonist is not the first choice for every person with obesity.

“It was a disastrous rollout,” says Catherine W. Varney, DO, a family and obesity medicine specialist at the University of Virginia, Charlottesville. “It’s frustrating to know that the treatment is there but not being able to use it,” she said in an interview.

“I had about 800 patients on Wegovy” when the supply dropped earlier this year, and “I couldn’t handle the volume of messages that I got from patients,” recalls Angela Fitch, MD, associate director of the Massachusetts General Hospital Weight Center, Boston. “It was painful,” she said in an interview.

“Frustrating and chaotic,” is the description from Ivania M. Rizo, MD, director of obesity medicine at Boston Medical Center.
 

The liraglutide/Saxenda workaround

The upshot is that people with obesity and their health care providers have been busy devising workarounds to try to meet the intense demand for this drug-assisted approach to appetite control and weight loss. Their tactics run a wide gamut based on the crazy-quilt diversity of health insurance coverage across America.

Because the bottleneck for starting Wegovy resulted from unavailable starting doses (dosing starts at 0.25 mg delivered subcutaneously once a week, eventually ramping up to a maximum of 2.4 mg weekly), one option was to start patients on a different GLP-1 agonist, such as liraglutide (Saxenda, approved for obesity).

Starting a patient on liraglutide involves the same sort of up-titration and acclimation to a GLP-1 agonist that semaglutide requires, and transition between these agents seems feasible for at least some. It also means daily injections of liraglutide rather than the weekly schedule for semaglutide, although some patients prefer maintaining a daily dosing schedule. Another limitation of liraglutide is that evidence shows it is not nearly as effective for weight loss as semaglutide.

Results from the head-to-head STEP 8 trial, published in JAMA, showed an average weight loss from baseline of about 16% with semaglutide and about 6% with liraglutide (and about 2% with placebo).
 

A ‘reasonable’ evidence base, but more work

Changing from Saxenda to Wegovy, or from Wegovy to Saxenda, “would be reasonably evidence-based medicine,” said Dr. Oshman in an interview. She has managed a Wegovy-to-Saxenda switch for a “handful” of patients to deal with Wegovy shortages, but she has not yet moved anyone to Wegovy after a Saxenda initiation.

“No prospective study has looked at this transition,” but dose equivalence tables exist based on expert opinion, noted Dr. Oshman, as in this 2020 report.

Dr. Varney has several patients on the Saxenda-to-Wegovy track. She up-titrates patients on Saxenda to the maximum daily dose of 3.0 mg and then switches them to the 1.7 mg weekly dose of Wegovy, one of the “destination” Wegovy doses that has remained generally available during the shortage. But Dr. Varney’s experience is that only half of her patients made the changeover smoothly, with the others having “severe gastrointestinal distress,” including vomiting, she notes.

Dr. Fitch has also successfully used this Saxenda-to-Wegovy approach for some of her patients, but it hasn’t been easy.

“It’s more work and more prior authorizations. It’s harder and adds a layer of stress,” but, Dr. Fitch adds, “people are willing to work on it because the weight loss is worth it.”

The liraglutide to semaglutide shuffle is “doable,” says Dr. Rizo, “but I’m looking forward to not having to do it and being able to just start Wegovy.”
 

The tirzepatide coupon program works ‘off label’ for obesity

Another workaround depends on the FDA approval in May for tirzepatide (Mounjaro) for type 2 diabetes. Tirzepatide is a related GLP-1 agonist that also adds a second incretin-like agonist activity that mimics the glucose-dependent insulinotropic polypeptide.

Soon after approval, Lilly, the company that markets tirzepatide, started a U.S. coupon program geared exclusively to people with commercial insurance. Within certain refill and dollar limits, the program lets patients buy tirzepatide at pharmacies at an out-of-pocket cost of $25 for a 4-week supply (tirzepatide is also dosed by weekly subcutaneous injections). The program will extend into 2023.

Novo Nordisk offered U.S. patients with commercial insurance a similar discount when Wegovy first hit the U.S. market in 2021, but the program closed down once the supply shortage began.

Despite tirzepatide’s current approval only for type 2 diabetes, Dr. Varney has been successfully prescribing it to patients without diabetes off-label for weight loss.

“The coupons still work even when tirzepatide is used off-label,” she notes. And while the drug’s rollout is still only a couple of months old, so far, it’s gone “beautifully” with no hints of supply issues, she says.

But a major drawback to relying on an introductory coupon program that makes these agents affordable to patients is their ability to maintain treatment once the discounts inevitably end.

“We try to only prescribe agents that patients can continue to access,” says Dr. Fitch, who has had some patients with commercial insurance start on Wegovy with coupon discounts only to later lose access.

Many commercial U.S. insurers do not cover obesity treatments, a decision often driven by the employers who sponsor the coverage, she notes.

Study results have documented that when people with obesity stop taking a GLP-1 agonist their lost weight rebounds, as in a study that tracked people who stopped taking semaglutide.

Dr. Fitch has had success prescribing tirzepatide to patients with obesity but without diabetes who have certain types of Medicare drug coverage policies, which often do not deny off-label drug coverage. That approach works until patients reach the “donut hole” in their drug coverage and are faced with a certain level of out-of-pocket costs that can balloon to several thousand dollars.
 

Even more workarounds

Other approaches patients have used to acquire Wegovy include purchasing it in other countries, such as Canada or Brazil, says Dr. Fitch. But prices outside the United States, while substantially lower, can still be a barrier for many patients, notes Dr. Oshman.

Semaglutide in Canada goes for about $300 for a 4-week supply, roughly a quarter the U.S. price, she says, but is “still too high for many of my patients.”

Intense patient demand sometimes bordering on desperation has prompted some to seek semaglutide from private compounding pharmacies, a step clinicians regard as downright dangerous.

“Semaglutide from compounding pharmacies is not known to be safe. We feel strongly that it’s not something that people should do,” says Dr. Fitch.

“Compounding pharmacies have no FDA regulation. People don’t know what they’re getting. It’s dangerous,” agrees Dr. Varney. Physicians who refer people for privately compounded semaglutide “are taking advantage of desperate people,” she adds.

Although it seems likely that Novo Nordisk will soon sort out the supply problems and Wegovy will once again become more widely available, some of the issues patients have had with access to the weight loss medication stem from more systemic issues in the United States health insurance landscape: an unwillingness by payers to cover the costs of weight loss medications, a shortcoming that also exists for Medicare and Medicaid.

“We need to make obesity treatment a standard benefit, and not something that can be carved out,” says Dr. Fitch. People with obesity “deserve access to effective treatments for their disease,” she declares.

Dr. Oshman, Dr. Varney, and Dr. Rizo have reported no relevant financial relationships. Dr. Fitch has reported being an advisor to Jenny Craig.

A version of this article first appeared on Medscape.com.

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

U.S. Medicare beneficiaries with type 2 diabetes who had health coverage through a Medicare Advantage (MA) plan received treatment with an sodium-glucose cotransporter 2 inhibitor or glucagonlike peptide–1 receptor agonist significantly less often than patients with traditional fee-for-service (FFS) Medicare coverage in 2014-2019, according to a study of more than 411,000 patients.

“MA beneficiaries had modestly but significantly poorer intermediate health outcomes and were less likely to be treated with newer evidence-based antihyperglycemic therapies, compared with Medicare FFS beneficiaries,” concluded Utibe R. Essien, MD, and coauthors in a study published in Diabetes Care.

The report comes as the U.S. Congress is looking closely at the MA program and evidence that insurance companies that provide these policies sometimes impose inappropriate barriers on enrolled beneficiaries by denying or limiting access to treatments and interventions in ways that run counter to Medicare’s coverage policies.

According to Representative Diana DeGette (D-Colo.), who chaired a hearing on MA plans on June 28 by the House of Representatives’ Energy and Commerce Subcommittee on Oversight and Investigations, beneficiaries who are covered through an MA plan “do not always get the care that they are entitled to.”

The study by Dr. Essien and colleagues also documents some positives of care delivered through MA plans for patients with type 2 diabetes, compared with what FFS Medicare beneficiaries generally receive, such as significantly higher rates of screening for nephropathy and ophthalmologic disorders, and foot examinations.

But the apparently dampened use of SGLT2 inhibitors and GLP-1 receptor agonists among MA beneficiaries stand out as notable shortcomings, Dr. Essien maintained.
 

Cost containment may limit use

“The differences in health outcomes and in treatments in MA plans are important to highlight,” Dr. Essien said in an interview. “We worry that the cost-containment challenges [associated with MA plans] may be limiting use of these newer treatments.”

The study was based on 2014-2019 data from the Diabetes Collaborative Registry, which collects information from more than 5,000 U.S. clinicians whose practices include patients with diabetes, as well as claims data recorded by the Centers for Medicare and Medicaid Services during 2014-2017.

The main analysis focused on 345,911 Medicare beneficiaries with diabetes, which included 34% with MA coverage and 66% with FFS coverage. The two subgroups had similar ages, about 75 years old, and roughly half were women in both subgroups. The rate at which both subgroups received statin treatment was nearly the same: 72% for those with MA coverage and 71% for those with FFS Medicare.

But MA beneficiaries differed from those with FFS coverage in several other ways. MA beneficiaries had a higher prevalence of Medicaid eligibility than the FFS group (20% vs 12%) and lower rates of consultations with cardiologists (41% vs. 45%) or endocrinologists (7% vs. 10%).

Some of the positive differences in the care received by MA beneficiaries, compared with FFS beneficiaries, after adjustment for potential clinical and sociodemographic confounders, included:

• Screening for nephropathy, at a significant 14% higher relative rate.
• Screening for ophthalmologic disorders, at a significant 8% higher relative rate.
• Undergoing a diabetic foot examination, at a significant 13% higher relative rate.
• Receiving smoking-cessation counseling, at a significant 5% higher relative rate.
• Receiving treatment with an ACE inhibitor or angiotensin-receptor blocker (87% vs. 81%).
• More consistently receiving treatment with metformin, with rates of 72% versus 69% in 2017.

However, these positive differences were accompanied by these relative shortcomings for those with MA, compared with FFS coverage:

• Lower rates of treatment with an SGLT2 inhibitor (5.4% vs. 6.7%), a significant 9% relative difference after adjustment.
• Lower rates of treatment with a GLP-1 agonist (6.9% vs. 9.0%), a significant 20% relative difference after adjustment.
• Higher average levels of LDL cholesterol (81.5 vs. 78.9 mg/dL), a significantly higher average hemoglobin A1c level (7.1% vs. 7.0%), and a trend toward a lower prevalence of blood pressure control (70.3% vs. 71.5%).

Researchers also highlight that the lower rate at which people with MA coverage received SGLT2 inhibitors or GLP-1 agonists was consistent in patients with established cardiovascular or kidney disease, for whom these agents are particularly recommended.

In addition, a secondary analysis of data for another 65,000 Medicare beneficiaries in 2018 and 2019 showed the disparity in use of agents from these two drug classes continued.
 

Low systemic use of SGLT2 inhibitors, GLP-1 agonists

Dr. Essien acknowledged that, even in people with FFS Medicare coverage, use of SGLT2 inhibitors and GLP-1 agonists was low, but the difference between those with MA coverage is “important.”

Researchers offered four factors that might drive reduced prescribing of agents from these two classes for patients with type 2 diabetes with MA coverage: cost-containment strategies put in place by MA plans; the lower rate of consultations with specialists (cardiologists and endocrinologists); possible exclusion of clinicians from MA provider networks who tend to prescribe these higher-price agents; and lower household incomes of people with MA plans, which may lead to cost-related nonadherence.

Most SGLT2 inhibitors have an average retail cost of about $6,000/year, and some GLP-1 agonists cost more than $10,000/year.

In general, MA coverage includes more oversight of care and its cost than occurs with FFS coverage, noted Dr. Essien, an internal medicine physician at the University of Pittsburgh and a researcher at the Center for Health Equity Research and Promotion of the VA Pittsburgh Healthcare System.

“Incentives for using these more expensive treatments may not be there in MA plans,” he explained. Overcoming cost-related barriers is a challenge that will require “bold policy changes,” as well as better education of clinicians so they make correct treatment decisions, and of patients to resolve possible concerns about treatment safety.

Rep. DeGette hinted during her remarks at the June hearing that policy changes may be coming from Congress.

“Our seniors and their doctors should not be required to jump through numerous hoops to get coverage for straightforward and medically necessary procedures,” she said.

The study received no commercial funding. Dr. Essien reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A cost-saving, stepwise approach to treating diabetic macular edema was as effective and at least as safe as what’s been the standard approach, which jumps straight to the costlier treatment, in a head-to-head, multicenter, U.S. randomized trial of the two regimens that included 312 eyes in 270 adults with type 1 or type 2 diabetes.

The findings validate a treatment regimen for diabetic macular edema that’s already common in U.S. practice based on requirements by many health insurance providers because of the money it saves.

The step-therapy approach studied involves starting off-label treatment with the relatively inexpensive agent bevacizumab (Avastin), followed by a switch to the much pricier aflibercept (Eylea) when patients don’t adequately respond, following a prespecified algorithm that applies four criteria to determine when patients need to change agents.

These new findings build on a 2016 study that compared aflibercept monotherapy with bevacizumab monotherapy and showed that after 2 years of treatment aflibercept produced clearly better outcomes.

The new trial findings “are particularly relevant given the increasing frequency of insurers mandating step therapy with bevacizumab before the use of other drugs” such as aflibercept, noted Chirag D. Jhaveri, MD, and colleagues in the study published online in the New England Journal of Medicine.
 

Opportunity for ‘substantial cost reductions’

Jhaveri, a retina surgeon in Austin, Texas, and associates note that, based on Medicare reimbursement rates of $1,830 for a single dose of aflibercept and $70 for one dose of bevacizumab, starting treatment with bevacizumab could produce “substantial cost reductions for the health care system.”

The authors of an accompanying editorial agree. Step therapy that starts with bevacizumab would probably result in “substantial” cost savings, and the findings document “similar outcomes” from the two tested regimens based on improvements in visual acuity and changes in the thickness measurement of the central retina during the 2-year trial, write David C. Musch, PhD, and Emily Y. Chew, MD.

Dr. Musch, a professor and ophthalmology epidemiologist at the University of Michigan in Ann Arbor, and Dr. Chew, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute in Bethesda, Md., also laud the “rigorous” study for its design and conduct that was “beyond reproach,” and for producing evidence that “applies well to clinical practice.”

The only potential drawback to the step-therapy approach, they write, is that people with diabetes often have “numerous coexisting conditions that make it more difficult for them to adhere to frequent follow-up visits,” a key element of the tested step-care protocol, which mandated follow-up visits every 4 weeks during the first year and every 4-16 weeks during the second year.
 

312 eyes of 270 patients

The new trial, organized by the DRCR Retinal Network and the Jaeb Center for Health Research in Tampa, Fla., ran at 54 U.S. sites from December 2017 to November 2019. The study randomized 158 eyes in 137 patients to aflibercept monotherapy, and 154 eyes in 133 patients to the step-care regimen (both eyes were treated in several patients in each group, with each eye receiving a different regimen). Participants were around 60 years old, 48% were women, and 95% had type 2 diabetes.

To be eligible for enrollment, patients had at least one eye with a best-corrected visual-acuity letter score of 24-69 on an Electronic Early Treatment Diabetic Retinopathy Study chart (ranges from 0 to 100, with higher values indicating better visual acuity), which corresponds to Snellen chart values of 20/320-20/50, readings that encompass most patients with diabetic macular edema, noted study authors Adam R. Glassman and Jennifer K. Sun, MD, in an interview.

“Very few patients with diabetic macular edema have vision due to this alone that is worse than 20/320, which meets criteria for legal blindness,” said Dr. Glassman, who is executive director of the Jaeb Center for Health Research, and Dr. Sun, who is chief of the center for clinical eye research and trials at the Joslin Diabetes Center in Boston and chair of the DRCR Retinal Network.

The primary outcome was time-averaged change in visual-acuity letter score from baseline to 2 years, which improved by an average of 15.0 letters in the aflibercept monotherapy group and an average of 14.0 letters in the step-therapy group, an adjusted difference of 0.8 letters, which was not significant. An improvement from baseline of at least 15 letters occurred in 53% of the eyes in the aflibercept monotherapy group and in 58% of those who had step therapy, and 77% of eyes in both groups had improvements of at least 10 letters.  

Central retinal thickness dropped from baseline by an average of 192 mcm with aflibercept monotherapy and 198 mcm with step therapy. The average number of total treatments (by intravitreous injection) was 14.6 in the aflibercept monotherapy group and 16.1 in the step-therapy group. After the first 24 weeks of the study, 39% of eyes in the step-therapy group had switched from bevacizumab to aflibercept injections; after 1 year, 60% of eyes had switched; and by study end, after 2 years, 70% had changed.

The bevacizumab-first group also showed at least comparable if not better safety, with similar rates of prespecified ocular events in both groups, but with a significantly lower rate of serious systemic adverse events, which occurred in 52% of the eyes treated with aflibercept only and 36% of eyes that began treatment on bevacizumab. Serious systemic adverse events occurred in 43% of patients who had two eyes treated as part of the trial.
 

‘Bevacizumab first was noninferior’

The team that designed the trial opted for a superiority design rather than a noninferiority trial and powered the study based on the presumption that aflibercept monotherapy would prove superior, said Dr. Glassman and Dr. Sun. “We feel that the clinical interpretation of these results will be similar to the interpretation if we had conducted a noninferiority study, and we found that bevacizumab first was noninferior to aflibercept monotherapy,” they maintained in an interview.

Dr. Glassman and Dr. Sun said they and their coauthors are now analyzing the results to try to find patient characteristics that could identify eyes most likely to respond to the bevacizumab-first approach. “It would be clinically valuable” to use the results to identify characteristics that could help guide clinicians’ treatment approach and enhance patient counseling, they said.

The study received funding from the National Institutes of Health. Dr. Jhaveri has reported being a consultant for Genentech, Novartis, and Regenxbio. Dr. Glassman has reported receiving grants from Genentech and Regeneron. Dr. Sun has reported receiving grants from Boehringer Ingelheim, Janssen Biotech, KalVista, Optovue, and Physical Sciences, grants and travel support from Novartis and Novo Nordisk, travel support from Merck, writing support from Genentech, and equipment supplied by Adaptive Sensory and Boston Micromachines. Dr. Musch and Dr. Chew have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A cost-saving, stepwise approach to treating diabetic macular edema was as effective and at least as safe as what’s been the standard approach, which jumps straight to the costlier treatment, in a head-to-head, multicenter, U.S. randomized trial of the two regimens that included 312 eyes in 270 adults with type 1 or type 2 diabetes.

The findings validate a treatment regimen for diabetic macular edema that’s already common in U.S. practice based on requirements by many health insurance providers because of the money it saves.

The step-therapy approach studied involves starting off-label treatment with the relatively inexpensive agent bevacizumab (Avastin), followed by a switch to the much pricier aflibercept (Eylea) when patients don’t adequately respond, following a prespecified algorithm that applies four criteria to determine when patients need to change agents.

These new findings build on a 2016 study that compared aflibercept monotherapy with bevacizumab monotherapy and showed that after 2 years of treatment aflibercept produced clearly better outcomes.

The new trial findings “are particularly relevant given the increasing frequency of insurers mandating step therapy with bevacizumab before the use of other drugs” such as aflibercept, noted Chirag D. Jhaveri, MD, and colleagues in the study published online in the New England Journal of Medicine.
 

Opportunity for ‘substantial cost reductions’

Jhaveri, a retina surgeon in Austin, Texas, and associates note that, based on Medicare reimbursement rates of $1,830 for a single dose of aflibercept and $70 for one dose of bevacizumab, starting treatment with bevacizumab could produce “substantial cost reductions for the health care system.”

The authors of an accompanying editorial agree. Step therapy that starts with bevacizumab would probably result in “substantial” cost savings, and the findings document “similar outcomes” from the two tested regimens based on improvements in visual acuity and changes in the thickness measurement of the central retina during the 2-year trial, write David C. Musch, PhD, and Emily Y. Chew, MD.

Dr. Musch, a professor and ophthalmology epidemiologist at the University of Michigan in Ann Arbor, and Dr. Chew, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute in Bethesda, Md., also laud the “rigorous” study for its design and conduct that was “beyond reproach,” and for producing evidence that “applies well to clinical practice.”

The only potential drawback to the step-therapy approach, they write, is that people with diabetes often have “numerous coexisting conditions that make it more difficult for them to adhere to frequent follow-up visits,” a key element of the tested step-care protocol, which mandated follow-up visits every 4 weeks during the first year and every 4-16 weeks during the second year.
 

312 eyes of 270 patients

The new trial, organized by the DRCR Retinal Network and the Jaeb Center for Health Research in Tampa, Fla., ran at 54 U.S. sites from December 2017 to November 2019. The study randomized 158 eyes in 137 patients to aflibercept monotherapy, and 154 eyes in 133 patients to the step-care regimen (both eyes were treated in several patients in each group, with each eye receiving a different regimen). Participants were around 60 years old, 48% were women, and 95% had type 2 diabetes.

To be eligible for enrollment, patients had at least one eye with a best-corrected visual-acuity letter score of 24-69 on an Electronic Early Treatment Diabetic Retinopathy Study chart (ranges from 0 to 100, with higher values indicating better visual acuity), which corresponds to Snellen chart values of 20/320-20/50, readings that encompass most patients with diabetic macular edema, noted study authors Adam R. Glassman and Jennifer K. Sun, MD, in an interview.

“Very few patients with diabetic macular edema have vision due to this alone that is worse than 20/320, which meets criteria for legal blindness,” said Dr. Glassman, who is executive director of the Jaeb Center for Health Research, and Dr. Sun, who is chief of the center for clinical eye research and trials at the Joslin Diabetes Center in Boston and chair of the DRCR Retinal Network.

The primary outcome was time-averaged change in visual-acuity letter score from baseline to 2 years, which improved by an average of 15.0 letters in the aflibercept monotherapy group and an average of 14.0 letters in the step-therapy group, an adjusted difference of 0.8 letters, which was not significant. An improvement from baseline of at least 15 letters occurred in 53% of the eyes in the aflibercept monotherapy group and in 58% of those who had step therapy, and 77% of eyes in both groups had improvements of at least 10 letters.  

Central retinal thickness dropped from baseline by an average of 192 mcm with aflibercept monotherapy and 198 mcm with step therapy. The average number of total treatments (by intravitreous injection) was 14.6 in the aflibercept monotherapy group and 16.1 in the step-therapy group. After the first 24 weeks of the study, 39% of eyes in the step-therapy group had switched from bevacizumab to aflibercept injections; after 1 year, 60% of eyes had switched; and by study end, after 2 years, 70% had changed.

The bevacizumab-first group also showed at least comparable if not better safety, with similar rates of prespecified ocular events in both groups, but with a significantly lower rate of serious systemic adverse events, which occurred in 52% of the eyes treated with aflibercept only and 36% of eyes that began treatment on bevacizumab. Serious systemic adverse events occurred in 43% of patients who had two eyes treated as part of the trial.
 

‘Bevacizumab first was noninferior’

The team that designed the trial opted for a superiority design rather than a noninferiority trial and powered the study based on the presumption that aflibercept monotherapy would prove superior, said Dr. Glassman and Dr. Sun. “We feel that the clinical interpretation of these results will be similar to the interpretation if we had conducted a noninferiority study, and we found that bevacizumab first was noninferior to aflibercept monotherapy,” they maintained in an interview.

Dr. Glassman and Dr. Sun said they and their coauthors are now analyzing the results to try to find patient characteristics that could identify eyes most likely to respond to the bevacizumab-first approach. “It would be clinically valuable” to use the results to identify characteristics that could help guide clinicians’ treatment approach and enhance patient counseling, they said.

The study received funding from the National Institutes of Health. Dr. Jhaveri has reported being a consultant for Genentech, Novartis, and Regenxbio. Dr. Glassman has reported receiving grants from Genentech and Regeneron. Dr. Sun has reported receiving grants from Boehringer Ingelheim, Janssen Biotech, KalVista, Optovue, and Physical Sciences, grants and travel support from Novartis and Novo Nordisk, travel support from Merck, writing support from Genentech, and equipment supplied by Adaptive Sensory and Boston Micromachines. Dr. Musch and Dr. Chew have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A cost-saving, stepwise approach to treating diabetic macular edema was as effective and at least as safe as what’s been the standard approach, which jumps straight to the costlier treatment, in a head-to-head, multicenter, U.S. randomized trial of the two regimens that included 312 eyes in 270 adults with type 1 or type 2 diabetes.

The findings validate a treatment regimen for diabetic macular edema that’s already common in U.S. practice based on requirements by many health insurance providers because of the money it saves.

The step-therapy approach studied involves starting off-label treatment with the relatively inexpensive agent bevacizumab (Avastin), followed by a switch to the much pricier aflibercept (Eylea) when patients don’t adequately respond, following a prespecified algorithm that applies four criteria to determine when patients need to change agents.

These new findings build on a 2016 study that compared aflibercept monotherapy with bevacizumab monotherapy and showed that after 2 years of treatment aflibercept produced clearly better outcomes.

The new trial findings “are particularly relevant given the increasing frequency of insurers mandating step therapy with bevacizumab before the use of other drugs” such as aflibercept, noted Chirag D. Jhaveri, MD, and colleagues in the study published online in the New England Journal of Medicine.
 

Opportunity for ‘substantial cost reductions’

Jhaveri, a retina surgeon in Austin, Texas, and associates note that, based on Medicare reimbursement rates of $1,830 for a single dose of aflibercept and $70 for one dose of bevacizumab, starting treatment with bevacizumab could produce “substantial cost reductions for the health care system.”

The authors of an accompanying editorial agree. Step therapy that starts with bevacizumab would probably result in “substantial” cost savings, and the findings document “similar outcomes” from the two tested regimens based on improvements in visual acuity and changes in the thickness measurement of the central retina during the 2-year trial, write David C. Musch, PhD, and Emily Y. Chew, MD.

Dr. Musch, a professor and ophthalmology epidemiologist at the University of Michigan in Ann Arbor, and Dr. Chew, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute in Bethesda, Md., also laud the “rigorous” study for its design and conduct that was “beyond reproach,” and for producing evidence that “applies well to clinical practice.”

The only potential drawback to the step-therapy approach, they write, is that people with diabetes often have “numerous coexisting conditions that make it more difficult for them to adhere to frequent follow-up visits,” a key element of the tested step-care protocol, which mandated follow-up visits every 4 weeks during the first year and every 4-16 weeks during the second year.
 

312 eyes of 270 patients

The new trial, organized by the DRCR Retinal Network and the Jaeb Center for Health Research in Tampa, Fla., ran at 54 U.S. sites from December 2017 to November 2019. The study randomized 158 eyes in 137 patients to aflibercept monotherapy, and 154 eyes in 133 patients to the step-care regimen (both eyes were treated in several patients in each group, with each eye receiving a different regimen). Participants were around 60 years old, 48% were women, and 95% had type 2 diabetes.

To be eligible for enrollment, patients had at least one eye with a best-corrected visual-acuity letter score of 24-69 on an Electronic Early Treatment Diabetic Retinopathy Study chart (ranges from 0 to 100, with higher values indicating better visual acuity), which corresponds to Snellen chart values of 20/320-20/50, readings that encompass most patients with diabetic macular edema, noted study authors Adam R. Glassman and Jennifer K. Sun, MD, in an interview.

“Very few patients with diabetic macular edema have vision due to this alone that is worse than 20/320, which meets criteria for legal blindness,” said Dr. Glassman, who is executive director of the Jaeb Center for Health Research, and Dr. Sun, who is chief of the center for clinical eye research and trials at the Joslin Diabetes Center in Boston and chair of the DRCR Retinal Network.

The primary outcome was time-averaged change in visual-acuity letter score from baseline to 2 years, which improved by an average of 15.0 letters in the aflibercept monotherapy group and an average of 14.0 letters in the step-therapy group, an adjusted difference of 0.8 letters, which was not significant. An improvement from baseline of at least 15 letters occurred in 53% of the eyes in the aflibercept monotherapy group and in 58% of those who had step therapy, and 77% of eyes in both groups had improvements of at least 10 letters.  

Central retinal thickness dropped from baseline by an average of 192 mcm with aflibercept monotherapy and 198 mcm with step therapy. The average number of total treatments (by intravitreous injection) was 14.6 in the aflibercept monotherapy group and 16.1 in the step-therapy group. After the first 24 weeks of the study, 39% of eyes in the step-therapy group had switched from bevacizumab to aflibercept injections; after 1 year, 60% of eyes had switched; and by study end, after 2 years, 70% had changed.

The bevacizumab-first group also showed at least comparable if not better safety, with similar rates of prespecified ocular events in both groups, but with a significantly lower rate of serious systemic adverse events, which occurred in 52% of the eyes treated with aflibercept only and 36% of eyes that began treatment on bevacizumab. Serious systemic adverse events occurred in 43% of patients who had two eyes treated as part of the trial.
 

‘Bevacizumab first was noninferior’

The team that designed the trial opted for a superiority design rather than a noninferiority trial and powered the study based on the presumption that aflibercept monotherapy would prove superior, said Dr. Glassman and Dr. Sun. “We feel that the clinical interpretation of these results will be similar to the interpretation if we had conducted a noninferiority study, and we found that bevacizumab first was noninferior to aflibercept monotherapy,” they maintained in an interview.

Dr. Glassman and Dr. Sun said they and their coauthors are now analyzing the results to try to find patient characteristics that could identify eyes most likely to respond to the bevacizumab-first approach. “It would be clinically valuable” to use the results to identify characteristics that could help guide clinicians’ treatment approach and enhance patient counseling, they said.

The study received funding from the National Institutes of Health. Dr. Jhaveri has reported being a consultant for Genentech, Novartis, and Regenxbio. Dr. Glassman has reported receiving grants from Genentech and Regeneron. Dr. Sun has reported receiving grants from Boehringer Ingelheim, Janssen Biotech, KalVista, Optovue, and Physical Sciences, grants and travel support from Novartis and Novo Nordisk, travel support from Merck, writing support from Genentech, and equipment supplied by Adaptive Sensory and Boston Micromachines. Dr. Musch and Dr. Chew have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

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“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

[embed:render:related:node:231793]

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

[embed:render:related:node:231793]

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Patorno_Elisabetta_MA_web.JPG

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

Inzucchi_Silvio_E_CT_web.JPG

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

[embed:render:related:node:247936]

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Patorno_Elisabetta_MA_web.JPG

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

Inzucchi_Silvio_E_CT_web.JPG

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

[embed:render:related:node:247936]

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Patorno_Elisabetta_MA_web.JPG

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

Inzucchi_Silvio_E_CT_web.JPG

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

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SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

Luo_Jing_PA_web.jpg

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

Inzucchi_Silvio_E_CT_web.JPG

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

[embed:render:related:node:247936]

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

Luo_Jing_PA_web.jpg

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

Inzucchi_Silvio_E_CT_web.JPG

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

[embed:render:related:node:247936]

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

Luo_Jing_PA_web.jpg

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

Inzucchi_Silvio_E_CT_web.JPG

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

[embed:render:related:node:247936]

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

Jastreboff_Ania_M_CT_web.JPG

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

Kaplan_Lee_M_BOSTON_web.jpg

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

[embed:render:related:node:254624]

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

Jastreboff_Ania_M_CT_web.JPG

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

Kaplan_Lee_M_BOSTON_web.jpg

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

[embed:render:related:node:254624]

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

Jastreboff_Ania_M_CT_web.JPG

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

Kaplan_Lee_M_BOSTON_web.jpg

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

[embed:render:related:node:254624]

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

[embed:render:related:node:255005]

Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

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Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

All U.S. patients with diabetes should undergo annual biomarker testing to allow for early diagnosis of progressive but presymptomatic heart failure, and treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class should expand among such patients to include everyone with stage B heart failure (“pre–heart failure”) or more advanced stages.

That’s a recommendation from an American Diabetes Association consensus report published June 1 in Diabetes Care.

The report notes that until now, “implementation of available strategies to detect asymptomatic heart failure [in patients with diabetes] has been suboptimal.” The remedy for this is that, “among individuals with diabetes, measurement of a natriuretic peptide or high-sensitivity cardiac troponin is recommended on at least a yearly basis to identify the earliest heart failure stages and to implement strategies to prevent transition to symptomatic heart failure.”

Written by a 10-member panel, chaired by Rodica Pop-Busui, MD, PhD, and endorsed by the American College of Cardiology, the document also set threshold for levels of these biomarkers that are diagnostic for a more advanced stage (stage B) of heart failure in patients with diabetes but without heart failure symptoms:

• A B-type natriuretic peptide (BNP) level of ≥50 pg/mL;
• An N-terminal pro-BNP level of ≥125 pg/mL; or
• Any high sensitivity cardiac troponin value that’s above the usual upper reference limit set at >99th percentile.

‘Inexpensive’ biomarker testing

“Addition of relatively inexpensive biomarker testing as part of the standard of care may help to refine heart failure risk prediction in individuals with diabetes,” the report says.

“Substantial data indicate the ability of these biomarkers to identify those in stage A or B [heart failure] at highest risk of progressing to symptomatic heart failure or death,” and this identification is useful because “the risk in such individuals may be lowered through targeted intervention or multidisciplinary care.”

It is “impossible to understate the importance of early recognition of heart failure” in patients with heart failure, the authors declare. However, the report also cautions that, “using biomarkers to identify and in turn reduce risk for heart failure should always be done within the context of a thoughtful clinical evaluation, supported by all information available.”

The report, written during March 2021 – March 2022, cites the high prevalence and increasing incidence of heart failure in patients with diabetes as the rationale for the new recommendations.

For a person with diabetes who receives a heart failure diagnosis, the report details several management steps, starting with an evaluation for obstructive coronary artery disease, given the strong link between diabetes and atherosclerotic cardiovascular disease.

It highlights the importance of interventions that involve nutrition, smoking avoidance, minimized alcohol intake, exercise, weight loss, and relevant social determinants of health, but focuses in greater detail on a range of pharmacologic interventions. These include treatment of hypertension for people with early-stage heart failure with an ACE inhibitor or an angiotensin receptor blocker, a thiazide-type diuretic, and a mineralocorticoid receptor antagonist, such as spironolactone or the newer, nonsteroidal agent finerenone for patients with diabetic kidney disease.

Dr. Busui of the division of metabolism, endocrinology, and diabetes at the University of Michigan, Ann Arbor, and colleagues cite recent recommendations for using guidelines-directed medical therapy to treat patients with more advanced, symptomatic stages of heart failure, including heart failure with reduced or with preserved ejection fraction.

‘Prioritize’ the SGLT2-inhibitor class

The consensus report also summarizes the roles for agents in the various classes of antidiabetes drugs now available, with particular emphasis on the role for the SGLT2-inhibitor class.

SGLT2 inhibitors “are recommended for all individuals with [diabetes and] heart failure,” it says. “This consensus recommends prioritizing the use of SGLT2 inhibitors in individuals with stage B heart failure, and that SGLT2 inhibitors be an expected element of care in all individuals with diabetes and symptomatic heart failure.”

[embed:render:related:node:255005]

Other agents for glycemic control that receive endorsement from the report are those in the glucagonlike peptide 1 receptor agonist class. “Despite the lack of conclusive evidence of direct heart failure risk reduction” with this class, it gets a “should be considered” designation, based on its positive effects on weight loss, blood pressure, and atherothrombotic disease.

Similar acknowledgment of potential benefit in a “should be considered” role goes to metformin. But the report turned a thumb down for both the class of dipeptidyl peptidase 4 inhibitors and the thiazolidinedione class, and said that agents from the insulin and sulfonylurea classes should be used “judiciously.”

The report did not identify any commercial funding. Several of the writing committee members listed personal commercial disclosures.

Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.

This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.

According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.

Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.

A version of this article first appeared on Medscape.com.

Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.

This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.

According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.

Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.

A version of this article first appeared on Medscape.com.

Tirzepatide (Mounjaro) – the new twincretin approved by the Food and Drug Administration for glycemic control in patients with type 2 diabetes – was priced by Lilly, the company that will market the drug, at a list price of $974.33 for four weekly doses regardless of dose size, a cost that adds up to about $12,666 per year, according to a statement made on May 20 by a Lilly spokesperson.

This price puts tirzepatide, which combines the activity of two of the primary human incretins in one molecule, roughly in the same ballpark as what might be its main competitor, semaglutide (Ozempic) for type 2 diabetes, which retails at many U.S. pharmacies for about $925 for four weekly doses, or about $12,025 per year, although Ozempic’s posted retail price is about $100 higher for four doses.

According to the Lilly spokesperson, discount programs could reduce the monthly out-of-pocket cost for patients to as little as $25.

Tirzepatide, which received approval from the FDA on May 13, is a dual glucagonlike peptide–1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide agonist. Several GLP-1 receptor agonists are already approved in the United States, including semaglutide, which is indicated as Wegovy for weight loss in patients with obesity regardless of diabetes status.

A version of this article first appeared on Medscape.com.