Pharmacology

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has approved the gene therapy fidanacogene elaparvovec (Beqvez) for adults with hemophilia B, a rare bleeding disorder that affects almost 4 in 100,000 US men.

Patients are eligible for a one-time infusion of Pfizer’s gene therapy if they are currently using clotting factor IX prophylaxis therapy; have current or historical life-threatening hemorrhages; or have repeated, serious spontaneous bleeding episodes. 

Beqvez is the second gene therapy the agency has approved for hemophilia B, a deficiency in clotting factor IX because of a faulty gene that occurs mostly in males. The FDA approved the first gene therapy, etranacogene dezaparvovec (Hemgenix), in November 2022. 

Both therapies deliver a functional copy of the factor IX gene to liver cells via a viral vector. 

Pfizer said the list price of Beqvez will be $3.5 million — the same price as Hemgenix. The argument for this hefty price tag is that these gene therapies offer the possibility of a cure whereas ongoing factor IX infusions can cost more than $20 million over a patient’s lifetime. Uptake of Hemgenix, however, has been slow, given the cost and concerns about the therapy’s durability and safety.

Beqvez was approved on the basis of the phase 3 BENEGENE-2 trial in 45 men with moderate to severe hemophilia B. These men had been on factor IX prophylaxis for at least 6 months and had tested negative for antibodies against the viral delivery vector. 

The annualized bleeding rate fell from a mean of 4.5 events during the pretreatment period of at least 6 months to a mean of 2.5 events between week 12 and data cutoff (median, 1.8 years of follow-up), according to Pfizer’s press release. Overall, bleeding events were eliminated in 60% of patients who received the one-time infusion vs 29% of patients on factor IX prophylaxis therapy.

Overall, Pfizer reported that the gene therapy was “generally well-tolerated,” with an increase in transaminases reported as the most common adverse event. No deaths, serious infusion reactions, thrombotic events, or development of factor IX antibodies occurred. 

Pfizer has said it will continue to monitor patients to assess the therapy’s long-term durability and safety over a 15-year period.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

VIENNA — The glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide (Wegovy) not only induced weight loss but also improved knee pain in people with knee osteoarthritis (OA) and obesity, according to results from the STEP 9 study reported at the Osteoarthritis Research Society International (OARSI) 2024  World Congress.

From baseline to week 68, the mean change in knee pain assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was a reduction of 41.7 points for semaglutide and a decrease of 27.5 points for a matching placebo. The estimated treatment difference of 14.1 points between the groups was statistically significant (P < .001).

As for weight loss, this also fell by a significantly greater amount in the people treated with semaglutide vs those given placebo, with respective reductions of 13.7% and 3.2% from baseline, with an estimated 10.5% greater weight loss with semaglutide.

167824_Bliddal_Henning_web.jpg

“The interesting thing is whether there’s a specific action of GLP-1 receptor agonists on the joint, not through the weight loss but by itself,” principal study investigator Henning Bliddal, MD, DMSc, told this news organization ahead of reporting the results at OARSI 2024.

Weight loss is “obviously good” because “the knees suffer from the weight. But whether it’s good for the knee or just for the health or the well-being of the person is another matter,” said Dr. Bliddal, who is director of the Parker Institute at Bispebjerg Frederiksberg Hospital in Copenhagen, Denmark.
 

Not Approved in OA

Semaglutide and other potentially weight loss-inducing drugs are not currently indicated for use specifically in OA, Tonia Vincent, MBBS, PhD, told this news organization, and so “I think we have to be very cautious,” she said.

“Weight loss is one of the few things that has been shown to be successful in clinical trials,” said Dr. Vincent, who is a professor of musculoskeletal biology and an honorary rheumatologist at the Kennedy Institute of Rheumatology at Oxford University in Oxford, England.

“People always feel better too when they lose weight, so that helps manage pain. So, I’d be very surprised if there isn’t a benefit,” she added.

“I just think we need to know more about the long-term use of these drugs, whether the healthcare system can afford them, and how we would ration them.”
 

Previous Work

The STEP 9 study is not the first time that Dr. Bliddal has investigated the effects of a GLP-1 receptor agonist in people with knee OA, but it is the first to have shown a significant effect on knee pain.

Previously, results from the LOSEIT trial with liraglutide demonstrated that, after an 8-week dietary intervention run-in phase, people who were treated with the GLP-1 receptor agonist lost an average of 2.8 kg in body weight over a period of 1 year, vs a 1.2 kg gain in the placebo group. Knee injury and Osteoarthritis Outcome Scores, however, were largely unaffected.

“The study was more or less negative for knee pain because at that time we had to pretreat patients with some kind of weight loss before they were allowed to have the liraglutide,” Dr. Bliddal said.

“There’s so many different considerations with diets and the different ways that [dietary modification] is performed, that could be part of the explanation why some people didn’t find the pain relief,” Dr. Bliddal suggested.
 

STEP 9 Study Design

No pre-study dietary intervention was required in the STEP 9 trial, although a reduced-calorie diet and increased physical exercise were used alongside both semaglutide and placebo treatment.

STEP 9 was a multicenter, multinational phase 3 clinical trial that enrolled people if they had a body mass index (BMI) of > 30, had a clinical diagnosis of knee OA with moderate radiographic changes (Kellgren-Lawrence grade of 2-3), and were experiencing knee pain.

In addition to a baseline WOMAC pain score of at least 40 points (where 0 represents no and 100 the worst pain), the participants had to have a WOMAC numerical rating scale (NRS) score of ≥ 3.1.

A total of 407 participants were recruited and randomly allocated, 2:1, to receive once-weekly subcutaneous injections of either semaglutide 2.4 mg or placebo for a total of 68 weeks.

Dr. Bliddal presented demographic information only for the study population as a whole, showing that the mean was 56 years, 81.6% were women, 60.9% were White, 11.8% Native American, 7.6% Black, and 19.7% of other ethnic origin.

Moreover, the mean bodyweight at baseline was 108.6 kg, and the mean baseline BMI was 40.3, with 75% of participants having a BMI ≥ 35. The mean waist circumference was 118.7 cm. The mean baseline WOMAC pain score was 70.9.
 

Other Findings

In addition to the reductions seen in the coprimary endpoints of weight loss and knee pain, the WOMAC physical function score was also reduced from baseline to week 68 to a greater degree in the semaglutide than placebo arm, by a respective 41.5 vs 26.7 points, with a significant estimated treatment difference of -14.9 points.

“The use of pain medication went down as well; you can see the drop was faster in the semaglutide group than the placebo group, and it was maintained throughout the study,” Dr. Bliddal said during his presentation. He noted that patients had to temporarily stop taking pain relievers such as acetaminophen 3 days before their pain was assessed.

Additional findings reported in the abstract, but not presented at the meeting, were a significant estimated treatment difference of -1.0 in NRS pain intensity, more people treated with semaglutide than placebo achieving ≥ 5% (87.0% vs 29.2%) or ≥ 10% (70.4% vs 9.2%) weight loss.

“Safety and tolerability with semaglutide were consistent with the global STEP program and the GLP-1 receptor agonist class in general,” Dr. Bliddal reported.

Serious adverse events occurred in a respective 10.0% and 8.1% of participants, and adverse events leading to discontinuation were recorded in 6.7% and 3%. Around one third (2.2%) of those leading to discontinuation in the semaglutide arm were gastrointestinal adverse events.

The STEP 9 study was funded by Novo Nordisk. Henning is a principal investigator for the trial and acknowledged that research grants were received from Novo Nordisk to his institution, as well as consulting fees and honoraria. He has also received congress and travel support from Contura. Dr. Vincent was not involved in the study and had no relevant conflicts of interest to disclose.

A version of this article appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

PARIS — Irritable bowel syndrome (IBS) is a common brain-gut axis disorder, and patients are often dissatisfied with conventional treatments.

The role of the microbiota in IBS is now well established, and patients frequently take probiotics on their own initiative or on the advice of a physician or pharmacist. However, not all probiotics have equal efficacy, so which ones should be recommended?

Jean-Marc Sabaté, MD, PhD, a gastroenterologist at Avicenne Hospital in Bobigny, France, shared insights about probiotics at the Francophone Days of Hepatology, Gastroenterology, and Digestive Oncology.

IBS, according to the Rome IV symptom-based classification, is a “disorder of brain-gut axis interactions” with a prevalence of about 4% in the adult population. In France, during an average care pathway of about 8 years, patients try an average of five therapeutic strategies (and as many as 11), including antispasmodics (85%), diets (78%), and probiotics. In addition, 66.4% of patients had either taken or were taking probiotics at the time of a recent survey.

While the 2022 recommendations from the American College of Gastroenterology on the diagnosis and management of IBS do not support the use of probiotics for overall symptom relief — a recommendation for which they cite a low level of evidence — “there is nevertheless a rationale for prescribing probiotics in IBS due to the significant role of the microbiota (or dysbiosis) in this condition,” said Dr. Sabaté.
 

Microbiota in IBS 

Evidence indicating that antibiotics exacerbate IBS symptoms and revealing chronic bacterial overgrowth in the small intestine of patients with IBS supports the role of the microbiota. Studies using a molecular approach (16s rRNA) have settled the debate, confirming differences in the intestinal flora between patients with IBS and healthy subjects. Data also indicate differences in flora between patient subtypes, such as an increased Firmicutes to Bacteroidetes ratio. However, one subgroup, which can represent as much as a third of patients, seems to harbor a “normal” microbiota. 

Nonetheless, the microbiota plays a significant role in IBS. A Swedish study highlighted the influence of bacterial enterotypes on transit type associated with IBS and symptom severity, independent of diet composition or medication use. 

This dysbiosis could play a significant role as it interacts with other mechanisms involved in IBS, including changes in intestinal motility related to diet (related to fermentable carbohydrates, for example). Moreover, the microbiota seems to induce a low level of immune activation in patients with IBS, leading to microinflammation and increased intestinal permeability, especially after an infection.

Furthermore, alterations in the regulation of bile acid deconjugation by the microbiota partly explain the frequency and consistency of stools in diarrhea-predominant IBS patients.

In addition, colonic gas production is higher in these patients. Those complaining of flatulence have poor tolerance to intestinal gases after a flatulent meal, associated with microbiota instability.

Data regarding the interaction between the microbiota and central mechanisms mainly come from animal studies. In rodents, microbiota constituents seem to affect brain development, function, and morphology. Emotional and physical traumas during childhood appear to be risk factors. Moreover, even brief exposure to broad-spectrum antibiotics in neonates could cause subsequent visceral hypersensitivity.

Lastly, the role of the microbiota in changes in medullary pain control after visceral stimulation (eg, rectal distension) has still not been demonstrated in humans.
 

Recent Guideline 

In its February 2023 Global Guideline “Probiotics and Prebiotics” for IBS, the World Gastroenterology Organization looked at the level of evidence for probiotics.

Three strains, as well as a combination of several strains, were supported by level 2 evidence, meaning at least two randomized studies with converging results. These are Bifidobacterium bifidum MIMBb75, which improves overall symptoms and quality of life; Lactobacillus plantarum 299v (DSM 9843), which acts on the severity of abdominal pain and bloating; and B infantis 35624 (new name: B longum 35624), which improves the overall assessment of IBS symptoms, as does the multistrain product containing L rhamnosus GG, L rhamnosus LC705, Propionibacterium freudenreichii ssp shermanii JS DSM 7067, and B animalis ssp lactis B012 DSM 15954.
 

Efficacy and Availability 

Probiotics belonging to the category of dietary supplements or medical devices are not required to provide evidence for a mechanism of action or even efficacy to be marketed. Thus, for most probiotics sold, there are no human or even animal studies available.

Dr. Sabaté proposed a choice of probiotics based on the literature and the presence of at least one randomized placebo-controlled trial conducted in patients with IBS showing positive results.

“Probiotic efficacy largely depends on the bacterial species, strain, and clinical situation treated. Only probiotics with demonstrated clinical efficacy in randomized placebo-controlled trials should be recommended,” he emphasized. The parameters that can be improved include symptom severity, quality of life, abdominal pain, and bloating.
 

Effective Probiotics 

B longum 35624, which was developed with researchers from University College Cork in Ireland, is probably the most studied in animals and humans. Research has encompassed the mechanistic, clinical, and safety aspects of the probiotic. It has shown good results on the IBS-Symptom Severity Score (SSS), quality of life, abdominal pain, bowel disturbances, and bloating. The treatment duration in studies is 4-8 weeks.

L plantarum 299v (DSM 9843) affects the frequency of abdominal pain and pain score. The treatment duration in studies is 4 weeks.

The multistrain product that includes L plantarum CECT 7484/L plantarum CECT 7485/ Pediococcus acidilactici CECT 7483 allows for an improvement in quality of life and anxiety related to digestive symptoms. No positive effect has been described on digestive symptoms, especially diarrhea. The treatment duration is 6 weeks.

B bifidum MIMBb75 (both normal and heat-inactivated forms) is beneficial for pain, the composite IBS-SSS score, and quality of life. The treatment duration is 4-8 weeks.

“Except for the multistrain combination, which is more suited to patients with diarrhea-predominant IBS, the other three probiotics can be prescribed regardless of the IBS subtype,” said Dr. Sabaté. “Treatment durations are typically 4 weeks, but it is possible to continue up to 8 weeks, which is the maximum duration of these studies. In practice, there are no tolerance issues with probiotics prescribed for IBS based on the literature. These should be tested under the conditions and for the duration of the published studies and should only be continued if there is individual benefit on symptoms or quality of life.”

Note that microbiota analyses conducted for individual purposes are of no help in choosing probiotics.
 

Mechanisms of Action 

In a murine model, but not in humans, some strains, especially L acidophilus NCFM, have shown an antinociceptive effect by inducing opioid and cannabinoid receptors.

Only in animals to date, L farciminis and B lactis CNCM I-2494 have shown prevention of induced hypersensitivity (ie, inhibition of the cytoskeleton contraction of colon epithelial cells and subsequent opening of tight junctions).

B infantis 35624 has an anti-inflammatory action by modifying the IL-10 and IL-12 cytokine ratio in animals and humans. It has an immunomodulatory action by increasing dendritic cells in the mucosa and decreasing Th1 and Th7 helper T cells.

B infantis 35624 and L farciminis are two strains that decrease visceral sensitivity in mice.

Escherichia coli Nissle 1917 acts on lipopeptide production with an antinociceptive effect, as observed in mice, by decreasing visceral sensitivity through calcium nociceptor flux blockade (action on GABA type B receptor).

Acting on dysbiosis by modifying fecal microbiota during probiotic intake is possible but depends on the probiotics, like B infantis 35624. In humans, B longum NCC 3001 could modify brain activations.

Dr. Sabaté disclosed financial relationships with Mayoly Spindler, Kyowa Kirin, Tillotts, Servier, Norgine, Biocodex, Merck, Viatris, Abivax, and Inventiva.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Results from a preliminary clinical trial demonstrated the obesity drug, tirzepatide, effectively treated obstructive sleep apnea (OSA), according to information sent to investors of the pharmaceutical company, Eli Lilly.

Indiana-based Eli Lilly sells tirzepatide under the brand name Zepbound, which was approved by the FDA in November to treat overweight and obesity. Tirzepatide is also marketed under the name Mounjaro to treat diabetes, and it’s among the same class of drugs as other well-known weight loss and diabetes drugs like Ozempic and Wegovy.

The newly announced results came from a pair of studies that followed people with moderate to severe OSA who also had obesity. People in the study took tirzepatide, which is given by injection, for one year. One study evaluated people who were using CPAP during sleep, and another study included people who didn’t use the device. People in both studies taking tirzepatide had significant reductions in sleep events and also lost about 20% of body weight. About 70% of people in the studies were men.

The findings have not yet been published in a peer-reviewed medical journal, and the preliminary results were announced by Eli Lilly because of reporting requirements related to information that could affect stock prices. The company indicated that detailed results will be presented at a conference of the American Diabetes Association in June and will be submitted to a peer-reviewed journal for consideration of publication. The company also plans to submit the information to the FDA for approval consideration mid-year, the investor news release stated.

People in the study taking tirzepatide on average experienced 63% fewer instances of reduced oxygen due to breathing changes, or events when breathing entirely stopped, Eli Lilly reported.

A sleep expert from Washington University in St. Louis told The New York Times the initial findings were extremely positive and noted that tirzepatide works to treat the underlying cause of sleep apnea, rather than current treatments that just address symptoms.

Tirzepatide “is a great alternative for people who are obese and can’t use CPAP or are on CPAP and want to improve the effect,” Eric Landsness, MD, PhD, told The New York Times. 

Eli Lilly indicated the most commonly reported adverse events in the studies were diarrhea, nausea, vomiting, and constipation.

An estimated 39 million people have OSA and about 33 million people use CPAP machines, according to The National Council on Aging. The condition has been increasingly diagnosed in recent years and becomes more likely to affect people as they get older.

A version of this article appeared on WebMD.com.

Results from a preliminary clinical trial demonstrated the obesity drug, tirzepatide, effectively treated obstructive sleep apnea (OSA), according to information sent to investors of the pharmaceutical company, Eli Lilly.

Indiana-based Eli Lilly sells tirzepatide under the brand name Zepbound, which was approved by the FDA in November to treat overweight and obesity. Tirzepatide is also marketed under the name Mounjaro to treat diabetes, and it’s among the same class of drugs as other well-known weight loss and diabetes drugs like Ozempic and Wegovy.

The newly announced results came from a pair of studies that followed people with moderate to severe OSA who also had obesity. People in the study took tirzepatide, which is given by injection, for one year. One study evaluated people who were using CPAP during sleep, and another study included people who didn’t use the device. People in both studies taking tirzepatide had significant reductions in sleep events and also lost about 20% of body weight. About 70% of people in the studies were men.

The findings have not yet been published in a peer-reviewed medical journal, and the preliminary results were announced by Eli Lilly because of reporting requirements related to information that could affect stock prices. The company indicated that detailed results will be presented at a conference of the American Diabetes Association in June and will be submitted to a peer-reviewed journal for consideration of publication. The company also plans to submit the information to the FDA for approval consideration mid-year, the investor news release stated.

People in the study taking tirzepatide on average experienced 63% fewer instances of reduced oxygen due to breathing changes, or events when breathing entirely stopped, Eli Lilly reported.

A sleep expert from Washington University in St. Louis told The New York Times the initial findings were extremely positive and noted that tirzepatide works to treat the underlying cause of sleep apnea, rather than current treatments that just address symptoms.

Tirzepatide “is a great alternative for people who are obese and can’t use CPAP or are on CPAP and want to improve the effect,” Eric Landsness, MD, PhD, told The New York Times. 

Eli Lilly indicated the most commonly reported adverse events in the studies were diarrhea, nausea, vomiting, and constipation.

An estimated 39 million people have OSA and about 33 million people use CPAP machines, according to The National Council on Aging. The condition has been increasingly diagnosed in recent years and becomes more likely to affect people as they get older.

A version of this article appeared on WebMD.com.

Results from a preliminary clinical trial demonstrated the obesity drug, tirzepatide, effectively treated obstructive sleep apnea (OSA), according to information sent to investors of the pharmaceutical company, Eli Lilly.

Indiana-based Eli Lilly sells tirzepatide under the brand name Zepbound, which was approved by the FDA in November to treat overweight and obesity. Tirzepatide is also marketed under the name Mounjaro to treat diabetes, and it’s among the same class of drugs as other well-known weight loss and diabetes drugs like Ozempic and Wegovy.

The newly announced results came from a pair of studies that followed people with moderate to severe OSA who also had obesity. People in the study took tirzepatide, which is given by injection, for one year. One study evaluated people who were using CPAP during sleep, and another study included people who didn’t use the device. People in both studies taking tirzepatide had significant reductions in sleep events and also lost about 20% of body weight. About 70% of people in the studies were men.

The findings have not yet been published in a peer-reviewed medical journal, and the preliminary results were announced by Eli Lilly because of reporting requirements related to information that could affect stock prices. The company indicated that detailed results will be presented at a conference of the American Diabetes Association in June and will be submitted to a peer-reviewed journal for consideration of publication. The company also plans to submit the information to the FDA for approval consideration mid-year, the investor news release stated.

People in the study taking tirzepatide on average experienced 63% fewer instances of reduced oxygen due to breathing changes, or events when breathing entirely stopped, Eli Lilly reported.

A sleep expert from Washington University in St. Louis told The New York Times the initial findings were extremely positive and noted that tirzepatide works to treat the underlying cause of sleep apnea, rather than current treatments that just address symptoms.

Tirzepatide “is a great alternative for people who are obese and can’t use CPAP or are on CPAP and want to improve the effect,” Eric Landsness, MD, PhD, told The New York Times. 

Eli Lilly indicated the most commonly reported adverse events in the studies were diarrhea, nausea, vomiting, and constipation.

An estimated 39 million people have OSA and about 33 million people use CPAP machines, according to The National Council on Aging. The condition has been increasingly diagnosed in recent years and becomes more likely to affect people as they get older.

A version of this article appeared on WebMD.com.

Antipsychotic use in older adults with dementia is associated with a significant increased risk for stroke, myocardial infarction, heart failure, pneumonia, fracture, acute kidney injury, and a range of other health problems compared with nonuse, new research showed.

The adverse events are far broader and pose more severe health risks than previously reported, investigators noted, and suggested greater caution is needed when prescribing antipsychotics to treat psychological symptoms of dementia.

The matched cohort study used patient registry data on nearly 174,000 people with dementia and compared those who were prescribed an antipsychotic on or after their dementia diagnosis with those who had not received a prescription for the drugs.

Any antipsychotic use was associated with double the risk for pneumonia, a 1.7-fold increased risk for acute kidney injury, and 1.6-fold higher odds of venous thromboembolism compared to nonuse.

Investigators found an increased risk for all outcomes studied, except for ventricular arrythmia, and risk was highest for most within the first week of treatment.

“Any potential benefits of antipsychotic treatment therefore need to be weighed against the risk of serious harm across multiple outcomes. Although there may be times when an antipsychotic prescription is the least bad option, clinicians should actively consider the risks, considering patients’ pre-existing comorbidities and living support,” lead investigator Pearl Mok, research fellow at the Centre for Pharmacoepidemiology and Drug Safety, The University of Manchester, Manchester, England, and colleagues wrote.

The findings were published online in The BMJ.
 

High Risk

Depression, aggression, anxiety, psychosis, and other behavioral and psychological symptoms are common in people with dementia. Despite earlier reports of increased risk for stroke and mortality with antipsychotic use, the drugs are frequently prescribed to treat these symptoms.

While some preliminary studies identified other adverse outcomes from antipsychotic use, results are limited and inconsistent.

Investigators used primary and secondary care data from the Clinical Practice Research Datalink in England. A total of 173,910 adults (63% women) had a dementia diagnosis between January 1998 and May 2018.

Of the total cohort, 35,339 patients were prescribed an antipsychotic on, or after, a dementia diagnosis. Each was matched with up to 15 patients with dementia with no history of antipsychotic use following diagnosis.

Almost 80% of antipsychotic prescriptions were for risperidone, quetiapine, haloperidol, and olanzapine.

Any antipsychotic use was associated with significantly higher risks for pneumonia (hazard ratio [HR], 2.03; 95% CI, 1.96-2.10), acute kidney injury (HR, 1.57; 95% CI, 1.48-1.66), stroke (HR, 1.54; 95% CI, 1.46-1.63), venous thromboembolism (HR, 1.52; 95% CI, 1.38-1.67), fracture (HR, 1.36; 95% CI, 1.30-1.44), myocardial infarction (HR, 1.22; 95% CI, 1.12-1.34), and heart failure (HR, 1.16; 95% CI, 1.09-1.24).

The risk for all conditions was highest within the first 3 months of treatment, with a cumulative incidence of pneumonia among antipsychotic users of 4.48% vs 1.49% among nonusers. At 1 year, this increased to 10.41% for users vs 5.63% for nonusers.

“Given the higher risks of adverse events in the early days after drug initiation, clinical examinations should be taken before, and clinical reviews conducted shortly after, the start of treatment,” the authors wrote. “Our study reaffirms that these drugs should only be prescribed for the shortest period possible.”
 

‘Serious Harms’

In an accompanying editorial, Raya Elfadel Kheirbek, MD, and Cristina LaFont, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, said the findings “highlight the need for careful justification of antipsychotic use in dementia care, including a comprehensive assessment of the benefits weighed against a broader range of serious harms than previously acknowledged.”

“Using antipsychotics for the management of dementia-related behaviors requires nuanced decision-making after careful assessment, informed by a personalized approach,” they continued. “Dr. Mok and colleagues call for a critical re-evaluation of antipsychotic use in this clinical setting.”

While the findings add to and expand what was already known, “we need to be clear that they don’t show antipsychotics cause all the adverse outcomes reported,” Masud Husain, DPhil, professor of neurology, University of Oxford, England, said in a statement.

While investigators attempted to use matched controls with dementia who had not received antipsychotics, “the people who were prescribed the drugs may simply have been more vulnerable to some of the conditions that occurred more frequently in them, such as pneumonia and cardiovascular disorders,” said Dr. Husain, who was not part of the research.

Although the study was not designed to explore reverse causality, the findings are important for clinicians who prescribe antipsychotics for patients with dementia, Robert Howard, professor of old age psychiatry, at the University of College London, London, England said in a statement.

“Initiation of these drugs in people with dementia should only ever be under specialist supervision, with involvement of patients and family members in informed discussion and review,” said Dr. Howard, who was not involved in the study.

The study was funded by the National Institute for Health and Care Research. Dr. Mok reported no relevant conflicts. Other authors’ disclosures are included in the original article. Dr. Hussain, Dr. Howard, Dr. Kheirbek, and Dr. LeFon reported no relevant conflicts.

A version of this article appeared on Medscape.com.

Antipsychotic use in older adults with dementia is associated with a significant increased risk for stroke, myocardial infarction, heart failure, pneumonia, fracture, acute kidney injury, and a range of other health problems compared with nonuse, new research showed.

The adverse events are far broader and pose more severe health risks than previously reported, investigators noted, and suggested greater caution is needed when prescribing antipsychotics to treat psychological symptoms of dementia.

The matched cohort study used patient registry data on nearly 174,000 people with dementia and compared those who were prescribed an antipsychotic on or after their dementia diagnosis with those who had not received a prescription for the drugs.

Any antipsychotic use was associated with double the risk for pneumonia, a 1.7-fold increased risk for acute kidney injury, and 1.6-fold higher odds of venous thromboembolism compared to nonuse.

Investigators found an increased risk for all outcomes studied, except for ventricular arrythmia, and risk was highest for most within the first week of treatment.

“Any potential benefits of antipsychotic treatment therefore need to be weighed against the risk of serious harm across multiple outcomes. Although there may be times when an antipsychotic prescription is the least bad option, clinicians should actively consider the risks, considering patients’ pre-existing comorbidities and living support,” lead investigator Pearl Mok, research fellow at the Centre for Pharmacoepidemiology and Drug Safety, The University of Manchester, Manchester, England, and colleagues wrote.

The findings were published online in The BMJ.
 

High Risk

Depression, aggression, anxiety, psychosis, and other behavioral and psychological symptoms are common in people with dementia. Despite earlier reports of increased risk for stroke and mortality with antipsychotic use, the drugs are frequently prescribed to treat these symptoms.

While some preliminary studies identified other adverse outcomes from antipsychotic use, results are limited and inconsistent.

Investigators used primary and secondary care data from the Clinical Practice Research Datalink in England. A total of 173,910 adults (63% women) had a dementia diagnosis between January 1998 and May 2018.

Of the total cohort, 35,339 patients were prescribed an antipsychotic on, or after, a dementia diagnosis. Each was matched with up to 15 patients with dementia with no history of antipsychotic use following diagnosis.

Almost 80% of antipsychotic prescriptions were for risperidone, quetiapine, haloperidol, and olanzapine.

Any antipsychotic use was associated with significantly higher risks for pneumonia (hazard ratio [HR], 2.03; 95% CI, 1.96-2.10), acute kidney injury (HR, 1.57; 95% CI, 1.48-1.66), stroke (HR, 1.54; 95% CI, 1.46-1.63), venous thromboembolism (HR, 1.52; 95% CI, 1.38-1.67), fracture (HR, 1.36; 95% CI, 1.30-1.44), myocardial infarction (HR, 1.22; 95% CI, 1.12-1.34), and heart failure (HR, 1.16; 95% CI, 1.09-1.24).

The risk for all conditions was highest within the first 3 months of treatment, with a cumulative incidence of pneumonia among antipsychotic users of 4.48% vs 1.49% among nonusers. At 1 year, this increased to 10.41% for users vs 5.63% for nonusers.

“Given the higher risks of adverse events in the early days after drug initiation, clinical examinations should be taken before, and clinical reviews conducted shortly after, the start of treatment,” the authors wrote. “Our study reaffirms that these drugs should only be prescribed for the shortest period possible.”
 

‘Serious Harms’

In an accompanying editorial, Raya Elfadel Kheirbek, MD, and Cristina LaFont, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, said the findings “highlight the need for careful justification of antipsychotic use in dementia care, including a comprehensive assessment of the benefits weighed against a broader range of serious harms than previously acknowledged.”

“Using antipsychotics for the management of dementia-related behaviors requires nuanced decision-making after careful assessment, informed by a personalized approach,” they continued. “Dr. Mok and colleagues call for a critical re-evaluation of antipsychotic use in this clinical setting.”

While the findings add to and expand what was already known, “we need to be clear that they don’t show antipsychotics cause all the adverse outcomes reported,” Masud Husain, DPhil, professor of neurology, University of Oxford, England, said in a statement.

While investigators attempted to use matched controls with dementia who had not received antipsychotics, “the people who were prescribed the drugs may simply have been more vulnerable to some of the conditions that occurred more frequently in them, such as pneumonia and cardiovascular disorders,” said Dr. Husain, who was not part of the research.

Although the study was not designed to explore reverse causality, the findings are important for clinicians who prescribe antipsychotics for patients with dementia, Robert Howard, professor of old age psychiatry, at the University of College London, London, England said in a statement.

“Initiation of these drugs in people with dementia should only ever be under specialist supervision, with involvement of patients and family members in informed discussion and review,” said Dr. Howard, who was not involved in the study.

The study was funded by the National Institute for Health and Care Research. Dr. Mok reported no relevant conflicts. Other authors’ disclosures are included in the original article. Dr. Hussain, Dr. Howard, Dr. Kheirbek, and Dr. LeFon reported no relevant conflicts.

A version of this article appeared on Medscape.com.

Antipsychotic use in older adults with dementia is associated with a significant increased risk for stroke, myocardial infarction, heart failure, pneumonia, fracture, acute kidney injury, and a range of other health problems compared with nonuse, new research showed.

The adverse events are far broader and pose more severe health risks than previously reported, investigators noted, and suggested greater caution is needed when prescribing antipsychotics to treat psychological symptoms of dementia.

The matched cohort study used patient registry data on nearly 174,000 people with dementia and compared those who were prescribed an antipsychotic on or after their dementia diagnosis with those who had not received a prescription for the drugs.

Any antipsychotic use was associated with double the risk for pneumonia, a 1.7-fold increased risk for acute kidney injury, and 1.6-fold higher odds of venous thromboembolism compared to nonuse.

Investigators found an increased risk for all outcomes studied, except for ventricular arrythmia, and risk was highest for most within the first week of treatment.

“Any potential benefits of antipsychotic treatment therefore need to be weighed against the risk of serious harm across multiple outcomes. Although there may be times when an antipsychotic prescription is the least bad option, clinicians should actively consider the risks, considering patients’ pre-existing comorbidities and living support,” lead investigator Pearl Mok, research fellow at the Centre for Pharmacoepidemiology and Drug Safety, The University of Manchester, Manchester, England, and colleagues wrote.

The findings were published online in The BMJ.
 

High Risk

Depression, aggression, anxiety, psychosis, and other behavioral and psychological symptoms are common in people with dementia. Despite earlier reports of increased risk for stroke and mortality with antipsychotic use, the drugs are frequently prescribed to treat these symptoms.

While some preliminary studies identified other adverse outcomes from antipsychotic use, results are limited and inconsistent.

Investigators used primary and secondary care data from the Clinical Practice Research Datalink in England. A total of 173,910 adults (63% women) had a dementia diagnosis between January 1998 and May 2018.

Of the total cohort, 35,339 patients were prescribed an antipsychotic on, or after, a dementia diagnosis. Each was matched with up to 15 patients with dementia with no history of antipsychotic use following diagnosis.

Almost 80% of antipsychotic prescriptions were for risperidone, quetiapine, haloperidol, and olanzapine.

Any antipsychotic use was associated with significantly higher risks for pneumonia (hazard ratio [HR], 2.03; 95% CI, 1.96-2.10), acute kidney injury (HR, 1.57; 95% CI, 1.48-1.66), stroke (HR, 1.54; 95% CI, 1.46-1.63), venous thromboembolism (HR, 1.52; 95% CI, 1.38-1.67), fracture (HR, 1.36; 95% CI, 1.30-1.44), myocardial infarction (HR, 1.22; 95% CI, 1.12-1.34), and heart failure (HR, 1.16; 95% CI, 1.09-1.24).

The risk for all conditions was highest within the first 3 months of treatment, with a cumulative incidence of pneumonia among antipsychotic users of 4.48% vs 1.49% among nonusers. At 1 year, this increased to 10.41% for users vs 5.63% for nonusers.

“Given the higher risks of adverse events in the early days after drug initiation, clinical examinations should be taken before, and clinical reviews conducted shortly after, the start of treatment,” the authors wrote. “Our study reaffirms that these drugs should only be prescribed for the shortest period possible.”
 

‘Serious Harms’

In an accompanying editorial, Raya Elfadel Kheirbek, MD, and Cristina LaFont, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, said the findings “highlight the need for careful justification of antipsychotic use in dementia care, including a comprehensive assessment of the benefits weighed against a broader range of serious harms than previously acknowledged.”

“Using antipsychotics for the management of dementia-related behaviors requires nuanced decision-making after careful assessment, informed by a personalized approach,” they continued. “Dr. Mok and colleagues call for a critical re-evaluation of antipsychotic use in this clinical setting.”

While the findings add to and expand what was already known, “we need to be clear that they don’t show antipsychotics cause all the adverse outcomes reported,” Masud Husain, DPhil, professor of neurology, University of Oxford, England, said in a statement.

While investigators attempted to use matched controls with dementia who had not received antipsychotics, “the people who were prescribed the drugs may simply have been more vulnerable to some of the conditions that occurred more frequently in them, such as pneumonia and cardiovascular disorders,” said Dr. Husain, who was not part of the research.

Although the study was not designed to explore reverse causality, the findings are important for clinicians who prescribe antipsychotics for patients with dementia, Robert Howard, professor of old age psychiatry, at the University of College London, London, England said in a statement.

“Initiation of these drugs in people with dementia should only ever be under specialist supervision, with involvement of patients and family members in informed discussion and review,” said Dr. Howard, who was not involved in the study.

The study was funded by the National Institute for Health and Care Research. Dr. Mok reported no relevant conflicts. Other authors’ disclosures are included in the original article. Dr. Hussain, Dr. Howard, Dr. Kheirbek, and Dr. LeFon reported no relevant conflicts.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

An analysis of molecular-targeted cancer drug therapies recently approved in the United States found that fewer than one-third demonstrated substantial clinical benefits at the time of approval.

METHODOLOGY:

• The strength and quality of evidence supporting genome-targeted cancer drug approvals vary. A big reason is the growing number of cancer drug approvals based on surrogate endpoints, such as disease-free and progression-free survival, instead of clinical endpoints, such as overall survival or quality of life. The US Food and Drug Administration (FDA) has also approved genome-targeted cancer drugs based on phase 1 or single-arm trials.
• Given these less rigorous considerations for approval, “the validity and value of the targets and surrogate measures underlying FDA genome-targeted cancer drug approvals are uncertain,” the researchers explained.
• In the current analysis, researchers assessed the validity of the molecular targets as well as the clinical benefits of genome-targeted cancer drugs approved in the United States from 2015 to 2022 based on results from pivotal trials.
• The researchers evaluated the strength of evidence supporting molecular targetability using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) and the clinical benefit using the ESMO–Magnitude of Clinical Benefit Scale (ESMO-MCBS).
• The authors defined a substantial clinical benefit as an A or B grade for curative intent and a 4 or 5 for noncurative intent. High-benefit genomic-based cancer treatments were defined as those associated with a substantial clinical benefit (ESMO-MCBS) and that qualified as ESCAT category level I-A (a clinical benefit based on prospective randomized data) or I-B (prospective nonrandomized data).

TAKEAWAY:

• The analyses focused on 50 molecular-targeted cancer drugs covering 84 indications. Of which, 45 indications (54%) were approved based on phase 1 or 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials and the remaining 39 (46%) by randomized trial, and 48 (57%) were approved based on subgroup analyses.
• Among the 84 indications, more than half (55%) of the pivotal trials supporting approval used overall response rate as a primary endpoint, 31% used progression-free survival, and 6% used disease-free survival. Only seven indications (8%) were supported by pivotal trials demonstrating an improvement in overall survival.
• Among the 84 trials, 24 (29%) met the ESMO-MCBS threshold for substantial clinical benefit.
• Overall, when combining all ratings, only 24 of the 84 indications (29%) were considered high-benefit genomic-based cancer treatments.

IN PRACTICE:

“We applied the ESMO-MCBS and ESCAT value frameworks to identify therapies and molecular targets providing high clinical value that should be widely available to patients” and “found that drug indications supported by these characteristics represent a minority of cancer drug approvals in recent years,” the authors said. Using these value frameworks could help payers, governments, and individual patients “prioritize the availability of high-value molecular-targeted therapies.”

SOURCE:

The study, with first author Ariadna Tibau, MD, PhD, Brigham and Women’s Hospital and Harvard Medical School, Boston, was published online in JAMA Oncology.

LIMITATIONS:

The study evaluated only trials that supported regulatory approval and did not include outcomes of postapproval clinical studies, which could lead to changes in ESMO-MCBS grades and ESCAT levels of evidence over time.

DISCLOSURES:

The study was funded by the Kaiser Permanente Institute for Health Policy, Arnold Ventures, and the Commonwealth Fund. The authors had no relevant disclosures.

A version of this article appeared on Medscape.com.

Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

Statins raise the risks for increased glucose levels and the development of type 2 diabetes among people who don’t have it at baseline, but those risks are outweighed by the cardiovascular benefit, new data suggested.

The findings come from an analysis of individual participant data from a total of 23 randomized trials of statin therapy involving 154,664 individuals. In people without diabetes at baseline, statin therapy produces a dose-dependent increase in the risk for diabetes diagnosis, particularly among those whose glycemia marker levels are already at the diagnostic threshold.

Statins also tend to raise glucose levels in people who already have diabetes, but “the diabetes-related risks arising from the small changes in glycemia resulting from statin therapy are greatly outweighed by the benefits of statins on major vascular events when the direct clinical consequences of these outcomes are taken into consideration,” wrote the authors of the Cholesterol Treatment Trialists’ (CTT) Collaboration in their paper, published online in The Lancet Diabetes & Endocrinology.

Moreover, they say, “since the effect of statin therapy on measures of glycemia within an individual is small, there is likely to be little clinical benefit in measuring glucose concentrations and A1c values routinely after starting statin therapy with the aim of making comparisons to values taken before the initiation of a statin. However, people should continue to be screened for diabetes and associated risk factors and have their glycemic control monitored in accordance with current clinical guidelines.”

The CTT is co-led by Christina Reith, MBChB, PhD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health, University of Oxford, England.

In an accompanying editorial, Hertzel C. Gerstein, MD, and Marie Pigeyre, MD, PhD, both of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, noted that the decreased absolute annual incidence of life-threatening cardiovascular outcomes with statins in people at high risk for type 2 diabetes “clearly exceeds the 0.1%-1.3% per year increased absolute incidence of type 2 diabetes.”

Dr. Gerstein and Dr. Pigeyre also said “these findings emphasize the importance of holistic care. As people at risk for cardiovascular outcomes are also at risk for type 2 diabetes, any prescription of a statin should be accompanied by promoting proven strategies to prevent or delay diabetes, such as modest weight reduction and increased physical activity. Finally, these findings emphasize the importance of always being alert for harmful adverse effects, even with the most beneficial and successful preventive therapies.”
 

Statins Raise Diabetes Risk, Glucose Levels Slightly

The meta-analysis of trials in the CTT Collaboration included individual participant data from 19 double-blind randomized, controlled trials with a median follow-up of 4.3 years comparing statins with placebo in a total of 123,940 participants, including 18% who had known type 2 diabetes at randomization. Also analyzed were another four double-blind trials of lower- vs higher-intensity statins involving a total of 30,724 participants followed for a median of 4.9 years, with 15% having diabetes at baseline.

In the 19 trials of low- or moderate-intensity statins vs placebo, statins resulted in a significant 10% increase in new-onset diabetes compared with placebo (rate ratio, 1.10), while high-intensity statins raised the risk by an also significant 36% (1.36). This translated to a mean absolute excess of 0.12% per year of treatment.

Compared with less intensive statin therapy, more intensive statin therapy resulted in a significant 10% proportional increase in new-onset diabetes (1.10), giving an absolute annual excess of 0.22%.

In the statin vs placebo trials, differences in A1c values from placebo were 0.06 percentage points higher for low- or moderate-intensity statins and 0.08 points greater for high-intensity statins.

Nearly two thirds (62%) of the excess cases of new-onset diabetes occurred among participants in the highest quarter of the baseline glycemia distribution for both low-intensity or moderate-intensity and high-intensity statin therapy.

And among participants who already had diabetes at baseline, there was a significant 10% relative increase in worsening glycemia (defined by adverse glycemic event, A1c increase of ≥ 0.5 percentage points, or medication escalation) with low- or moderate-intensity statins compared with placebo and a 24% relative increase in the high-intensity trials.

The Nuffield Department of Population Health has an explicit policy of not accepting any personal honoraria payments directly or indirectly from the pharmaceutical and food industries. It seeks reimbursement to the University of Oxford for the costs of travel and accommodation to participate in scientific meetings. Dr. Reith reported receiving funding to the University of Oxford from the UK National Institute for Health and Care Research Health Technology Assessment Programme and holding unpaid roles on the Clinical Data Interchange Standards Consortium as a board member and WHO as a scientific advisor. Dr. Preiss reported receiving funding to his research institution (but no personal funding) from Novartis for the ORION 4 trial of inclisiran, Novo Nordisk for the ASCEND PLUS trial of semaglutide, and Boehringer Ingelheim and Eli Lilly for the EMPA-KIDNEY trial and being a committee member for a National Institute for Health and Care Excellence guideline.

Dr. Gerstein holds the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He reported research grants from Eli Lilly, AstraZeneca, Novo Nordisk, Hanmi, and Merck; continuing medical education grants to McMaster University from Eli Lilly, Abbott, Sanofi, Novo Nordisk, and Boehringer Ingelheim; honoraria for speaking from AstraZeneca, Eli Lilly, Novo Nordisk, DKSH, Zuellig Pharma, Sanofi, and Jiangsu Hanson; and consulting fees from Abbott, Eli Lilly, Novo Nordisk, Pfizer, Carbon Brand, Sanofi, Kowa, and Hanmi. Pigeyre had no disclosures.
 

A version of this article appeared on Medscape.com.

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

ATLANTA — A novel antisense therapy called olezarsen reduced triglycerides (TGs) by approximately 50% with either of the two study doses relative to placebo and did so with a low relative risk for adverse events, new data from a phase 2b trial showed.

“The reduction in triglycerides was greater than that currently possible with any available therapy,” reported Brian A. Bergmark, MD, an interventional cardiologist at Brigham and Women’s Hospital, Boston.

The drug also produced meaningful improvements in multiple other lipid subfractions associated with increased cardiovascular (CV) risk, including ApoC-III, very low–density lipoprotein (VLDL) cholesterol, ApoB, and non-LDL cholesterol. High-density lipoprotein (HDL) cholesterol levels were significantly raised.

The results were presented on April 7 as a late breaker at the American College of Cardiology (ACC) Scientific Session 2024 and published online simultaneously in The New England Journal of Medicine.
 

No Major Subgroup Failed to Respond

The effect was seen across all the key subgroups evaluated, including women and patients with diabetes, obesity, and severe as well as moderate elevations in TGs at baseline, Dr. Bergmark reported.

Olezarsen is a N-acetylgalactosamine–conjugated antisense oligonucleotide targeting APOC3 RNA. The results of this randomized trial, called BRIDGE-TIMI 73a, are consistent with other evidence that inhibiting expression of ApoC-III lowers the levels of TGs and other lipid subfractions to a degree that would predict clinical benefit.

In this study, 154 patients at 24 sites in North America were randomized in a 1:1 ratio to 50 or 80 mg olezarsen. Those in each of these cohorts were then randomized in a 3:1 ratio to active therapy or placebo. All therapies were administered by subcutaneous injection once per month.

Patients were eligible for the trial if they had moderate hypertriglyceridemia, defined as a level of 150-499 mg/dL, and elevated CV risk or if they had severe hypertriglyceridemia (≥ 500 mg/dL) with or without other evidence of elevated CV risk. The primary endpoint was a change in TGs at 6 months. Complete follow-up was available in about 97% of patients regardless of treatment assignment.

With a slight numerical advantage for the higher dose, the TG reductions were 49.1% for the 50-mg dose and 53.1% for the 80-mg dose relative to no significant change in the placebo group (P < .001 for both olezarsen doses). The reductions in ApoC-III, an upstream driver of TG production and a CV risk factor, were 64.2% and 73.2% relative to placebo (both P < .001), respectively, Dr. Bergmark reported.

In those with moderate hypertriglyceridemia, normal TG levels, defined as < 150 mg/dL, were reached at 6 months in 85.7% and 93.3% in the 40-mg and 80-mg dose groups, respectively. Relative to these reductions, normalization was seen in only 11.8% of placebo patients (P < .001).
 

TG Lowering Might Not Be Best Endpoint

The primary endpoint in this trial was a change in TGs, but this target was questioned by an invited ACC discussant, Daniel Soffer, MD, who is both an adjunct professor assistant professor of medicine at Penn Medicine, Philadelphia, and current president of the National Lipid Association.

Dr. Soffer noted that highly elevated TGs are a major risk factor for acute pancreatitis, so this predicts a clinical benefit for this purpose, but he thought the other lipid subfractions are far more important for the goal of reducing atherosclerotic cardiovascular disease (ASCVD).

Indeed, he said categorically that it is not TGs that drive ASCVD risk and therefore not what is the real importance of these data. Rather, “it is the non-HDL cholesterol and ApoB lowering” that will drive the likely benefits from this therapy in CV disease.

In addition to the TG reductions, olezarsen did, in fact, produce significant reductions in many of the lipid subfractions associated with increased CV risk. While slightly more favorable in most cases with the higher dose of olezarsen, even the lower dose reduced Apo C-III from baseline by 64.2% (P < .001), VLDL by 46.2% (P < .001), remnant cholesterol by 46.6% (P < .001), ApoB by 18.2% (P < .001), and non-HDL cholesterol by 25.4% (P < .001). HDL cholesterol was increased by 39.6% (P < .001).

These favorable effects on TG and other lipid subfractions were achieved with a safety profile that was reassuring, Dr. Bergmark said. Serious adverse events leading to discontinuation occurred in 0%, 1.7%, and 1.8% of the placebo, lower-dose, and higher-dose arms, respectively. These rates did not differ significantly.
 

Increased Liver Enzymes Is Common

Liver enzymes were significantly elevated (P < .001) for both doses of olezarsen vs placebo, but liver enzymes > 3× the upper limit of normal did not reach significance on either dose of olezarsen relative to placebo. Low platelet counts and reductions in kidney function were observed in a minority of patients but were generally manageable, according to Dr. Bergmark. There was no impact on hemoglobin A1c levels.

Further evaluation of change in hepatic function is planned in the ongoing extension studies.

Characterizing these results as “exciting,” Neha J. Pagidipati, MD, a member of the Duke Clinical Research Institute and an assistant professor at the Duke School of Medicine, Durham, North Carolina, said that identifying a drug effective for hypertriglyceridemia is likely to be a major advance. While elevated TGs are “one of the toughest” lipid abnormalities to manage, “there is not much out there to offer for treatment.”

She, like Dr. Soffer, was encouraged by the favorable effects on multiple lipid abnormalities associated with increased CV risk, but she said the ultimate clinical utility of this or other agents that lower TGs for ASCVD requires a study showing a change in CV events.

Dr. Bergmark reported financial relationships with 15 pharmaceutical companies, including Ionis, which provided funding for the BRIDGE-TIMI 73a trial. Soffer had financial relationships with Akcea, Amgen, Amryt, AstraZeneca, Ionis, Novartis, Regeneron, and Verve. Dr. Pagidipati had financial relationships with more than 10 pharmaceutical companies but was not involved in the design of management of the BRIDGE-TIMI 73a trial.

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

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .

Paxlovid does not significantly alleviate symptoms of COVID-19 compared with placebo among nonhospitalized adults, a new study published April 3 in The New England Journal of Medicine found. 

The results suggest that the drug, a combination of nirmatrelvir and ritonavir, may not be particularly helpful for patients who are not at high risk for severe COVID-19. However, although the rate of hospitalization and death from any cause was low overall, the group that received Paxlovid had a reduced rate compared with people in the placebo group, according to the researchers. 

“Clearly, the benefit observed among unvaccinated high-risk persons does not extend to those at lower risk for severe COVID-19,” Rajesh T. Gandhi, MD, and Martin Hirsch, MD, of Massachusetts General Hospital in Boston, wrote in an editorial accompanying the journal article. “This result supports guidelines that recommend nirmatrelvir–ritonavir only for persons who are at high risk for disease progression.”

The time from onset to relief of COVID-19 symptoms — including cough, shortness of breath, body aches, and chills — did not differ significantly between the two study groups, the researchers reported. The median time to sustained alleviation of symptoms was 12 days for the Paxlovid group compared with 13 days in the placebo group (P = .60).

However, the phase 2/3 trial found a 57.6% relative reduction in the risk for hospitalizations or death among people who took Paxlovid and were vaccinated but were at high risk for poor outcomes, according to Jennifer Hammond, PhD, head of antiviral development for Pfizer, which makes the drug, and the corresponding author on the study.

Paxlovid has “an increasing body of evidence supporting the strong clinical value of the treatment in preventing hospitalization and death among eligible patients across age groups, vaccination status, and predominant variants,” Dr. Hammond said. 

She and her colleagues analyzed data from 1250 adults with symptomatic COVID-19. Participants were fully vaccinated and had a high risk for progression to severe disease or were never vaccinated or had not been in the previous year and had no risk factors for progression to severe disease.

More than half of participants were women, 78.5% were White and 41.4% identified as Hispanic or Latinx. Almost three quarters underwent randomization within 3 days of the start of symptoms, and a little over half had previously received a COVID-19 vaccination. Almost half had one risk factor for severe illness, the most common of these being hypertension (12.3%). 

In a subgroup analysis of high-risk participants, hospitalization or death occurred in 0.9% of patients in the Paxlovid group and 2.2% in the placebo group (95% CI, -3.3 to 0.7). 

The study’s limitations include that the statistical analysis of COVID-19–related hospitalizations or death from any cause was only descriptive, “because the results for the primary efficacy end point were not significant,” the authors wrote. 

Participants who were vaccinated and at high risk were also enrolled regardless of when they had last had a vaccine dose. Furthermore, Paxlovid has a telltale taste, which may have affected the blinding. Finally, the trial was started when the B.1.617.2 (Delta) variant was predominant.

Dr. Gandhi and Dr. Hirsch pointed out that only 5% of participants in the trial were older than 65 years and that other than risk factors such as obesity and smoking, just 2% of people had heart or lung disease. 

“As with many medical interventions, there is likely to be a gradient of benefit for nirmatrelvir–ritonavir, with the patients at highest risk for progression most likely to derive the greatest benefit,” Dr. Gandhi and Dr. Hirsch wrote in the editorial. “Thus, it appears reasonable to recommend nirmatrelvir–ritonavir primarily for the treatment of COVID-19 in older patients (particularly those ≥ 65 years of age), those who are immunocompromised, and those who have conditions that substantially increase the risk of severe COVID-19, regardless of previous vaccination or infection status.”

The study was supported by Pfizer. 

A version of this article appeared on Medscape.com .