Clinician Reviews

Glucagonlike peptide–1 receptor agonists (GLP-1 RAs), used for diabetes or obesity, are associated with a significantly lower quality of bowel preparation and a greater need for repeat colonoscopy, new research suggests.

“We began observing inadequate bowel preparation in our patients undergoing colonoscopy who were on GLP-1 RAs, which raised questions, especially given the association between these medications and delays in intestinal transit,” study investigator Eric. J. Vargas, MD, of the Mayo Clinic, Rochester, Minn., told this news organization. The team decided to investigate.

The “most surprising finding” was the “notably higher rate of inadequate bowel preparation, which necessitates a repeat colonoscopy within 12 months to ensure adequate screening and surveillance for colorectal cancers,” he said. “Specifically, for every 14 patients treated with GLP-1 RAs, one patient would require a repeat colonoscopy due to suboptimal preparation.”

In light of the findings, “clinicians should consider patients on GLP-1 RAs to be a population at risk for poor quality of bowel preparation,” he said.

The study was published online in the American Journal of Gastroenterology.
 

Low prep scores

The investigators analyzed a cohort of patients who underwent screening or surveillance colonoscopy at Mayo Clinic between 2021 and 2022. Patients taking any GLP-1 RA for diabetes or obesity at the time of colonoscopy were defined as “cases,” and those who were prescribed a GLP-1 RA at one point but had not taken it within 3 months of colonoscopy were controls.

The Boston Bowel Preparation Scale (BBPS) was used to assess bowel preparation quality.

The study included 446 patients: 265 (59%) taking a GLP-1 RA and 181 controls (41%). Overall, the average age was 59 years, about 54% were women, and 91% were White. Among those taking a GLP-1 RA, 86% had diabetes, as did 74% of controls.

Of patients on a GLP-1 RA, 48.8% took subcutaneous semaglutide, 3.1% took oral semaglutide, 34.6% took dulaglutide, 11% took liraglutide, and very small percentages took tirzepatide or exenatide.

There were no statistically significant differences between groups at baseline except for the diabetes diagnosis.

After diabetes was controlled for, the mean BBPS was significantly higher in controls than in GLP-1 RA recipients (7.5 vs. 7), and the percentage of patients with a total BBPS score less than 5 was significantly higher in the GLP-1 RA group than in the control group (15.5% vs. 6.6%).

In a secondary analysis of those with diabetes, the proportion of patients with a BBPS score less than or equal to 1 in any segment was higher in those taking a GLP-1 RA than in controls (24.9% vs. 13.3%).

The proportion of patients who required a repeat colonoscopy owing to inadequate bowel prep was higher among those taking a GLP-1 RA than among controls (18.9% vs. 11.1%). This corresponded to a number needed to harm of 14.

“GLP-1 RAs are increasingly used for the treatment of diabetes and obesity and have been demonstrated to reduce gastrointestinal motility,” the authors write. “Our data signal that the use of these medications in this patient population may be an additional factor in suboptimal bowel preparation.”

Limitations include the retrospective nature of the study, its focus on a single health system with a large majority of non-Hispanic White patients, and lack of data on diabetic complications and the use of insulin – all of which “necessitate caution in interpreting the findings,” the authors write.
 

Research ‘evolving rapidly’

“We will continue gathering more information on colonoscopy preparations and GLP-1 RA medication use, and whether the newer type 2 diabetes medications have a similar effect,” Dr. Vargas said. “The newer and upcoming medications are double and/or triple agonists, and it remains to be determined if these have a similar effect on gastric transit times.”

The recent lowering of the recommended colorectal cancer screening age for average-risk individuals to 45 combined with increasing use of GLP-1 RAs make it important to minimize repeat colonoscopies, he added.

“In the absence of specific guidance on timing of periprocedural discontinuation of GLP-1 RAs, clinicians can enhance counseling and educational efforts in this population,” Dr. Vargas suggested. They can also consider interventions such as “extending bowel preparation regimens, issuing a clear liquid diet recommendation 48-72 hours before colonoscopy, and nurse education visits on colonoscopy preparation.”

Commenting on the study, David A. Greenwald, MD, director of clinical gastroenterology and endoscopy at Mount Sinai Hospital, New York City, noted the potential confounding in a retrospective study, as well as the relatively small sample size. “Nonetheless, the findings make sense and are important to guide clinical decision-making,” he told this news organization.

Gastric emptying with GLP-1 RAs can lead to retained fluid and food in the stomach, which increase the risk for aspiration at endoscopy, he said.

“We are concerned about that primarily for upper endoscopy but have seen vomiting and aspiration occur during colonoscopy in patients who have been using [these] medications,” Dr. Greenwald said. It’s reasonable to postulate that GLP-1 RAs could delay passage of colonoscopy preps through the gastrointestinal tract, which would affect the outcome of prep, he added.

“Research around GLP-1 agonist use and endoscopy is evolving rapidly, and we hope to have data-driven guidance soon on whether these agents need to be held in the peri-endoscopic period, and if so, for how long,” Dr. Greenwald noted. “At the moment, guidance has been published but is very much driven by expert opinion and limited studies.”

The study received no financial support. Dr. Vargas and Dr. Greenwald report no relevant conflicts of interest.

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

Glucagonlike peptide–1 receptor agonists (GLP-1 RAs), used for diabetes or obesity, are associated with a significantly lower quality of bowel preparation and a greater need for repeat colonoscopy, new research suggests.

“We began observing inadequate bowel preparation in our patients undergoing colonoscopy who were on GLP-1 RAs, which raised questions, especially given the association between these medications and delays in intestinal transit,” study investigator Eric. J. Vargas, MD, of the Mayo Clinic, Rochester, Minn., told this news organization. The team decided to investigate.

The “most surprising finding” was the “notably higher rate of inadequate bowel preparation, which necessitates a repeat colonoscopy within 12 months to ensure adequate screening and surveillance for colorectal cancers,” he said. “Specifically, for every 14 patients treated with GLP-1 RAs, one patient would require a repeat colonoscopy due to suboptimal preparation.”

In light of the findings, “clinicians should consider patients on GLP-1 RAs to be a population at risk for poor quality of bowel preparation,” he said.

The study was published online in the American Journal of Gastroenterology.
 

Low prep scores

The investigators analyzed a cohort of patients who underwent screening or surveillance colonoscopy at Mayo Clinic between 2021 and 2022. Patients taking any GLP-1 RA for diabetes or obesity at the time of colonoscopy were defined as “cases,” and those who were prescribed a GLP-1 RA at one point but had not taken it within 3 months of colonoscopy were controls.

The Boston Bowel Preparation Scale (BBPS) was used to assess bowel preparation quality.

The study included 446 patients: 265 (59%) taking a GLP-1 RA and 181 controls (41%). Overall, the average age was 59 years, about 54% were women, and 91% were White. Among those taking a GLP-1 RA, 86% had diabetes, as did 74% of controls.

Of patients on a GLP-1 RA, 48.8% took subcutaneous semaglutide, 3.1% took oral semaglutide, 34.6% took dulaglutide, 11% took liraglutide, and very small percentages took tirzepatide or exenatide.

There were no statistically significant differences between groups at baseline except for the diabetes diagnosis.

After diabetes was controlled for, the mean BBPS was significantly higher in controls than in GLP-1 RA recipients (7.5 vs. 7), and the percentage of patients with a total BBPS score less than 5 was significantly higher in the GLP-1 RA group than in the control group (15.5% vs. 6.6%).

In a secondary analysis of those with diabetes, the proportion of patients with a BBPS score less than or equal to 1 in any segment was higher in those taking a GLP-1 RA than in controls (24.9% vs. 13.3%).

The proportion of patients who required a repeat colonoscopy owing to inadequate bowel prep was higher among those taking a GLP-1 RA than among controls (18.9% vs. 11.1%). This corresponded to a number needed to harm of 14.

“GLP-1 RAs are increasingly used for the treatment of diabetes and obesity and have been demonstrated to reduce gastrointestinal motility,” the authors write. “Our data signal that the use of these medications in this patient population may be an additional factor in suboptimal bowel preparation.”

Limitations include the retrospective nature of the study, its focus on a single health system with a large majority of non-Hispanic White patients, and lack of data on diabetic complications and the use of insulin – all of which “necessitate caution in interpreting the findings,” the authors write.
 

Research ‘evolving rapidly’

“We will continue gathering more information on colonoscopy preparations and GLP-1 RA medication use, and whether the newer type 2 diabetes medications have a similar effect,” Dr. Vargas said. “The newer and upcoming medications are double and/or triple agonists, and it remains to be determined if these have a similar effect on gastric transit times.”

The recent lowering of the recommended colorectal cancer screening age for average-risk individuals to 45 combined with increasing use of GLP-1 RAs make it important to minimize repeat colonoscopies, he added.

“In the absence of specific guidance on timing of periprocedural discontinuation of GLP-1 RAs, clinicians can enhance counseling and educational efforts in this population,” Dr. Vargas suggested. They can also consider interventions such as “extending bowel preparation regimens, issuing a clear liquid diet recommendation 48-72 hours before colonoscopy, and nurse education visits on colonoscopy preparation.”

Commenting on the study, David A. Greenwald, MD, director of clinical gastroenterology and endoscopy at Mount Sinai Hospital, New York City, noted the potential confounding in a retrospective study, as well as the relatively small sample size. “Nonetheless, the findings make sense and are important to guide clinical decision-making,” he told this news organization.

Gastric emptying with GLP-1 RAs can lead to retained fluid and food in the stomach, which increase the risk for aspiration at endoscopy, he said.

“We are concerned about that primarily for upper endoscopy but have seen vomiting and aspiration occur during colonoscopy in patients who have been using [these] medications,” Dr. Greenwald said. It’s reasonable to postulate that GLP-1 RAs could delay passage of colonoscopy preps through the gastrointestinal tract, which would affect the outcome of prep, he added.

“Research around GLP-1 agonist use and endoscopy is evolving rapidly, and we hope to have data-driven guidance soon on whether these agents need to be held in the peri-endoscopic period, and if so, for how long,” Dr. Greenwald noted. “At the moment, guidance has been published but is very much driven by expert opinion and limited studies.”

The study received no financial support. Dr. Vargas and Dr. Greenwald report no relevant conflicts of interest.

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

Glucagonlike peptide–1 receptor agonists (GLP-1 RAs), used for diabetes or obesity, are associated with a significantly lower quality of bowel preparation and a greater need for repeat colonoscopy, new research suggests.

“We began observing inadequate bowel preparation in our patients undergoing colonoscopy who were on GLP-1 RAs, which raised questions, especially given the association between these medications and delays in intestinal transit,” study investigator Eric. J. Vargas, MD, of the Mayo Clinic, Rochester, Minn., told this news organization. The team decided to investigate.

The “most surprising finding” was the “notably higher rate of inadequate bowel preparation, which necessitates a repeat colonoscopy within 12 months to ensure adequate screening and surveillance for colorectal cancers,” he said. “Specifically, for every 14 patients treated with GLP-1 RAs, one patient would require a repeat colonoscopy due to suboptimal preparation.”

In light of the findings, “clinicians should consider patients on GLP-1 RAs to be a population at risk for poor quality of bowel preparation,” he said.

The study was published online in the American Journal of Gastroenterology.
 

Low prep scores

The investigators analyzed a cohort of patients who underwent screening or surveillance colonoscopy at Mayo Clinic between 2021 and 2022. Patients taking any GLP-1 RA for diabetes or obesity at the time of colonoscopy were defined as “cases,” and those who were prescribed a GLP-1 RA at one point but had not taken it within 3 months of colonoscopy were controls.

The Boston Bowel Preparation Scale (BBPS) was used to assess bowel preparation quality.

The study included 446 patients: 265 (59%) taking a GLP-1 RA and 181 controls (41%). Overall, the average age was 59 years, about 54% were women, and 91% were White. Among those taking a GLP-1 RA, 86% had diabetes, as did 74% of controls.

Of patients on a GLP-1 RA, 48.8% took subcutaneous semaglutide, 3.1% took oral semaglutide, 34.6% took dulaglutide, 11% took liraglutide, and very small percentages took tirzepatide or exenatide.

There were no statistically significant differences between groups at baseline except for the diabetes diagnosis.

After diabetes was controlled for, the mean BBPS was significantly higher in controls than in GLP-1 RA recipients (7.5 vs. 7), and the percentage of patients with a total BBPS score less than 5 was significantly higher in the GLP-1 RA group than in the control group (15.5% vs. 6.6%).

In a secondary analysis of those with diabetes, the proportion of patients with a BBPS score less than or equal to 1 in any segment was higher in those taking a GLP-1 RA than in controls (24.9% vs. 13.3%).

The proportion of patients who required a repeat colonoscopy owing to inadequate bowel prep was higher among those taking a GLP-1 RA than among controls (18.9% vs. 11.1%). This corresponded to a number needed to harm of 14.

“GLP-1 RAs are increasingly used for the treatment of diabetes and obesity and have been demonstrated to reduce gastrointestinal motility,” the authors write. “Our data signal that the use of these medications in this patient population may be an additional factor in suboptimal bowel preparation.”

Limitations include the retrospective nature of the study, its focus on a single health system with a large majority of non-Hispanic White patients, and lack of data on diabetic complications and the use of insulin – all of which “necessitate caution in interpreting the findings,” the authors write.
 

Research ‘evolving rapidly’

“We will continue gathering more information on colonoscopy preparations and GLP-1 RA medication use, and whether the newer type 2 diabetes medications have a similar effect,” Dr. Vargas said. “The newer and upcoming medications are double and/or triple agonists, and it remains to be determined if these have a similar effect on gastric transit times.”

The recent lowering of the recommended colorectal cancer screening age for average-risk individuals to 45 combined with increasing use of GLP-1 RAs make it important to minimize repeat colonoscopies, he added.

“In the absence of specific guidance on timing of periprocedural discontinuation of GLP-1 RAs, clinicians can enhance counseling and educational efforts in this population,” Dr. Vargas suggested. They can also consider interventions such as “extending bowel preparation regimens, issuing a clear liquid diet recommendation 48-72 hours before colonoscopy, and nurse education visits on colonoscopy preparation.”

Commenting on the study, David A. Greenwald, MD, director of clinical gastroenterology and endoscopy at Mount Sinai Hospital, New York City, noted the potential confounding in a retrospective study, as well as the relatively small sample size. “Nonetheless, the findings make sense and are important to guide clinical decision-making,” he told this news organization.

Gastric emptying with GLP-1 RAs can lead to retained fluid and food in the stomach, which increase the risk for aspiration at endoscopy, he said.

“We are concerned about that primarily for upper endoscopy but have seen vomiting and aspiration occur during colonoscopy in patients who have been using [these] medications,” Dr. Greenwald said. It’s reasonable to postulate that GLP-1 RAs could delay passage of colonoscopy preps through the gastrointestinal tract, which would affect the outcome of prep, he added.

“Research around GLP-1 agonist use and endoscopy is evolving rapidly, and we hope to have data-driven guidance soon on whether these agents need to be held in the peri-endoscopic period, and if so, for how long,” Dr. Greenwald noted. “At the moment, guidance has been published but is very much driven by expert opinion and limited studies.”

The study received no financial support. Dr. Vargas and Dr. Greenwald report no relevant conflicts of interest.

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

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

Intensive lowering of blood pressure to a systolic target less than 120 mm Hg reduced cardiovascular events among individuals at high risk for cardiovascular disease, compared with standard treatment using a target less than 140 mm Hg in the ESPRIT trial.

“Intensive blood pressure–lowering treatment targeting a systolic pressure below 120 mm Hg for 3 years resulted in a 12% lower incidence of major vascular events, a 39% lower cardiovascular mortality, and 21% lower all-cause mortality than the standard treatment targeting a systolic pressure below 140 mm Hg,” reported lead investigator, Jing Li, MD, PhD, director of the department of preventive medicine at the National Center for Cardiovascular Diseases in Beijing.

The trial included patients with diabetes and those with a history of stroke, two important groups that were excluded in the previous SPRINT trial of intensive BP lowering. Results suggested that the benefit of intensive BP lowering extends to these groups.

The results translate into the prevention of 14 major vascular events and 8 deaths for every 1,000 individuals are treated for 3 years to a target systolic pressure less than 120 mm Hg rather than less than 140 mm Hg, at the cost of an additional three patients experiencing the serious adverse event of syncope, Dr. Li said.

“Our study generates new evidence about benefit and safety of treatment targeting systolic blood pressure below 120 mm Hg among a diverse Asian population, which is generally consistent with those from other ethnicities. Implementing this intensive treatment strategy for high-risk adults has the potential to save more lives and reduce the public health burden of heart disease worldwide,” she concluded.

Dr. Li presented the ESPRIT trial at the annual scientific sessions of the American Heart Association.

The ESPRIT trial included 11,255 Chinese adults (average age, 64 years; 41% women) who had a baseline systolic BP measurement of 130-180 mm Hg (average was 147/83 mm Hg) and either established cardiovascular disease or at least two major risk factors for cardiovascular disease. Of those enrolled, 39% had diabetes, and 27% had a history of stroke.

They were randomly assigned to receive intensive BP treatment, with a systolic BP target less than 120 mm Hg, or standard treatment, with a target measurement less than 140 mm Hg, over a 3-year period. After 1 year, systolic pressure was lowered to 135.6 mm Hg in the standard care group and to 120.3 mm Hg in the intensive treatment group, with values remaining at around the same level for the remainder of the follow-up.

The primary outcome was a composite of myocardial infarction, coronary or noncoronary revascularization, hospitalization/ED visit for heart failure, stroke, or cardiovascular death.

After 3.4 years of follow-up, 624 primary outcome events had occurred in the standard arm (3.6%) versus 547 events in intensive arm (3.2%), a reduction of 12% (hazard ratio, 0.88; 95% confidence interval, 0.78-0.99). This gives a number needed to treat to prevent one event of 74.

Cardiovascular death occurred in 0.5% of the standard group versus 0.3% of the intensive group (HR 0.61; 95% CI, 0.44-0.84); and all-cause death occurred in 1.1% of the standard group versus 0.9% of the intensive group (HR, 0.79; 95% CI, 0.64-0.97).

The individual endpoints of MI, stroke, and heart failure showed positive trends to a reduction with intensive BP lowering, but these did not reach statistical significance.

In terms of serious adverse events, syncope was increased in the intensive group (0.4% vs 0.1%), but there were no significant differences in hypotension, electrolyte abnormality, falls resulting in an injury, acute kidney injury, or renal failure.
 

Should 120 mm Hg be new target?

Commenting on the study, Paul Whelton, MD, chair in global public health at Tulane University, New Orleans, said that the results were consistent with several other trials.  

“When we look at meta-analysis of trials of different levels of blood pressure reduction, all the studies show the same thing – the lower the blood pressure, the better the outcome, with those starting at higher levels gaining the greatest the benefit of blood pressure reductions,” he noted.

“There are four trials that have looked at systolic targets of less than 120 mm Hg versus less than 140 mm Hg (SPRINT, ACCORD BP, RESPECT, and now ESPRIT), and when analyzed properly, they all show a similar benefit for cardiovascular outcomes with the lower 120 target,” said Dr. Whelton, who led the SPRINT trial. 

“ESPRIT is a nicely done trial. It is reassuring because it is consistent with the other trials, in that it seems that the benefits are much greater than the risk of adverse effects,” he added.

Dr. Whelton pointed out that there are three more trials to come looking at this question, two in Brazil (one in individuals with diabetes and one in stroke survivors) and another trial in China in people with diabetes. “So, we will get more information from these.”

He said that guidelines committees will have to consider a lower systolic BP of 120 mm Hg as the optimal treatment target. In the United States, at present, the target is 130 mm Hg.

The current U.S. guidelines were based on the SPRINT trial, which showed a reduction in cardiovascular events in patients treated to a systolic target of 120 mm Hg versus 140 mm Hg.

Dr. Whelton, who was chair of the 2017 American College of Cardiology/American Heart Association hypertension guidelines committee, explained that, at the time the guidelines were written, there was only one trial, SPRINT, to base the evidence on.

“The committee could all comfortably agree on the 130 mm Hg target, but it was felt that there wasn’t enough evidence at the time to make a recommendation for 120 mm Hg,” he said. “But now we have four trials.”

He said that the trials included patients with high risk for cardiovascular disease, but they all brought some differences to the table, with ACCORD BP conducted in patients with diabetes; SPRINT having enrichment with African American patients, older adults, and patients with kidney disease; RESPECT was in stroke survivors; and ESPRIT had a mix of Chinese patients.

“I think we’ve got a nice mix of different participants and they’re all showing the same signal – that 120 mm Hg is better,” Dr. Whelton said.

But he stressed that although there is now good evidence in favor of lower BP targets, these findings were not being implemented in clinical practice.

“We are doing very badly in terms of implementation. There is a big gap between science and what’s happening in the real world.”

Dr. Whelton pointed out that only 30% of patients in high-income countries are controlled to the 140/90 target and that in low- and middle-income countries, only 8.8% get to that level, never mind lower targets. “The next job is to work on implementing these findings.”

He noted that several studies have shown better results in this regard using a team approach, with nonphysicians playing a major role in following up with patients.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Omega-3 polyunsaturated fatty acids reduce hepatic dysfunction in nonalcoholic steatohepatitis (NASH) by lowering betacellulin (BTC), a protein growth factor that contributes to liver fibrosis and progression to cirrhosis and liver cancer, new data suggest.

METHODOLOGY:

• Because omega-3 polyunsaturated fatty acids have been shown to reduce hepatic dysfunction in NASH, but the molecular underpinnings of this action were elusive, researchers conducted a multiomic network analysis applied to a mouse model of Western diet–induced NASH to identify the key mechanisms involved.
• They also performed a meta-analysis of human liver cancer transcriptome data to evaluate which aspects of NASH pathogenesis leading to cancer are reversed by omega-3 polyunsaturated fatty acids.

TAKEAWAY:

• BTC, an epidermal growth factor–binding protein, was consistently upregulated in liver cancer and downregulated by omega-3 polyunsaturated fatty acids in mice and humans with NASH.
• BTC promotes NASH fibrosis by activating dormant hepatic stellate cells to produce transforming growth factor beta-2 and increase collagen production. It also exacerbates toll-like receptor-dependent inflammatory processes in NASH.
• By downregulating BTC, omega-3 polyunsaturated fatty acids have therapeutic potential in NASH and could serve as a novel drug target.

IN PRACTICE:

“BTC represents a candidate master regulator inducing two most important factors (collagens and integrins) contributing to liver fibrosis and consequently promoting liver cancer,” the researchers write. “Future studies should investigate if BTC-triggered gene expression signatures can serve as biomarkers guiding personalized [omega-3 polyunsaturated fatty acid] therapy, as targets of new NAFLD/NASH drugs, and finally as a predictors of hepatic cancer risk in humans.”

SOURCE:

The study, with lead first author Jyothi Padiadpu, PhD, Oregon State University College of Pharmacy, Corvallis, was published online  in EMBO Molecular Medicine (2023. doi: 10.15252/emmm.202318367).

LIMITATIONS:

The study authors report no limitations. However, the findings are based on mouse model and human transcriptome data.

DISCLOSURES:

This research was supported by the National Institute of Diabetes and Digestive Kidney Diseases and the U.S. Department of Agriculture. The authors report no conflicts of interest.

A version of this article appeared on Medscape.com.

The Food and Drug Administration has approved Medtronic’s Symplicity Spyral renal denervation system for the treatment of hypertension, the company has announced.

The Symplicity Spyral system, also known as the Symplicity blood pressure procedure, provides a catheter-based approach to denervate the renal arteries using radiofrequency energy.

Back in August, the FDA’s Circulatory System Devices Panel unanimously agreed that the Symplicity Spyral system is safe, but the panel was split on its efficacy and whether the benefits outweighed the risks associated with its use.

As part of the Medtronic SPYRAL HTN Global Clinical Program, more than 25,000 patients have been treated worldwide, both in the presence and absence of medication, and in patients with high baseline cardiovascular risk.

The SPYRAL HTN-OFF study enrolled patients with hypertension whose medications could be stopped at the start of the trial.

The primary effectiveness endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure (ASBP) from baseline to 3 months after renal denervation or sham procedure. The study showed a statistically significant reduction of 3.9 mm Hg ASBP in patients who received the device, compared with sham-control patients.

The SPYRAL HTN-ON study evaluated patients with uncontrolled hypertension who continued taking their BP medications during treatment with either the Spyral renal denervation device or a sham device.

The primary endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure at 6 months. The study showed a nonsignificant 24-hour 0.03 mm Hg reduction in ASBP in active-treatment patients, compared with sham-control patients.

“The Symplicity blood pressure procedure is safe and effective, providing significant ‘always-on’ blood pressure reductions for patients,” David Kandzari, MD, chief, Piedmont Heart Institute, Atlanta, and co–principal investigator of the SPYRAL clinical program, said in the news release.

“This approval paves the way for a transformation in hypertension treatment, offering a solution that complements medication and lifestyle changes,” added co–principal investigator Raymond Townsend, MD, with University of Pennsylvania, Philadelphia.

Medtronic notes that patient preference and shared decision-making are key components when considering the Symplicity blood pressure procedure.

In a patient preference study led by Medtronic, when presented with an interventional treatment with BP reduction and potential risks in line with those of the Symplicity blood pressure procedure, approximately one-third of patients were likely to choose the interventional treatment.

Earlier in November, the FDA also approved the Paradise Ultrasound Renal Denervation system (Recor Medical, Otsuka Medical Devices) for the treatment of hypertension.

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

The Food and Drug Administration has approved Medtronic’s Symplicity Spyral renal denervation system for the treatment of hypertension, the company has announced.

The Symplicity Spyral system, also known as the Symplicity blood pressure procedure, provides a catheter-based approach to denervate the renal arteries using radiofrequency energy.

Back in August, the FDA’s Circulatory System Devices Panel unanimously agreed that the Symplicity Spyral system is safe, but the panel was split on its efficacy and whether the benefits outweighed the risks associated with its use.

As part of the Medtronic SPYRAL HTN Global Clinical Program, more than 25,000 patients have been treated worldwide, both in the presence and absence of medication, and in patients with high baseline cardiovascular risk.

The SPYRAL HTN-OFF study enrolled patients with hypertension whose medications could be stopped at the start of the trial.

The primary effectiveness endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure (ASBP) from baseline to 3 months after renal denervation or sham procedure. The study showed a statistically significant reduction of 3.9 mm Hg ASBP in patients who received the device, compared with sham-control patients.

The SPYRAL HTN-ON study evaluated patients with uncontrolled hypertension who continued taking their BP medications during treatment with either the Spyral renal denervation device or a sham device.

The primary endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure at 6 months. The study showed a nonsignificant 24-hour 0.03 mm Hg reduction in ASBP in active-treatment patients, compared with sham-control patients.

“The Symplicity blood pressure procedure is safe and effective, providing significant ‘always-on’ blood pressure reductions for patients,” David Kandzari, MD, chief, Piedmont Heart Institute, Atlanta, and co–principal investigator of the SPYRAL clinical program, said in the news release.

“This approval paves the way for a transformation in hypertension treatment, offering a solution that complements medication and lifestyle changes,” added co–principal investigator Raymond Townsend, MD, with University of Pennsylvania, Philadelphia.

Medtronic notes that patient preference and shared decision-making are key components when considering the Symplicity blood pressure procedure.

In a patient preference study led by Medtronic, when presented with an interventional treatment with BP reduction and potential risks in line with those of the Symplicity blood pressure procedure, approximately one-third of patients were likely to choose the interventional treatment.

Earlier in November, the FDA also approved the Paradise Ultrasound Renal Denervation system (Recor Medical, Otsuka Medical Devices) for the treatment of hypertension.

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

The Food and Drug Administration has approved Medtronic’s Symplicity Spyral renal denervation system for the treatment of hypertension, the company has announced.

The Symplicity Spyral system, also known as the Symplicity blood pressure procedure, provides a catheter-based approach to denervate the renal arteries using radiofrequency energy.

Back in August, the FDA’s Circulatory System Devices Panel unanimously agreed that the Symplicity Spyral system is safe, but the panel was split on its efficacy and whether the benefits outweighed the risks associated with its use.

As part of the Medtronic SPYRAL HTN Global Clinical Program, more than 25,000 patients have been treated worldwide, both in the presence and absence of medication, and in patients with high baseline cardiovascular risk.

The SPYRAL HTN-OFF study enrolled patients with hypertension whose medications could be stopped at the start of the trial.

The primary effectiveness endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure (ASBP) from baseline to 3 months after renal denervation or sham procedure. The study showed a statistically significant reduction of 3.9 mm Hg ASBP in patients who received the device, compared with sham-control patients.

The SPYRAL HTN-ON study evaluated patients with uncontrolled hypertension who continued taking their BP medications during treatment with either the Spyral renal denervation device or a sham device.

The primary endpoint was the mean difference in the baseline adjusted 24-hour ambulatory systolic blood pressure at 6 months. The study showed a nonsignificant 24-hour 0.03 mm Hg reduction in ASBP in active-treatment patients, compared with sham-control patients.

“The Symplicity blood pressure procedure is safe and effective, providing significant ‘always-on’ blood pressure reductions for patients,” David Kandzari, MD, chief, Piedmont Heart Institute, Atlanta, and co–principal investigator of the SPYRAL clinical program, said in the news release.

“This approval paves the way for a transformation in hypertension treatment, offering a solution that complements medication and lifestyle changes,” added co–principal investigator Raymond Townsend, MD, with University of Pennsylvania, Philadelphia.

Medtronic notes that patient preference and shared decision-making are key components when considering the Symplicity blood pressure procedure.

In a patient preference study led by Medtronic, when presented with an interventional treatment with BP reduction and potential risks in line with those of the Symplicity blood pressure procedure, approximately one-third of patients were likely to choose the interventional treatment.

Earlier in November, the FDA also approved the Paradise Ultrasound Renal Denervation system (Recor Medical, Otsuka Medical Devices) for the treatment of hypertension.

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

A single injection of the investigational antihypertensive agent zilebesiran (Alnylam Pharmaceuticals) effectively lowered blood pressure in adults with mild to moderate hypertension for up to 6 months, with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.

“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.

“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.

The KARDIA-1 study was presented at the American Heart Association scientific sessions.

Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.

Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.

The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.

The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).

Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.

Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.

Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.

In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.

There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.

Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.

There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.

Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.

Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”

Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.

Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”

Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”

Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.

“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.

Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.

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

A single injection of the investigational antihypertensive agent zilebesiran (Alnylam Pharmaceuticals) effectively lowered blood pressure in adults with mild to moderate hypertension for up to 6 months, with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.

“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.

“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.

The KARDIA-1 study was presented at the American Heart Association scientific sessions.

Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.

Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.

The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.

The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).

Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.

Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.

Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.

In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.

There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.

Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.

There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.

Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.

Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”

Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.

Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”

Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”

Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.

“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.

Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.

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

A single injection of the investigational antihypertensive agent zilebesiran (Alnylam Pharmaceuticals) effectively lowered blood pressure in adults with mild to moderate hypertension for up to 6 months, with what appeared to be an encouraging side-effect profile, in the phase 2 dose-ranging KARDIA-1 study.

“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” said senior study investigator George Bakris, MD.

“Based on these results, zilebesiran has the potential to improve medication adherence, which will, in turn, reduce cardiovascular risk in people with hypertension,” added Dr. Bakris, who is professor of medicine and director of the Comprehensive Hypertension Center at the University of Chicago Medicine.

The KARDIA-1 study was presented at the American Heart Association scientific sessions.

Dr. Bakris noted that uncontrolled hypertension is a leading cause of morbidity and mortality, and despite availability of effective antihypertensives, many adults with hypertension are untreated, and up to 80% have uncontrolled disease, both globally and in the United States.

Zilebesiran is a subcutaneous RNA interference therapeutic that binds with high affinity to the hepatic asialoglycoprotein receptor, bringing about a reduction in the synthesis of angiotensinogen, the sole precursor of all angiotensin peptides. It is hoped that its hepatocyte-targeted delivery may allow extrahepatic angiotensinogen expression to be preserved, which could limit off-target effects in the kidney and other tissues.

The KARDIA-1 trial investigated the safety and efficacy of different doses of zilebesiran in patients with mild to moderate hypertension (systolic BP of 135-160 mm Hg), who are untreated or on stable therapy with up to two antihypertensive medications.

The study included 394 such patients (average baseline systolic BP was 142 mm Hg) who were randomly assigned to receive one of four different zilebesiran doses (150 mg, 300 mg, or 600 mg once every 6 months or 300 mg once every 2 months) or a placebo. The final analysis included 377 patients (56% men, 25% Black).

Results showed sustained reductions in serum angiotensinogen (between 88% and 98%) over the 6-month follow-up period.

Ambulatory systolic BP measured over 24 hours was significantly decreased with all zilebesiran regimens, with a mean reduction from baseline to month 6 of around 10 mm Hg in the three top doses studied and by around 14 mm Hg compared with placebo.

Patients receiving zilebesiran were more likely to achieve 24-hour average systolic BP measurements of 130 mm Hg or less at 6 months.

In addition, participants in all four zilebesiran groups consistently experienced significantly greater reductions in both daytime and nighttime systolic BP.

There were four nonserious adverse reactions leading to discontinuation in the zilebesiran groups: two instances of orthostatic hypotension, one of BP elevation, and one of injection site reaction.

Most hyperkalemia adverse events, which occurred in 6% of patients, were mild, did not require intervention, and generally resolved with repeat measurement; none were associated with acute kidney injury or led to study drug discontinuation. The incidence of hypotension events was low, and no clinically relevant changes in renal or hepatic function were observed, Dr. Bakris reported.

There was one death caused by cardiopulmonary arrest in a patient receiving zilebesiran 300 mg every 3 months, but this was not classified as drug related.

Zilebesiran is being further evaluated as an add-on therapy for treatment of hypertension in the ongoing KARDIA-2 phase 2 study.

Moderator of an AHA press conference at which the study was discussed, Sandra Taler, MD, professor of medicine at the Mayo Clinic, Rochester, Minn., said that “to have an injectable medicine that gives long-term blood pressure lowering is extremely exciting.”

Dr. Taler raised the point that some patients may not return for subsequent doses, but added that with subcutaneous dosing, administration at home may be a possibility.

Also commenting at the press conference, Keith Ferdinand, MD, professor of clinical medicine at Tulane University, New Orleans, said that this study “suggests we can now target the first step in the renin-angiotensin system – angiotensinogen – which then appears to lead to robust and continued blood pressure lowering for up to 6 months, which should improve adherence.”

Noting that only 50% of patients continue to take antihypertensive drugs after 1 year, Dr. Ferdinand added: “If we can increase adherence, we will increase efficacy and perhaps protect against some of the target organ damage.”

Designated discussant of the KARDIA-1 study at the AHA late-breaking clinical trial session, Anna Dominiczak, MD, University of Glasgow, noted that hypertension affects one in three adults worldwide, but only around 20% of people have it under control.

“An increase in the number of patients effectively treated for hypertension to levels observed in high-performing countries could prevent 76 million deaths, 120 million strokes, 79 million heart attacks, and 17 million cases of heart failure between now and 2050,” she said.

Dr. Bakris has received consulting fees from Alnylam Pharmaceuticals.

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

The American Heart Association (AHA) has unveiled a new heart disease risk calculator that aims to estimate an individual’s long-term risk for cardiovascular disease (CVD).

The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.

It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.

The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.

PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.

“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.

“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.

The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool. 

Going beyond the PCE

The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.

In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.

It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.

The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.

“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.

They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.

The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.

The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.

“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
 

Knowledge gaps

The scientific statement lists several knowledge gaps and areas for more research. These include:

• Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
• Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
• Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
• Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
• Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.

The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.

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

The American Heart Association (AHA) has unveiled a new heart disease risk calculator that aims to estimate an individual’s long-term risk for cardiovascular disease (CVD).

The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.

It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.

The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.

PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.

“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.

“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.

The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool. 

Going beyond the PCE

The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.

In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.

It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.

The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.

“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.

They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.

The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.

The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.

“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
 

Knowledge gaps

The scientific statement lists several knowledge gaps and areas for more research. These include:

• Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
• Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
• Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
• Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
• Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.

The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.

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

The American Heart Association (AHA) has unveiled a new heart disease risk calculator that aims to estimate an individual’s long-term risk for cardiovascular disease (CVD).

The new Predicting Risk of CVD Events (PREVENT) calculator is the first risk calculator that combines measures of cardiovascular, kidney, and metabolic health to estimate risk for CVD.

It follows an AHA presidential advisory and scientific statement published in October, formally defining cardiovascular-kidney-metabolic (CKM) syndrome.

The PREVENT calculator also “starts earlier and goes longer” than the pooled cohort equations (PCE), Sadiya Khan, MD, MSc, chair of the statement writing committee, told this news organization.

PREVENT is for use in adults aged 30-79 years and estimates the 10- and 30-year risk of total CVD including, for the first time, heart failure. The PCE were designed to assess 10-year risk of only myocardial infarction and stroke and only in adults aged 40-79 years.

“The new PREVENT equations are important for doctors because they allow us to start conversations earlier and more comprehensively and accurately calculate risk for our patients,” said Dr. Khan, preventive cardiologist at Northwestern Medicine and associate professor at Northwestern University in Chicago.

“We want to support clinicians in starting these conversations around optimizing CKM health earlier and begin to engage in discussions on ways to optimize health,” Dr. Khan added.

The AHA scientific statement on the PREVENT calculator, with Dr. Khan as lead author, was published online in Circulation, with an accompanying article that describes development and validation of the tool. 

Going beyond the PCE

The new calculator was developed using health information from more than 6 million adults from diverse racial and ethnic, socioeconomic, and geographic backgrounds.

In addition to blood pressure and cholesterol levels, the PREVENT equations allow for inclusion of hemoglobin A1c, if necessary, to monitor metabolic health.

It also includes estimated glomerular filtration rate (eGFR), a measure of kidney function, and allows for use of albumin excretion to monitor kidney disease to further individualize risk assessment and help inform personalized treatment options.

The new calculator also asks about tobacco use and use of medications for CVD risk factors and factors in age and sex, and it removes race from the risk calculations.

“The inclusion of race in risk prediction may imply that differences by race are not modifiable and may reify race as a biological construct, which may worsen health disparities. Therefore, it was decided a priori not to include race as a predictor in the development of PREVENT,” the writing group said.

They emphasized that the PREVENT calculator has similar accuracy among varied racial and ethnic groups.

The equations include an option to use the Social Deprivation Index, which incorporates measures of adverse social determinants of health such as education, poverty, unemployment, and factors based on a person’s environment.

The PREVENT equations are a “critical first step” toward including CKM health and social factors in risk prediction for CVD, Dr. Khan said in a news release.

“We are working on finalizing the online tool and it should be available soon – hopefully in a few weeks,” Dr. Khan told this news organization.
 

Knowledge gaps

The scientific statement lists several knowledge gaps and areas for more research. These include:

• Incorporating “net benefit” to identify the expected benefit of treatment recommendations based on an individual’s level of risk.
• Collecting more data from people of diverse race and ethnic backgrounds to better represent the increasing diversity in the United States. The number of Hispanic and Asian people included in the PREVENT datasets is lower than national estimates in the general U.S. population, so risk estimations in these populations may be less precise.
• Expanding the collection, reporting, and standardization of social determinants of health data, such as individual information rather than neighborhood information.
• Expanding risk assessment and prevention to earlier in life (childhood and/or adolescence) and in key life periods, such as during the peripartum period, since adverse pregnancy outcomes are associated with increased CVD risk.
• Investigating whether predicting adverse kidney outcomes, particularly among people with and without type 2 diabetes, may further optimize cardiovascular risk prediction.

The scientific statement was prepared by the volunteer writing group on behalf of the AHA. Dr. Khan reports no relevant financial relationships.

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

The drug alpha-difluoromethylornithine (DFMO) may help preserve beta-cell function in people with new-onset type 1 diabetes, new preliminary data suggest.

“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.

DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.

In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.

The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.

Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m², 750 mg/m², and 1,000 mg/m², respectively).

Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.

There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m² and 750-mg/m² treatment groups at the 6-month time point (P = .03 and .04, respectively).

In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.

“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.

However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”

But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”

Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”

Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.

She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”

Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.

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

The drug alpha-difluoromethylornithine (DFMO) may help preserve beta-cell function in people with new-onset type 1 diabetes, new preliminary data suggest.

“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.

DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.

In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.

The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.

Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m², 750 mg/m², and 1,000 mg/m², respectively).

Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.

There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m² and 750-mg/m² treatment groups at the 6-month time point (P = .03 and .04, respectively).

In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.

“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.

However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”

But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”

Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”

Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.

She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”

Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.

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

The drug alpha-difluoromethylornithine (DFMO) may help preserve beta-cell function in people with new-onset type 1 diabetes, new preliminary data suggest.

“I think we have lots of potential to improve people’s quality of life who are living with type 1 diabetes if we can increase their endogenous insulin secretion. ... I think long-term combination therapy is going to be the answer,” study author Emily K. Sims, MD, a pediatric endocrinologist at Indiana University, Indianapolis, said in an interview.

DFMO inhibits the polyamine biosynthesis pathway, which plays a role in the inflammatory responses in autoimmune diseases, including type 1 diabetes. It’s sold under the name eflornithine as an intravenous treatment for African sleeping sickness (trypanosomiasis) and as a cream for unwanted hair growth in women. It also has orphan designations for treating various cancers, including neuroblastoma.

In type 1 diabetes, the immune system destroys insulin-producing pancreatic beta cells. Insulin treatment is required. Recently, the monoclonal antibody teplizumab (Tzield, Sanofi) was approved as a treatment for delaying the onset of type 1 diabetes in people with autoantibodies that signify a preclinical stage of the condition. As yet, no agent has been approved for preserving beta-cell function after the onset of type 1 diabetes, but many are under investigation.

The new safety study by Dr. Sims and colleagues, which was published in Cell Medicine Reports, enrolled 41 people with type 1 diabetes who had been diagnosed within the previous 8 months, including 31 children. Participants were randomly assigned to undergo oral treatment with DFMO at one of five doses or placebo for 3 months, with 3 additional months of follow-up.

Following a mixed-meal tolerance test at 6 months, the C-peptide area under the curve – a measure of beta-cell function – was significantly higher with the three highest DFMO doses compared to placebo (P = .02, .03, and .02 for 125 mg/m², 750 mg/m², and 1,000 mg/m², respectively).

Two individuals dropped out, one because of anaphylaxis. There were no dose-limiting toxicities or serious adverse events, while mild gastrointestinal events, anemia, and headache were common. “Although there’s no [Food and Drug Administration] approval for the oral form right now, there’s a lot of safety data, including in kids from the neuroblastoma studies,” Dr. Sims explained.

There were no differences in C-peptide at 3 months or in hemoglobin A1c at any time point. Glucose areas under the curve were significantly lower for DFMO, compared with placebo in the 125-mg/m² and 750-mg/m² treatment groups at the 6-month time point (P = .03 and .04, respectively).

In their article, Dr. Sims and colleagues also reported confirmatory analyses in mice, as well as testing in the humans showing that there didn’t appear to be significant immune system modulation. “So, we can envision giving DFMO in addition to something that targets the immune system, as a combination therapy,” said Dr. Sims, who also worked on the pivotal study of teplizumab.

“I’m excited. The sample size is small, so I was kind of expecting no efficacy signals. ... It’s definitely worth following up,” she said.

However, she noted, “it wasn’t a slam-dunk huge effect. It was subtle. It seemed that things were kind of more stable compared to placebo over time versus ... a big increase in C-peptide over time.”

But, she added, “I believe that even teplizumab will need to be used in combination. It delays the onset of type 1 diabetes and improves C-peptide, but it didn’t get everyone off insulin. I don’t think we’ve seen any drug that won’t need to be used in combination.”

Dr. Sims pointed to other investigational agents, such as verapamil and various Janus kinase inhibitors, that may also serve in combination to forestall or reduce insulin dependency for people with either new-onset type 1 diabetes or those who have been identified via screening as having type 1 diabetes–related autoantibodies. “I think there are a lot of potential different interventions.”

Dr. Sims and colleagues are now conducting a larger six-center JDRF-funded study of DFMO in early-onset type 1 diabetes that will be fully powered and that will use the highest tolerated doses from the preliminary study.

She believes there will likely be benefit even if the agent doesn’t completely reverse the disease. “The people who are making more insulin are just easier to manage, with more time in range and less hypoglycemia.” Even if the drugs only delay but don’t prevent type 1 diabetes entirely in those at risk, “the improvement in quality of life of being able to delay insulin for a few years is really palpable. ... I’m really optimistic.”

Dr. Sims disclosed no relevant financial relationships. Three other authors are coauthors on a patent application for the use of DFMO for the treatment of beta-cell dysfunction in type 1 diabetes; one of those three authors is an employee of Cancer Prevention Pharmaceuticals.

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

Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction, the author commented on the discordance in practice among his peers at his hospital. It seemed that there was no consensus on whether fludrocortisone was necessary.

I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.

It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.

Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
 

Rethinking hydro/fludro

The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.

In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
 

Key takeaways

The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.

The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.

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

Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction, the author commented on the discordance in practice among his peers at his hospital. It seemed that there was no consensus on whether fludrocortisone was necessary.

I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.

It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.

Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
 

Rethinking hydro/fludro

The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.

In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
 

Key takeaways

The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.

The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.

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

Earlier this year, I stumbled across a podcast in a content update email from the Journal of the American Medical Association. The moderator was interviewing the first author of a study comparing hydrocortisone and fludrocortisone (hydro/fludro) to hydrocortisone alone for treatment of septic shock. In the introduction, the author commented on the discordance in practice among his peers at his hospital. It seemed that there was no consensus on whether fludrocortisone was necessary.

I thought this issue had been settled with publication of the COIITSS trial in 2010. This study randomly assigned 509 patients with septic shock to hydro/fludro versus hydrocortisone alone. There was a nonsignificant reduction in mortality with hydro/fludro and everyone I knew stopped adding fludrocortisone for septic shock. It wasn’t included in guidelines (and still isn›t). I figured the only docs still using it were also prescribing ivermectin and vitamin C – another treatment touted to work in an apocryphal podcast.

It wasn’t just COIITSS that killed fludrocortisone for me. Back in 2002, I was a loyal adherent. That year, a randomized controlled trial (RCT) published by “the lord of corticosteroids for critical illness” doctor, Djillali Annane, found benefit to hydro/fludro in septic shock . Everyone in that study had a cosyntropin stim test and only certain subgroups had better outcomes. As a medical resident paying obeisance to all things evidence-based medicine, I rigidly adopted their protocol for all septic patients. I also kept their insulin between 80 and 110 mg/dL, prescribed drotrecogin alfa, and made sure they were floating in crystalloid. But those are topics for another time.

Subsequent trials and meta-analyses cast doubt on the need for the stim test, and a consensus around hydrocortisone at moderate doses for patients with septic shock emerged. Because one part of the Annane protocol was already deemed unnecessary (the cosyntropin stim test), it was easy to dismiss fludrocortisone after COIITTS was published. Yes, I read Annane’s 2018 APROCCHSS trial, and I’m aware that it found that hydro/fludro reduced 90-day mortality. Like others, I rationalized this finding by framing it as a function of baseline mortality. The two Annane RCTs that found that hydro/fludro reduced mortality in enrolled patients who were considerably more likely to die than those enrolled in RCTs of hydrocortisone alone were negative. It was the target population mortality rate and not the addition of fludrocortisone that made the difference, right?
 

Rethinking hydro/fludro

The author interviewed for the recent JAMA podcast forced me to rethink my blithe dismissal of fludrocortisone. He contended that the COIITTS trial was underpowered and the two Annane RCTs that used fludrocortisone supply the evidence that shows corticosteroids reduce septic shock mortality. As discussed earlier, he found clinical equipoise among his colleagues. Last, he invoked pleiotropic mineralocorticoid effects, such as activation of innate immunity and clearance of alveolar fluid, to support the need to reexamine hydro/fludro.

In his study, he used Big Data to compare hospital records from 2016 to 2020. He analyzed a total of 88,275 patients with septic shock. Most were prescribed hydrocortisone alone (85,995 [97.4%] vs. only 2.6% hydro/fludro). After a number of statistical adjustments and sensitivity analyses, the authors concluded that the addition of fludrocortisone to hydrocortisone for patients with septic shock provides a 3.7% absolute risk reduction in mortality (or discharge to hospice) when compared with hydrocortisone alone. That’s a number needed to treat of 28 to prevent one death (or discharge to hospice).
 

Key takeaways

The study isn’t perfect. In their methods section they use terms like “ensemble machine learner (super learner)” and “immortal time bias.” The first is a fancy way of saying they did a form of propensity scoring, which in turn is a fancy way of saying they tried to control for confounding. The second is a way to adjust for time delays between drug administration. Both are attempts to compensate for the observational design, as is their argument for biologic plausibility. Here they’re on particularly thin ice when trying to prove causal inference. Biologic plausibility is never hard to find; after all, what compound doesn’t have pleiotropic effects? Furthermore, the analysis lacks any data to support their biologic plausibility hypothesis that fludrocortisone’s effect on mortality is mediated via activation of innate immunity and/or clearance of alveolar fluid.

The editorial accompanying this Big Data study endorsed adding fludrocortisone. We have very little that reduces ICU mortality so the low number needed to treat is enticing, especially in light of the low risk from adverse events, so I’m going to start using it. Do I think I’ll save one life for every 28 patients with septic shock to whom I give hydro/fludro instead of hydrocortisone alone? I sure don’t. No way an oral mineralocorticoid at that dose has that type of impact on top of hydrocortisone alone. I still believe that the Annane studies are positive because of the mortality rate in the population enrolled and not because fludrocortisone was added. It all comes full circle, though – 20 years after I abandoned hydro/fludro, I’m going back to it.

Aaron B. Holley, MD, is a professor of medicine at Uniformed Services University in Bethesda, Md., and a pulmonary/critical care and sleep medicine physician at MedStar Washington Hospital Center in Washington, D.C.

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

My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...

What is going on?

The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.

It’s pretty obvious that if the population and the health care systems of the United States were seriously interested in saving lives, they would strive diligently to control blood pressure, prevent obesity and diabetes, and eliminate combustible tobacco use.

We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.

All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.

That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?

At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.

A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.

PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.

At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.

These factors summarize why it works:

• Senior management belief, commitment, and leadership
• Informed buy-in from clinicians and patients
• A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
• An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
• Persistent clinician-patient follow-up
• Refusal to accept failure

Since this approach is so successful, why is its use not everywhere?

It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.

Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.

I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.

Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.

Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.

Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.

For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?

Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.

Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.

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

My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...

What is going on?

The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.

It’s pretty obvious that if the population and the health care systems of the United States were seriously interested in saving lives, they would strive diligently to control blood pressure, prevent obesity and diabetes, and eliminate combustible tobacco use.

We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.

All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.

That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?

At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.

A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.

PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.

At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.

These factors summarize why it works:

• Senior management belief, commitment, and leadership
• Informed buy-in from clinicians and patients
• A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
• An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
• Persistent clinician-patient follow-up
• Refusal to accept failure

Since this approach is so successful, why is its use not everywhere?

It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.

Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.

I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.

Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.

Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.

Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.

For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?

Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.

Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.

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

My Bing AI engine, when prompted, tells me that there are about 87 journals, 45 conferences, and 53 workshops presently dedicated exclusively to hypertension. All of that attention, and yet ...

What is going on?

The top killers of Americans remain coronary artery heart disease (26%), cancer (22%), and stroke (6%). The precursors and attributable risk factors for coronary artery heart disease include hypertension (40%), obesity (20%), diabetes (15%), and combustible tobacco use (15%). The key precursors and attributable risk factors for stroke are hypertension (53%), obesity (37%), diabetes (9%), and combustible tobacco use (11%). Obviously, these are estimates, with substantial overlap.

It’s pretty obvious that if the population and the health care systems of the United States were seriously interested in saving lives, they would strive diligently to control blood pressure, prevent obesity and diabetes, and eliminate combustible tobacco use.

We have addressed improving tobacco control and preventing obesity and diabetes on these pages many times, and lamented the medical, public health, and societal failings. Today we turn our attention to the control of hypertension. That is much easier and far less expensive.

All physicians and medical organizations know that hypertension is a major attributable cause of many serious, expensive, and fatal illnesses. As many as 119 million (48%) of American adults have hypertension. The American Heart Association (AHA), American Medical Association (AMA), American College of Cardiology (ACC), and hundreds of other organizations have set a new target of 130/80 (revised from 140/90) for blood pressure control and have launched a major initiative, Target: BP, to reach it.

That is just great. We all wish this massive effort to succeed where few others have. But do AHA, AMA, ACC, and others understand why most efforts to this point have failed? The blame is typically aimed at patients failing to adhere to their instructions. Maybe, but why? And how does Target: BP intend to convert chronic failure into success if it just continues to do everything they have been trying to do that doesn’t work?

At this point, the Centers for Disease Control and Prevention reports that fewer than 48% of American patients with hypertension meet even the less stringent historical 140/90 goal.

A group practice in Ohio, PriMed Physicians, has consistently exceeded 90% or even 95% blood pressure control for its patients with hypertension for more than 10 years. Exemplary. How do they do it? This video of the 13th annual Lundberg Institute lecture describes this unique and successful program.

PriMed’s clinicians use the MedsEngine AI tool from MediSync and the NICaS (noninvasive cardiac system with impedance cardiography) to determine each patient’s unique blood pressure pathophysiology. Clinicians and patients understand that the simplest explanation of this pathophysiology encompasses three factors: (1) the volume of “water” (blood) in the system; (2) the strength of the pumping (pulsatile) process; and (3) the tightness (resistance) of the tubes that carry the blood. Patients “get it” when it is explained this way, and they cooperate.

At the first patient encounter, the Food and Drug Administration–approved PhysioFlow is employed to assess those three vital hemodynamic factors. The individual patient’s data are loaded into a tightly programed EHR-based algorithm with 37 clinical factors and five classes of drugs, providing multiple ways to influence the three key pathophysiologic processes. In this way, they arrive at the precise drug(s) and dosages for that patient. During the second visit, most patients are already showing improvement. By the third visit, the blood pressures of most patients have reached target control. After that, it is maintenance and tweaking.

These factors summarize why it works:

• Senior management belief, commitment, and leadership
• Informed buy-in from clinicians and patients
• A test that determines root causes of too much fluid, too strong pump action, or too tight pipes, and their proportionality
• An AI tool that matches those three pathophysiologic factors and 35 other clinical factors with the best drug or drugs (of many, not just a few) and dosages
• Persistent clinician-patient follow-up
• Refusal to accept failure

Since this approach is so successful, why is its use not everywhere?

It is not as if nobody noticed, even if you and many organizations have not. The American Medical Group Association recognized the program’s success by giving its top award to PriMed in 2015.

Klepper and Rodis wrote about this approach for managing multiple chronic conditions in 2021. Here’s a background article and an explainer, Clinical use of impedance cardiography for hemodynamic assessment of early cardiovascular disease and management of hypertension.

I found one pragmatic controlled clinical trial of impedance cardiography with a decision-support system from Beijing that did demonstrate clinical and statistical significance.

Frankly, we do need more rigorous, unbiased, large, controlled clinical trials assessing the MedsEngine and NICaS approach to managing blood pressure to facilitate a massive switch from the old and established (but failing) approach to a starkly better way.

Almost no one ever “completes a database.” All decision makers must act based upon the best data to which they have access. Data are often incomplete. The difference between success and mediocrity is often the ability of an individual or system to decide when enough information is enough and act accordingly.

Cost-effectiveness studies in three countries (United Kingdom, United States, and China) confirm sharply lower lifelong costs when blood pressure is well controlled. Of course.

For the American medical-industrial complex, lowered costs for managing common serious diseases may be an undesired rather than a good thing. In money-driven medicine, lower costs to the payer and purchaser translate to less revenue for the providers. Imagine all of those invasive and noninvasive diagnostic and therapeutic procedures forgone by prevention of hypertension. Is it possible that such an underlying truth is the real reason why American medicine is habitually unsuccessful at controlling blood pressure?

Right now, if my blood pressure were not well controlled (it is), I would find my way to Cincinnati, to give PriMed physicians, MediSync, and MedsEngine a crack at prolonging my useful life.

Dr. Lundberg is editor in chief of Cancer Commons. He disclosed no relevant conflicts of interest.

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

PHILADELPHIA – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.

“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”

The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.

Lipid nanoparticle

VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.

“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.

Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.

They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.

Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.

Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”

Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
 

Safety outcomes

Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.

He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”

The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
 

First, do no harm

Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.

“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”

She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”

Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”

Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.

PHILADELPHIA – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.

“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”

The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.

Lipid nanoparticle

VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.

“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.

Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.

They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.

Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.

Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”

Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
 

Safety outcomes

Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.

He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”

The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
 

First, do no harm

Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.

“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”

She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”

Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”

Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.

PHILADELPHIA – The first in-human study of a gene therapy designed to reduce low-density lipoprotein cholesterol has shown a signal that the treatment works in a small group of patients with heterozygous familial hypercholesterolemia (HeFH).

While one of four patients in the highest-dose groups had a myocardial infarction the day after getting the treatment, investigators have enough confidence to go forward with the next phase of study.

“The HEART-1trial demonstrated the first human proof of concept for in vivo DNA-based editing,” said Andrew Bellinger, MD, PhD, chief scientific officer of Verve Therapeutics, the company developing the treatment. “We saw dose-dependent–based reductions in LDL and the PCSK9 protein.”

The HEART-1 study was a phase 1b trial of VERVE-101, a CRISPR-based gene editing mechanism designed to inactivate the liver gene PCSK9, which contributes to raising cholesterol. “Human genetics suggest that turning off the cholesterol-raising gene PCSK9 in the liver will durably reduce LDL cholesterol,” Dr. Bellinger said in presenting the results at the annual scientific sessions of the American Heart Association.

Lipid nanoparticle

VERVE-101 is designed to be a single-course treatment to specifically treat HeFH, Dr. Bellinger said. He explained how the therapy, given by intravenous infusion, differs from adeno-associated virus vectors that have dominated gene therapy platforms.

“It’s a lipid nanoparticle encapsulating two RNA nanoparticles that are taken up by hepatocytes in the liver from the blood by the LDL receptor,” he explained. “Then the A-to-G–based editor protein and the guide mRNA protein together find the PCSK9 gene in the liver.” That single DNA-base change in one position of the PCSK9 gene is able to turn off PCSK9 production in those liver cells.

Dr. Bellinger presented interim results of the first 10 patients treated in the open-label, single ascending dose study. The patients were male and female, ages 18-75, with HeFH, established atherosclerotic cardiovascular disease and uncontrolled hypercholesterolemia despite being on maximally tolerated lipid-lowering therapy.

They received four different doses: Three patients each received 0.1, 0.3, and 0.45 mg/kg; and one patient received 0.6 mg/kg.

Reductions in blood PCSK9 levels were measured across all dosing groups at 4 weeks, but they were most pronounced in the two highest groups, Dr. Bellinger said. Two patients in the 0.45-mg/kg group had reductions of 59% and 84%. The sole patient in the 0.6-mg/kg arm had a reduction of 47%.

Regarding the 84% reduction in one individual, Dr. Bellinger said, “Roughly 85% of PCSK9 comes from the liver. These data suggest that we have successfully made a single base pair change in both copies of the PCSK9 gene in nearly every hepatocyte in the liver of this individual.”

Those benefits carried over to LDL cholesterol measures, with the highest-dose patients registering 39%, 48% and 55% reductions.
 

Safety outcomes

Two patients had serious cardiovascular (CV) events. One in the 0.3-mg/kg arm died from cardiac arrest 5 weeks after receiving the infusion. A patient in the 0.45-mg/kg arm had a myocardial infarction a day after getting the infusion and then nonsustained ventricular tachycardia (NSVT) 4 weeks later. Dr. Bellinger said an independent review panel determined that the CV events were in line with outcomes for high-risk patients and weren’t directly related to treatment.

He added, “Increased liver transaminases were seen in patients treated in the higher-dose cohorts. It’s transient, asymptomatic, and it resolved quickly.”

The next step involves pursuing only the 0.45- and 0.6-mg/kg doses in the next dose-escalation phase and enrolling an expansion cohort in 2024, Dr. Bellinger said, with a plan to initiate a randomized, placebo-controlled phase 2 trial in 2025.
 

First, do no harm

Karol Watson, MD, PhD, a women’s cardiovascular disease specialist at UCLA, said the promise of gene therapy was “revolutionary,” but that proving safety was critical going forward.

“You’re changing the genome forever,” she said. “Safety is going to be of the utmost importance especially because there are currently safe and efficacious strategies available for lipid lowering. This is a strategy that could be revolutionary, but we have to make sure that it’s safe.”

She pointed to a multinational study from earlier this year that warned about pathogenic consequences from CRISPR-based gene editing. “There are concerns about gene editing,” Dr. Watson said. “This was a whole-genome analysis showing atypical nonhomologous on-target effects of genome editing. Of course this is a very different strategy from what we heard today, but, again, we have to know that this is safe.”

Despite the small sample size from the two highest-dose groups in the study, Dr. Watson said the investigators have reason for going forward. “I think the preclinical data supports moving forward, but the next studies will have to be scrutinized carefully,” she said. “This is a preventive therapy; the first tenet is to do no harm.”

Dr. Bellinger is an employee of Verve Therapeutics, which sponsored the trial. Dr. Watson disclosed relationships with Boehringer-Ingelheim, Amgen, Lilly and Novartis.