Hypertension

Taking midodrine can reduce vasovagal syncope in younger healthy patients, according to a new study.

Vasovagal syncope is the most common cause of fainting and is often triggered by dehydration and upright posture, according to Johns Hopkins Medicine. But it can also be caused by stimuli like the sight of blood or sudden emotional distress. The stimulus causes the heart rate and blood pressure to drop rapidly, according to the Mayo Clinic.

The randomized, placebo-controlled, double-blind trial included 133 patients with recurrent vasovagal syncope and was published in Annals of Internal Medicine. Those that received midodrine were less likely to have one syncope episode (28 of 66 [42%]), compared with those that took the placebo (41 of 67 [61%]). The absolute risk reduction for vasovagal syncope was 19 percentage points (95% confidence interval, 2-36 percentage points).

The study included patients from 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom, who were followed for 12 months. The trial participants were highly symptomatic for vasovagal syncope, having experienced a median of 23 episodes in their lifetime and 5 syncope episodes in the last year, and they had no comorbid conditions.

“We don’t have many arrows in our quiver,” said Robert Sheldon, MD, PhD, a cardiologist at University of Calgary (Alta.) and lead author of the study, referring to the lack of evidence-based treatments for syncope.

For 20 years Dr. Sheldon’s lab has been testing drugs that showed some potential. While a previous study of fludrocortisone (Florinef ) showed some benefit, “[midodrine] was the first to be unequivocally, slam-dunk positive,” he said in an interview.

Earlier trials of midodrine

Other studies have shown midodrine to prevent syncope on tilt tests. There have been two randomized trials where midodrine significantly reduced vasovagal syncope, but one of these was short and in children, and the other one was open label with no placebo control.

“Risk reduction was very high in previous studies,” Dr. Sheldon said in an interview. But, because they were open label, there was a huge placebo effect, he noted.

“There were no adequately done, adequately powered [studies] that have been positive,” Dr. Sheldon added.

New study methods and outcomes

The study published in Annals of Internal Medicine this week included patients over 18 years of age with a Calgary Syncope Symptom Score of at least 2. All were educated on lifestyle measures that can prevent syncopes before beginning to take 5 mg of study drug or placebo three times daily, 4 hours apart.

In these cases, the study authors wrote, “taking medication three times a day seems worth the effort.” But in patients with a lower frequency of episodes, midodrine might not have an adequate payoff.

These results are “impressive,” said Roopinder K. Sandhu, MD, MPH, clinical electrophysiologist at Cedar-Sinai in Los Angeles. “This study demonstrated that midodrine is the first medical therapy, in addition to education and lifestyle measures, to unequivocally pass the scrutiny of an international, placebo-controlled, RCT to show a significant reduction in syncope recurrence in a younger population with frequent syncope events.”

“[Taking midodrine] doesn’t carry the long-term consequence of pacemakers,” she added.

Study limitations

Limitations of the new study include its small size and short observation period, the authors wrote. Additionally, a large proportion of patients enrolled were also from a single center in Calgary that specializes in syncope care. Twenty-seven patients in the trial stopped taking their assigned medication during the year observation period, but the authors concluded these participants “likely would bias the results against midodrine.”

For doctors considering midodrine for their patients, it’s critical to confirm the diagnosis and to try patient education first, Dr. Sheldon advised.

Lifestyle factors like hydration, adequate sodium intake, and squatting or lying down when the syncope is coming on can sufficiently suppress syncopes in two-thirds of patients, he noted.

This is a treatment for young people, Dr. Sandhu said. The median age in the trial was 35, so patients taking midodrine should be younger than 50. Midodrine is also not effective in patients with high blood pressure or heart failure, she said.

“[Midodrine] is easy to use but kind of a pain at first,” Dr. Sheldon noted. Every patient should start out taking 5 mg doses, three times a day – during waking hours. But then you have to adjust the dosage, “and it’s tricky,” he said.

If a patient experiences goosebumps or the sensation of worms crawling in the hair, the dose might be too much, Dr. Sheldon noted.

If the patient is still fainting, first consider when they are fainting, he said. If it’s around the time they should take another dose, it might be trough effect.

Dr. Sandhu was not involved in the study, but Cedar Sinai was a participating center, and she considers Dr. Sheldon to be a mentor. Dr. Sandhu also noted that she has published papers with Dr. Sheldon, who reported no conflicts.

Taking midodrine can reduce vasovagal syncope in younger healthy patients, according to a new study.

Vasovagal syncope is the most common cause of fainting and is often triggered by dehydration and upright posture, according to Johns Hopkins Medicine. But it can also be caused by stimuli like the sight of blood or sudden emotional distress. The stimulus causes the heart rate and blood pressure to drop rapidly, according to the Mayo Clinic.

The randomized, placebo-controlled, double-blind trial included 133 patients with recurrent vasovagal syncope and was published in Annals of Internal Medicine. Those that received midodrine were less likely to have one syncope episode (28 of 66 [42%]), compared with those that took the placebo (41 of 67 [61%]). The absolute risk reduction for vasovagal syncope was 19 percentage points (95% confidence interval, 2-36 percentage points).

The study included patients from 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom, who were followed for 12 months. The trial participants were highly symptomatic for vasovagal syncope, having experienced a median of 23 episodes in their lifetime and 5 syncope episodes in the last year, and they had no comorbid conditions.

“We don’t have many arrows in our quiver,” said Robert Sheldon, MD, PhD, a cardiologist at University of Calgary (Alta.) and lead author of the study, referring to the lack of evidence-based treatments for syncope.

For 20 years Dr. Sheldon’s lab has been testing drugs that showed some potential. While a previous study of fludrocortisone (Florinef ) showed some benefit, “[midodrine] was the first to be unequivocally, slam-dunk positive,” he said in an interview.

Earlier trials of midodrine

Other studies have shown midodrine to prevent syncope on tilt tests. There have been two randomized trials where midodrine significantly reduced vasovagal syncope, but one of these was short and in children, and the other one was open label with no placebo control.

“Risk reduction was very high in previous studies,” Dr. Sheldon said in an interview. But, because they were open label, there was a huge placebo effect, he noted.

“There were no adequately done, adequately powered [studies] that have been positive,” Dr. Sheldon added.

New study methods and outcomes

The study published in Annals of Internal Medicine this week included patients over 18 years of age with a Calgary Syncope Symptom Score of at least 2. All were educated on lifestyle measures that can prevent syncopes before beginning to take 5 mg of study drug or placebo three times daily, 4 hours apart.

In these cases, the study authors wrote, “taking medication three times a day seems worth the effort.” But in patients with a lower frequency of episodes, midodrine might not have an adequate payoff.

These results are “impressive,” said Roopinder K. Sandhu, MD, MPH, clinical electrophysiologist at Cedar-Sinai in Los Angeles. “This study demonstrated that midodrine is the first medical therapy, in addition to education and lifestyle measures, to unequivocally pass the scrutiny of an international, placebo-controlled, RCT to show a significant reduction in syncope recurrence in a younger population with frequent syncope events.”

“[Taking midodrine] doesn’t carry the long-term consequence of pacemakers,” she added.

Study limitations

Limitations of the new study include its small size and short observation period, the authors wrote. Additionally, a large proportion of patients enrolled were also from a single center in Calgary that specializes in syncope care. Twenty-seven patients in the trial stopped taking their assigned medication during the year observation period, but the authors concluded these participants “likely would bias the results against midodrine.”

For doctors considering midodrine for their patients, it’s critical to confirm the diagnosis and to try patient education first, Dr. Sheldon advised.

Lifestyle factors like hydration, adequate sodium intake, and squatting or lying down when the syncope is coming on can sufficiently suppress syncopes in two-thirds of patients, he noted.

This is a treatment for young people, Dr. Sandhu said. The median age in the trial was 35, so patients taking midodrine should be younger than 50. Midodrine is also not effective in patients with high blood pressure or heart failure, she said.

“[Midodrine] is easy to use but kind of a pain at first,” Dr. Sheldon noted. Every patient should start out taking 5 mg doses, three times a day – during waking hours. But then you have to adjust the dosage, “and it’s tricky,” he said.

If a patient experiences goosebumps or the sensation of worms crawling in the hair, the dose might be too much, Dr. Sheldon noted.

If the patient is still fainting, first consider when they are fainting, he said. If it’s around the time they should take another dose, it might be trough effect.

Dr. Sandhu was not involved in the study, but Cedar Sinai was a participating center, and she considers Dr. Sheldon to be a mentor. Dr. Sandhu also noted that she has published papers with Dr. Sheldon, who reported no conflicts.

Taking midodrine can reduce vasovagal syncope in younger healthy patients, according to a new study.

Vasovagal syncope is the most common cause of fainting and is often triggered by dehydration and upright posture, according to Johns Hopkins Medicine. But it can also be caused by stimuli like the sight of blood or sudden emotional distress. The stimulus causes the heart rate and blood pressure to drop rapidly, according to the Mayo Clinic.

The randomized, placebo-controlled, double-blind trial included 133 patients with recurrent vasovagal syncope and was published in Annals of Internal Medicine. Those that received midodrine were less likely to have one syncope episode (28 of 66 [42%]), compared with those that took the placebo (41 of 67 [61%]). The absolute risk reduction for vasovagal syncope was 19 percentage points (95% confidence interval, 2-36 percentage points).

The study included patients from 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom, who were followed for 12 months. The trial participants were highly symptomatic for vasovagal syncope, having experienced a median of 23 episodes in their lifetime and 5 syncope episodes in the last year, and they had no comorbid conditions.

“We don’t have many arrows in our quiver,” said Robert Sheldon, MD, PhD, a cardiologist at University of Calgary (Alta.) and lead author of the study, referring to the lack of evidence-based treatments for syncope.

For 20 years Dr. Sheldon’s lab has been testing drugs that showed some potential. While a previous study of fludrocortisone (Florinef ) showed some benefit, “[midodrine] was the first to be unequivocally, slam-dunk positive,” he said in an interview.

Earlier trials of midodrine

Other studies have shown midodrine to prevent syncope on tilt tests. There have been two randomized trials where midodrine significantly reduced vasovagal syncope, but one of these was short and in children, and the other one was open label with no placebo control.

“Risk reduction was very high in previous studies,” Dr. Sheldon said in an interview. But, because they were open label, there was a huge placebo effect, he noted.

“There were no adequately done, adequately powered [studies] that have been positive,” Dr. Sheldon added.

New study methods and outcomes

The study published in Annals of Internal Medicine this week included patients over 18 years of age with a Calgary Syncope Symptom Score of at least 2. All were educated on lifestyle measures that can prevent syncopes before beginning to take 5 mg of study drug or placebo three times daily, 4 hours apart.

In these cases, the study authors wrote, “taking medication three times a day seems worth the effort.” But in patients with a lower frequency of episodes, midodrine might not have an adequate payoff.

These results are “impressive,” said Roopinder K. Sandhu, MD, MPH, clinical electrophysiologist at Cedar-Sinai in Los Angeles. “This study demonstrated that midodrine is the first medical therapy, in addition to education and lifestyle measures, to unequivocally pass the scrutiny of an international, placebo-controlled, RCT to show a significant reduction in syncope recurrence in a younger population with frequent syncope events.”

“[Taking midodrine] doesn’t carry the long-term consequence of pacemakers,” she added.

Study limitations

Limitations of the new study include its small size and short observation period, the authors wrote. Additionally, a large proportion of patients enrolled were also from a single center in Calgary that specializes in syncope care. Twenty-seven patients in the trial stopped taking their assigned medication during the year observation period, but the authors concluded these participants “likely would bias the results against midodrine.”

For doctors considering midodrine for their patients, it’s critical to confirm the diagnosis and to try patient education first, Dr. Sheldon advised.

Lifestyle factors like hydration, adequate sodium intake, and squatting or lying down when the syncope is coming on can sufficiently suppress syncopes in two-thirds of patients, he noted.

This is a treatment for young people, Dr. Sandhu said. The median age in the trial was 35, so patients taking midodrine should be younger than 50. Midodrine is also not effective in patients with high blood pressure or heart failure, she said.

“[Midodrine] is easy to use but kind of a pain at first,” Dr. Sheldon noted. Every patient should start out taking 5 mg doses, three times a day – during waking hours. But then you have to adjust the dosage, “and it’s tricky,” he said.

If a patient experiences goosebumps or the sensation of worms crawling in the hair, the dose might be too much, Dr. Sheldon noted.

If the patient is still fainting, first consider when they are fainting, he said. If it’s around the time they should take another dose, it might be trough effect.

Dr. Sandhu was not involved in the study, but Cedar Sinai was a participating center, and she considers Dr. Sheldon to be a mentor. Dr. Sandhu also noted that she has published papers with Dr. Sheldon, who reported no conflicts.

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

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

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

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

Today there are so many evidence-based drug therapies for heart failure with reduced ejection fraction (HFrEF) that physicians treating HF patients almost don’t know what to do them.

It’s an exciting new age that way, but to many vexingly unclear how best to merge the shiny new options with mainstay regimens based on time-honored renin-angiotensin system (RAS) inhibitors and beta-blockers.

To impart some clarity, the authors of a new HF guideline document recently took center stage at the Heart Failure Association of the European Society of Cardiology (ESC-HFA) annual meeting to preview their updated recommendations, with novel twists based on recent major trials, for the new age of HF pharmacotherapeutics.

The guideline committee considered the evidence base that existed “up until the end of March of this year,” Theresa A. McDonagh, MD, King’s College London, said during the presentation. The document “is now finalized, it’s with the publishers, and it will be presented in full with simultaneous publication at the ESC meeting” that starts August 27.

It describes a game plan, already followed by some clinicians in practice without official guidance, for initiating drugs from each of four classes in virtually all patients with HFrEF.
 

New indicated drugs, new perspective for HFrEF

Three of the drug categories are old acquaintances. Among them are the RAS inhibitors, which include angiotensin-receptor/neprilysin inhibitors, beta-blockers, and the mineralocorticoid receptor antagonists. The latter drugs are gaining new respect after having been underplayed in HF prescribing despite longstanding evidence of efficacy.

Completing the quartet of first-line HFrEF drug classes is a recent arrival to the HF arena, the sodium-glucose cotransporter 2 inhibitors.

“We now have new data and a simplified treatment algorithm for heart failure with reduced ejection fraction based on the early administration of the four major classes of drugs,” said Marco Metra, MD, University of Brescia (Italy), previewing the medical-therapy portions of the new guideline at the ESC-HFA sessions, which launched virtually and live in Florence, Italy, on July 29.

The new game plan offers a simple answer to a once-common but complex question: How and in what order are the different drug classes initiated in patients with HFrEF? In the new document, the stated goal is to get them all on board expeditiously and safely, by any means possible.

The guideline writers did not specify a sequence, preferring to leave that decision to physicians, said Dr. Metra, who stated only two guiding principles. The first is to consider the patient’s unique circumstances. The order in which the drugs are introduced might vary, depending on, for example, whether the patient has low or high blood pressure or renal dysfunction.

Second, “it is very important that we try to give all four classes of drugs to the patient in the shortest time possible, because this saves lives,” he said.

That there is no recommendation on sequencing the drugs has led some to the wrong interpretation that all should be started at once, observed coauthor Javed Butler, MD, MPH, University of Mississippi, Jackson, as a panelist during the presentation. Far from it, he said. “The doctor with the patient in front of you can make the best decision. The idea here is to get all the therapies on as soon as possible, as safely as possible.”

“The order in which they are introduced is not really important,” agreed Vijay Chopra, MD, Max Super Specialty Hospital Saket, New Delhi, another coauthor on the panel. “The important thing is that at least some dose of all the four drugs needs to be introduced in the first 4-6 weeks, and then up-titrated.”

Other medical therapy can be more tailored, Dr. Metra noted, such as loop diuretics for patients with congestion, iron for those with iron deficiency, and other drugs depending on whether there is, for example, atrial fibrillation or coronary disease.
 

Adoption of emerging definitions

The document adopts the emerging characterization of HFrEF by a left ventricular ejection fraction (LVEF) up to 40%.

And it will leverage an expanding evidence base for medication in a segment of patients once said to have HF with preserved ejection fraction (HFpEF), who had therefore lacked specific, guideline-directed medical therapies. Now, patients with an LVEF of 41%-49% will be said to have HF with mildly reduced ejection fraction (HFmrEF), a tweak to the recently introduced HF with “mid-range” LVEF that is designed to assert its nature as something to treat. The new document’s HFmrEF recommendations come with various class and level-of-evidence ratings.

That leaves HFpEF to be characterized by an LVEF of 50% in combination with structural or functional abnormalities associated with LV diastolic dysfunction or raised LV filling pressures, including raised natriuretic peptide levels.

The definitions are consistent with those proposed internationally by the ESC-HFA, the Heart Failure Society of America, and other groups in a statement published in March.
 

Expanded HFrEF med landscape

Since the 2016 ESC guideline on HF therapy, Dr. McDonagh said, “there’s been no substantial change in the evidence for many of the classical drugs that we use in heart failure. However, we had a lot of new and exciting evidence to consider,” especially in support of the SGLT2 inhibitors as one of the core medications in HFrEF.

The new data came from two controlled trials in particular. In DAPA-HF, patients with HFrEF who were initially without diabetes and who went on dapagliflozin (Farxiga, AstraZeneca) showed a 27% drop in cardiovascular (CV) death or worsening-HF events over a median of 18 months.

“That was followed up with very concordant results with empagliflozin [Jardiance, Boehringer Ingelheim/Eli Lilly] in HFrEF in the EMPEROR-Reduced trial,” Dr. McDonagh said. In that trial, comparable patients who took empagliflozin showed a 25% drop in a primary endpoint similar to that in DAPA-HF over the median 16-month follow-up.

Other HFrEF recommendations are for selected patients. They include ivabradine, already in the guidelines, for patients in sinus rhythm with an elevated resting heart rate who can’t take beta-blockers for whatever reason. But, Dr. McDonagh noted, “we had some new classes of drugs to consider as well.”

In particular, the oral soluble guanylate-cyclase receptor stimulator vericiguat (Verquvo) emerged about a year ago from the VICTORIA trial as a modest success for patients with HFrEF and a previous HF hospitalization. In the trial with more than 5,000 patients, treatment with vericiguat atop standard drug and device therapy was followed by a significant 10% drop in risk for CV death or HF hospitalization.

Available now or likely to be available in the United States, the European Union, Japan, and other countries, vericiguat is recommended in the new guideline for VICTORIA-like patients who don’t adequately respond to other indicated medications.
 

Little for HFpEF as newly defined

“Almost nothing is new” in the guidelines for HFpEF, Dr. Metra said. The document recommends screening for and treatment of any underlying disorder and comorbidities, plus diuretics for any congestion. “That’s what we have to date.”

But that evidence base might soon change. The new HFpEF recommendations could possibly be up-staged at the ESC sessions by the August 27 scheduled presentation of EMPEROR-Preserved, a randomized test of empagliflozin in HFpEF and – it could be said – HFmrEF. The trial entered patients with chronic HF and an LVEF greater than 40%.

Eli Lilly and Boehringer Ingelheim offered the world a peek at the results, which suggest the SGLT2 inhibitor had a positive impact on the primary endpoint of CV death or HF hospitalization. They announced the cursory top-line outcomes in early July as part of its regulatory obligations, noting that the trial had “met” its primary endpoint.

But many unknowns remain, including the degree of benefit and whether it varied among subgroups, and especially whether outcomes were different for HFmrEF than for HFpEF.
 

Upgrades for familiar agents

Still, HFmrEF gets noteworthy attention in the document. “For the first time, we have recommendations for these patients,” Dr. Metra said. “We already knew that diuretics are indicated for the treatment of congestion. But now, ACE inhibitors, ARBs, beta-blockers, mineralocorticoid antagonists, as well as sacubitril/valsartan, may be considered to improve outcomes in these patients.” Their upgrades in the new guidelines were based on review of trials in the CHARM program and of TOPCAT and PARAGON-HF, among others, he said.

The new document also includes “treatment algorithms based on phenotypes”; that is, comorbidities and less common HF precipitants. For example, “assessment of iron status is now mandated in all patients with heart failure,” Dr. Metra said.

AFFIRM-HF is the key trial in this arena, with its more than 1,100 iron-deficient patients with LVEF less than 50% who had been recently hospitalized for HF. A year of treatment with ferric carboxymaltose (Ferinject/Injectafer, Vifor) led to a 26% drop in risk for HF hospitalization, but without affecting mortality.

For those who are iron deficient, Dr. Metra said, “ferric carboxymaltose intravenously should be considered not only in patients with low ejection fraction and outpatients, but also in patients recently hospitalized for acute heart failure.”

The SGLT2 inhibitors are recommended in HFrEF patients with type 2 diabetes. And treatment with tafamidis (Vyndaqel, Pfizer) in patients with genetic or wild-type transthyretin cardiac amyloidosis gets a class I recommendation based on survival gains seen in the ATTR-ACT trial.

Also recommended is a full CV assessment for patients with cancer who are on cardiotoxic agents or otherwise might be at risk for chemotherapy cardiotoxicity. “Beta-blockers and ACE inhibitors should be considered in those who develop left ventricular systolic dysfunction after anticancer therapy,” Dr. Metra said.

The ongoing pandemic made its mark on the document’s genesis, as it has with most everything else. “For better or worse, we were a ‘COVID guideline,’ ” Dr. McDonagh said. The writing committee consisted of “a large task force of 31 individuals, including two patients,” and there were “only two face-to-face meetings prior to the first wave of COVID hitting Europe.”

The committee voted on each of the recommendations, “and we had to have agreement of more than 75% of the task force to assign a class of recommendation or level of evidence,” she said. “I think we did the best we could in the circumstances. We had the benefit of many discussions over Zoom, and I think at the end of the day we have achieved a consensus.”

With such a large body of participants and the 75% threshold for agreement, “you end up with perhaps a conservative guideline. But that’s not a bad thing for clinical practice, for guidelines to be conservative,” Dr. McDonagh said. “They’re mainly concerned with looking at evidence and safety.”

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

In the largest comparison of angiotensin receptor blockers (ARBs) and ACE inhibitors to date, a study of nearly 2.3 million patients starting the drugs as monotherapy shows no significant differences between the two in the long-term prevention of hypertension-related cardiovascular events.

However, side effects were notably lower with ARBs.

“This is a very large, well-executed observational study that confirms that ARBs appear to have fewer side effects than ACE inhibitors, and no unexpected ARB side effects were detected,” senior author George Hripcsak, MD, professor and chair of biomedical informatics at Columbia University, New York, told this news organization.

“Despite being equally guideline-recommended first-line therapies for hypertension, these results support preferentially starting ARBs rather than ACE inhibitors when initiating treatment for hypertension for physicians and patients considering renin-angiotensin system (RAS) inhibition,” the authors added in the study, published online July 26, 2021, in the journal Hypertension.

They noted that both drug classes have been on the market a long time, with proven efficacy in hypertension and “a wide availability of inexpensive generic forms.”

They also stressed that their findings only apply to patients with hypertension for whom a RAS inhibitor would be the best choice of therapy.

Commenting on the research, George Bakris, MD, of the American Heart Association’s Comprehensive Hypertension Center at the University of Chicago, said the findings were consistent with his experience in prescribing as well as researching the two drug classes.

“I have been in practice for over 30 years and studied both classes, including head-to-head prospective trials to assess blood pressure, and found in many cases better blood pressure lowering by some ARBs and always better tolerability,” he told this news organization. “I think this study confirms and extends my thoughts between the two classes of blood pressure–lowering agents.”
 

Head-to-head comparisons of ACE inhibitors and ARBs limited to date

ACE inhibitors and ARBs each have extensive evidence supporting their roles as first-line medications in the treatment of hypertension, and each have the strongest recommendations in international guidelines.

However, ACE inhibitors are prescribed more commonly than ARBs as the first-line drug for lowering blood pressure, and head-to-head comparisons of the two are limited, with conflicting results.

For the study, Dr. Hripcsak and colleagues evaluated data on almost 3 million patients starting monotherapy with an ACE inhibitor or ARB for the first time between 1996 and 2018 in the United States, Germany, and South Korea, who had no history of heart disease or stroke.

They identified a total of 2,297,881 patients initiating ACE inhibitors and 673,938 starting ARBs. Among new users of ACE inhibitors, most received lisinopril (80%), followed by ramipril and enalapril, while most patients prescribed ARBs received losartan (45%), followed by valsartan and olmesartan.

With follow-up times ranging from about 4 months to more than 18 months, the data show no statistically significant differences between ACE inhibitors versus ARBs in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11), heart failure (HR, 1.03), stroke (HR, 1.07), or composite cardiovascular events (HR, 1.06).

For secondary and safety outcomes, including an analysis of 51 possible side effects, ACE inhibitors, compared with ARBs, were associated with a significantly higher risk of angioedema (HR, 3.31; P < .01), cough (HR, 1.32; P < .01), acute pancreatitis (HR, 1.32; P = .02), gastrointestinal bleeding (HR, 1.18; P = .04), and abnormal weight loss (HR, 1.18; P = .04).

While the link between ACE inhibitors and pancreatitis has been previously reported, the association with GI bleeding may be a novel finding, with no prior studies comparing those effects in the two drug classes, the authors noted.

Despite most patients taking just a couple of drugs in either class, Dr. Hripcsak said, “we don’t expect that other drugs from those classes will have fewer differences. It is possible, of course, but that is not our expectation.”
 

Results only applicable to those starting therapy with RAS inhibitors

First author RuiJun Chen, MD, added that, importantly, the results may not apply to patients switching therapies or adding on therapy, “such as for the patient whose hypertension is not effectively controlled with one drug and requires the addition of a second medication,” he said in an interview.

“Also, the suggestion of preferentially prescribing ARBs only applies to those patients and providers intending to control blood pressure through RAS inhibition,” said Dr. Chen, an assistant professor in translational data science and informatics at Geisinger Medical Center in Danville, Pa., who was a National Library of Medicine postdoctoral fellow at Columbia University at the time of the study.

Hence, he stressed the results do not extend to other classes of recommended first-line blood pressure medications.

“Essentially, since this is an ACE inhibitor versus ARB study, we would not claim that ARBs are preferred over all other types of hypertension medications which were not studied here,” the researchers emphasize.

In addition to ARBs and ACE inhibitors, other medications recommended by the AHA/American College of Cardiology in the 2017 “Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults” for the primary treatment of hypertension include thiazide diuretics and calcium channel blockers.

The study received support from the National Library of Medicine and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health; the National Science Foundation; and the Ministries of Health & Welfare and of Trade, Industry & Energy of the Republic of Korea. Dr. Hripcsak reported receiving grants from the National Library of Medicine during the study and grants from Janssen Research outside the submitted work. Dr. Bakris reported being a consultant for Merck, KBP Biosciences, and Ionis.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

A study from Japan suggests that a history of cardiovascular events in a spouse may elevate risk for future CV events in the other partner, with one caveat: Men in the cohort study were at increased risk if their wives had such a history, but the association was only one way. The risk of events didn’t go up for women with husbands who had previously experienced a CV event.

byryo/iStock/Getty Images Plus

The results highlight the need for clinicians to screen and possibly intervene with a primary CV prevention strategy “not only first-degree relatives but also spouses with a history of cardiovascular disease,” which is not currently part of the primary prevention guidelines, Hiroyuki Ohbe, MD, University of Tokyo, told this news organization.

In their study published online July 9 in Circulation: Cardiovascular Quality and Outcomes, Dr. Ohbe and Hideo Yasunaga, MD, PhD, of the same institution, assessed the risk of subsequent CV events in adults with a spouse who had experienced a stroke of any kind or had clinical ischemic heart disease such as angina or myocardial infarction.

Johanna Contreras, MD, director of heart failure at Mount Sinai Health System in New York, is not surprised by the finding that a wife’s CV history is linked to the CV risk in the husband.

“I see this often in my practice. When you live with someone, you also behave in a similar way as the other person,” Dr. Contreras told this news organization. “For example, couples who live together are likely to both exercise and have a healthy diet and not smoke.”

And most notably, she said, “the women are usually the ones who drive the healthy behaviors in the family; they watch what the family eats, where they eat, when they eat, and the men tend to allow the women to guide this behavior.”

Dr. Ohbe and Dr. Yasunaga agree, proposing that different results for men and women in the analysis may be because of the dependence of working-aged men on their wives for major aspects of lifestyle, such as diet and exercise. Moreover, they write, increased psychological and physical stress from taking care of a spouse with CV disease may also play a role, as caregivers often neglect their own health.

The team identified 13,759 adults in a large administrative database with no history of CV disease whose spouse had such a history at their first health checkup; they were the exposure group. The team matched each of them with up to four individuals (n = 55,027) who had no CV disease history and spouses without CV disease at their first health checkup; they were the nonexposure group.

The mean observation period was 7.9 years from the first health checkup, at which the subjects’ mean age was 56 years. During the follow-up, more people in the exposure group than the nonexposure group had a history of CV events, 0.6% versus 0.4%.

In the overall cohort, the hazard ratio for future severe CV events – heart failure hospitalization or MI – in those with spouses with a history of CV disease was 1.48 (95% confidence interval, 1.15-1.90).

When stratified by sex, men whose wives had CV disease showed a significantly increased risk of a future severe CV event (HR, 1.68; 95% CI, 1.22-2.32). But women with husbands with CV disease did not (HR, 1.22; 95% CI, 0.82-1.83).

The results of all four sensitivity analyses were similar to those of the primary analysis, both in the overall cohort and in the cohorts stratified by sex. The investigators performed multivariate survival analyses: one that excluded people whose partners had died, one that included death by any cause as an outcome, and one with propensity score matching.

Further studies are needed to confirm their observations and test whether a primary prevention strategy targeted at married couples could reduce CV events, note Dr. Ohbe and Dr. Yasunaga.

The findings have implications for everyday clinical practice, Dr. Contreras said. “When I see a patient who is married and has had a heart attack, I will insist on seeing the partner as well, and I will counsel them on working together to change their lifestyle,” she said in an interview.

“Often when you have that discussion with the couple after one has a heart attack, they quit smoking together, they go the gym together, and they get healthier together,” she said. “That’s now a very important conversation we have before they leave the hospital.”

The study was supported by grants from the Japan Ministry of Health, Ministry of Labour and Welfare, and the Ministry of Education, Culture, Sports, Science and Technology. Dr. Ohbe, Dr. Yasunaga, and Dr. Contreras have disclosed no relevant financial relationships.

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

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

In type 2 diabetes (T2D), a greater degree of hyperlipidemia and hypertension, although not hyperglycemia, was associated with measurable cognitive impairment even among patients with only a 4-year mean disease duration, according to a substudy of the GRADE trial.

The association of these cardiovascular (CV) risk factors with impairments in cognition has been reported before, but the findings are notable because the mean duration of T2D was short in a relatively healthy study population, reported a multicenter team of investigators.

The relative impairments in cognitive function “may not be clinically significant given the very small size of the differences,” conceded the authors of this study, led by José A. Luchsinger, MD, but they are consistent with previous reports of the same association in older patients with a longer duration of diabetes. In other words, the data suggest the risk of cognitive loss from CV risk factors in T2D patients begins early.

“A potential explanation for the small differences, compared with those previously reported, is that the GRADE cohort is relatively young with a healthier cardiovascular profile and shorter diabetes duration compared with other studies,” reported the investigators, whose results were published online July 20, 2021, in Diabetes Care.
 

99% complete cognitive assessments

In the GRADE (Glycemia Reduction Approaches in Diabetes: Comparative Effectiveness) trial, 5,018 (99.4%) of the 5,047 enrolled patients completed a battery of cognitive assessments at baseline. Patients were excluded from this study if they had any major CV event in the previous year, if they had T2D for more than 10 years, if they had significant renal impairment, and if they had any history of stage 3 or greater heart failure. Their mean age was 56.7 years.

By cross-sectional analysis, cognitive evaluations, including the Digit Symbol Substitution Test (DSST) and the Spanish English Verbal Learning Test, were evaluated in relation to baseline LDL cholesterol levels, systolic and diastolic blood pressure, hemoglobin A1c, and statin use.

Unlike previous studies in T2D patients, no relationship was observed between cognitive function and A1c level at baseline. However, LDL cholesterol greater than 100 mg/dL was associated with cognitive impairment as measured with the DSST after adjustment for age, sex, education, and general health. The mean difference relative to LDL cholesterol below 70 mg/dL was only 1.8 points, but this was highly significant (P < .001).

Similarly, significant but modest cognitive impairment on DSST score after adjustment for variables were seen for those with a systolic BP between 120 mg and <140 mg relative to either <120 mm Hg or at least 140 mm Hg (P = .014). The same was seen for diastolic BPs of 80 to <90 when compared with either <80 mm Hg or to 90 mm Hg or higher (P = .01).

For those taking statins versus no statins at baseline, there was a 1.4-point mean advantage in DSST score after adjusting for variables (P < .001).

Modest cognitive impairments recorded

Again, the absolute mean differences in the DSST cognitive scores, despite their statistical significance, were modest, according to the authors. In general, the mean difference was rarely greater than 2.0 points and often 1.0 point or less. The authors acknowledged that these changes are of an uncertain clinical significance, but they considered the findings consistent with the association of CV risk factors with cognitive deficits in older T2DM patients or T2DM patients with longer duration of disease.

One difference between this GRADE substudy and previous studies was the lack of an association between cognitive impairment and hyperglycemia. In the ACCORD trial for example, increased levels of blood glycemia were associated with lower performance on numerous tests of cognitive function.

In the Diabetes Control and Complications Trial (DCCT), poorer glycemic control was related to poorer performance on tests of executive function.

Both of those studies also linked hypertension and hyperlipidemia with cognitive deficits, but given that patients in ACCORD had T2DM of substantially longer duration and those in DCCT were older, “it seems reasonable to speculate that, in patients with diabetes duration of less than 10 years, the association between hyperglycemia and cognitive performance may not yet be evident,” the GRADE authors reported.
 

GRADE trial compares drugs in four classes

The GRADE trial was conducted to compare four classes of T2D therapies for long-term glycemic control as expressed by A1c control over time. The results of the trial, presented recently at the 2021 annual scientific sessions of the American Diabetes Association, found that insulin glargine and the glucagonlike peptide–1 receptor agonist liraglutide performed best on the primary endpoint of maintaining A1c below 7.0%. Both performed significantly better than the sulfonylurea glimepiride and the dipeptidyl peptidase–4 inhibitor sitagliptin.

This substudy of baseline cognitive function in the relatively large GRADE trial provided a unique opportunity to evaluate the impact of CV risk factors in patients with T2D of relatively short duration.

While the data support the adverse impact of inadequately controlled modifiable risk factors on cognitive function in T2D patients, David R. Matthews, DPhil, BM, BCh, emeritus professor of diabetes medicine at the University of Oxford (England), noted that the association was weak and advised a cautious interpretation.

“The effect size is very small indeed. The data are found as a subset of multiple testing,” he said in an interview. He suggested the associations might be the result of “data farming,” and he emphasized that the relationships between these risk factors and cognitive deficits are associations that do not imply causation.

Nevertheless, and despite their unclear clinical implications, Dr. Matthews said that these data might still have a message.

“It is another reminder that for many reasons we all need to be alert to the need for lowering hyperlipidemia and hypertension to normal levels – the benefits may not just be limited to cardiovascular outcome,” Dr. Matthews stated.

The lead author of the study, Dr. Luchsinger, also cautioned against overinterpreting the data.

While the data show that “lipid and blood pressure control within recommended guidelines are associated with marginally better cognitive function in patients with type 2 diabetes of less than 5 years duration on average,” he added that “the study is limited by its cross-sectional nature.”

He indicated that further analysis will be helpful in assessing the implications.

“Longitudinal analyses of the same group of individuals will be conducted next year,” noted Dr. Luchsinger, associate professor of medicine and epidemiology, Columbia University Medical Center, New York.

Dr. Luchsinger reported financial relationships with vTv therapeutics. Dr. Matthews reported no potential conflicts of interest.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

Patients with stage 4 chronic kidney disease (CKD) who were in the DAPA-CKD trial had cardiorenal benefits from dapagliflozin that were similar to those of patients in the overall trial, with no added safety signal.

Sara Freeman/MDedge News

DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) was a landmark study of more than 4,000 patients with CKD, with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1.73 m² and albuminuria with/without type 2 diabetes.

The primary results showed that patients who received the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin for a median of 2.4 years were significantly less likely to have worsening kidney disease or die from all causes than were patients who received placebo.

“This prespecified subanalysis of people with an eGFR < 30 mL/min/1.73 m² [stage 4 CKD] in the DAPA-CKD study shows first, that in this very vulnerable population, use of the SGLT2 inhibitor is safe,” said Chantal Mathieu, MD, PhD.

Furthermore, there was no signal whatsoever of more adverse events and even a trend to fewer events, she said in an email to this news organization.

The analysis also showed that “although now in small numbers (around 300 each in the treated group vs. placebo group), there is no suggestion that the protective effect of dapagliflozin on the renal and cardiovascular front would not happen in this group” with advanced CKD. The efficacy findings just missed statistical significance, noted Dr. Mathieu, of Catholic University, Leuven, Belgium, who was not involved in the study.

Although dapagliflozin is now approved for treating patients with CKD who are at risk of kidney disease progression (on the basis of the DAPA-CKD results), guidelines have not yet been updated to reflect this, lead investigator Glenn M. Chertow, MD, MPH, of Stanford (Calif.) University, told this news organization in an email.

“For clinicians,” Dr. Mathieu said, “this is now the absolute reassurance that we do not have to stop an SGLT2 inhibitor in people with eGFR < 30 mL/min for safety reasons and that we should maintain them at these values for renal and cardiovascular protection!

“I absolutely hope labels will change soon to reflect these observations (and indeed movement on that front is happening),” she continued.

“The American Diabetes Association/European Association for the Study of Diabetes consensus on glucose-lowering therapies in type 2 diabetes already advocated keeping these agents until eGFR 30 mL/min (on the basis of evidence in 2019),” Dr. Mathieu added, “but this study will probably push the statements even further.”

“Of note,” she pointed out, “at these low eGFRs, the glucose-lowering potential of the SGLT2 inhibitor is negligible.”
 

Dapagliflozin risks and benefits in advanced CKD

Based on the DAPA-CKD study, published in the New England Journal of Medicine Oct. 8, 2020, the Food and Drug Administration expanded the indication for dapagliflozin (Farxiga, AstraZeneca) in April of 2021.

However, relatively little is known about the safety and efficacy of SGLT2 inhibitors in patients with advanced CKD, who are particularly vulnerable to cardiovascular events and progressive kidney failure, Dr. Chertow and colleagues wrote.

The DAPA-CKD trial randomized 4,304 patients with CKD 1:1 to dapagliflozin 10 mg/day or placebo, including 624 patients (14%) who had eGFR < 30 mL/min per 1.73 m² and albuminuria at baseline.

Patients in the subgroup with advanced CKD had a mean age of 62 years, and 37% were female. About two-thirds had type 2 diabetes and about one-third had cardiovascular disease.

A total of 293 patients received dapagliflozin and 331 patients received placebo.

During a median follow-up of 2.4 years, patients who received dapagliflozin as opposed to placebo had a lower risk of the primary efficacy outcome – a composite of a 50% or greater sustained decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes (hazard ratio, 0.73; 95% confidence interval, 0.53-1.02).

In secondary efficacy outcomes, patients who received dapagliflozin as opposed to placebo also had a lower risk of the following:

• A renal composite outcome – a ≥ 50% sustained decline in eGFR, end-stage kidney disease, or death from renal causes (HR, 0.71; 95% CI, 0.49-1.02).
• A cardiovascular composite outcome comprising cardiovascular death or hospitalization for heart failure (HR, 0.83; 95% CI, 0.45-1.53).
• All-cause mortality (HR, 0.68; 95% CI, 0.39 to 1.21).

The eGFR slope declined by 2.15 mL/min per 1.73 m² per year and by 3.38 mL/min per 1.73 m² per year in the dapagliflozin and placebo groups, respectively (P = .005).

“The trial was not powered to detect a statistically significant difference in the primary and key secondary endpoints in modest-sized subgroups,” the researchers noted.

The researchers limited their safety analysis to serious adverse events or symptoms of volume depletion, kidney-related events, major hypoglycemia, bone fractures, amputations, and potential diabetic ketoacidosis.

There was no evidence of increased risk of these adverse events in patients who received dapagliflozin.

The subanalysis of the DAPA-CKD trial was published July 16 in the Journal of the American Society of Nephrology.

The study was funded by AstraZeneca. Dr. Chertow has received fees from AstraZeneca for the DAPA-CKD trial steering committee. The disclosures of the other authors are listed in the article. Dr. Mathieu has served on the advisory panel/speakers bureau for AstraZeneca. Dr. Chertow and Dr. Mathieu also have financial relationships with many other pharmaceutical companies.

In what could be a model for other states, Texas has become the first state to exempt physicians from prior authorizations for meeting insurer benchmarks.

The law was passed in June and will take effect in September. It excuses physicians from having to obtain prior authorization if, during the previous 6 months, 90% of their treatments met medical necessity criteria by the health insurer. Through this law, doctors in the state will spend less time getting approvals for treatments for their patients.

Automatic approval of authorizations for treatments – or what the Texas Medical Association calls a “gold card” – “allows patients to get the care they need in a more timely fashion,” says Debra Patt, MD, an Austin, Tex.–based oncologist and former chair of the council on legislation for the TMA.

About 87% of Texas physicians reported a “drastic increase over the past 5 years in the burden of prior authorization on their patients and their practices,” per a 2020 survey by the TMA. Nearly half (48%) of Texas physicians have hired staff whose work focuses on processing requests for prior authorization, according to the survey.

Jack Resneck Jr., MD, a San Francisco–based dermatologist and president-elect of the American Medical Association, said other states have investigated ways to ease the impact of prior authorizations on physicians, but no other state has passed such a law.

Administrative burdens plague physicians around the country. The Medscape Physician Compensation Report 2021 found that physicians spend on average 15.6 hours per week on paperwork and administrative duties.
 

Better outcomes, less anxiety for patients

Dr. Patt, who testified in support of the law’s passage in the Texas legislature, says automatic approval of authorizations “is better for patients because it reduces their anxiety about whether they’re able to get the treatments they need now, and they will have better outcomes if they’re able to receive more timely care.”

Recently, a chemotherapy treatment Dr. Patt prescribed for one of her patients was not authorized by an insurer. The result is “a lot of anxiety and potentially health problems” for the patient.

She expects that automatic approval for treatments will be based on prescribing patterns during the preceding 6 months. “It means that when I order a test today, the [health insurer] looks back at my record 6 months previously,” she said. Still, Dr. Patt awaits guidance from the Texas Department of Insurance, which regulates health insurers in the state, regarding the law.

Dr. Resneck said the pharmacy counter is where most patients encounter prior authorization delays. “That’s when the pharmacist looks at them and says: ‘Actually, this isn’t covered by your health insurer’s formulary,’ or it isn’t covered fully on their formulary.”

One of Dr. Resneck’s patients had a life-altering case of eczema that lasted many years. Because of the condition, the patient couldn’t work or maintain meaningful bonds with family members. A biologic treatment transformed his patient’s life. The patient was able to return to work and to reengage with family, said Dr. Resneck. But a year after his patient started the treatment, the health insurer wouldn’t authorize the treatment because the patient wasn’t experiencing the same symptoms.

The patient didn’t have the same symptoms because the biologic treatment worked, said Dr. Resneck.

Kristine Grow, a spokesperson for America’s Health Insurance Plans, a national association for health insurers, said: “The use of prior authorization is relatively small – typically, less than 15% – and can help ensure safer opioid prescribing, help prevent dangerous drug interactions, and help protect patients from unnecessary exposure to potentially harmful radiation for inappropriate diagnostic imaging. Numerous studies show that Americans frequently receive inappropriate care, and 25% of unnecessary treatments are associated with complications or adverse events.”

Medical management tools, such as prior authorization, are “an important way” to deliver “safe, high-quality care” to patients, she added.
 

Potential for harm?

Sadeea Abbasi, MD, a practicing physician at Cedars-Sinai in the gastroenterology clinical office in Santa Monica, Calif., can attest that these practices are harmful for her patients.

“Prior authorization requirements have been on the rise across various medical specialties. For GI, we have seen an increase of required approvals for procedures like upper endoscopy, colonoscopy, and wireless capsule endoscopy and in medications prescribed, including biologic infusions for inflammatory bowel disease.”

Dr. Abbasi added: “One of the largest concerns I have with this growing ‘cost-savings’ trend is the impact it has on clinical outcomes. I have seen patients suffer with symptoms while waiting for a decision on a prior authorization for a medication. My patients have endured confusion and chaos when arriving for imaging appointments, only to learn the insurance has not reached a decision on whether the study is approved. When patients learn their procedure has been delayed, they have to reschedule the appointment, take another day off work, coordinate transportation and most importantly, postpone subsequent treatments to alleviate symptoms.”

According to an AMA survey, almost all physicians (94%) said prior authorization delays care and 79% percent have had patients abandon their recommended treatment because of issues related to prior authorization. This delay causes potentially irreversible damage to patients’ digestive system and increases the likelihood of hospitalization. This is a huge issue for America’s seniors: Medicare Advantage (MA) plans, which represent 24.1 million of the 62 million Medicare beneficiaries, the increase in prior authorization requests has been substantial.
 

State and federal efforts to curb prior authorization

In addition to efforts to curb prior authorization in other states, the AMA and nearly 300 other stakeholders, including the American Gastroenterological Association, support the Improving Seniors’ Timely Access to Care Act (H.R. 3173). The legislation includes a provision related to “gold carding,” said Robert Mills, an AMA spokesperson.

The bill aims to establish transparency requirements and standards for prior authorization processes related to MA plans. The requirements and standards for MA plans include the following:

• Establishing an electronic prior authorization program that meets specific standards, such as the ability to provide real-time decisions in response to requests for items and services that are routinely approved.
• Publishing on an annual basis specific prior authorization information, including the percentage of requests approved and the average response time.
• Ensuring prior authorization requests are reviewed by qualified medical personnel.
• Meeting standards set by the Centers for Medicare & Medicaid Services related to the quality and timeliness of prior authorization determinations.

This legislation was introduced in the U.S. House of Representatives in May by representatives Suzan DelBene (D-Wash.); Mike Kelly (R-Pa.); Ami Bera, MD (D-Calif.); and Larry Bucshon (R-Ind.), after which it was referred to the House Committee on Energy and Commerce and the House Committee on Ways and Means for consideration.

Gaining support for this legislation is a priority for AGA and as such the legislation will be featured as a top policy request at AGA’s upcoming fall Advocacy Day on Sept. 23. The AGA encourages all physicians to contact their lawmakers, urging for support of the bill in the 117th Congress.

In addition to AGA’s advocacy efforts on prior authorization reform, the Regulatory Relief Coalition, a group of national physician specialty organizations, advocates for regulatory burden reduction in Medicare so that physicians can spend more time treating patients. The physician community has banded together to address prior authorization burdens in our field and improve delivery of patient care. Learn more about prior authorization burdens and the various advocacy efforts being pursued.

With additional reporting by staff from this news organization.

In what could be a model for other states, Texas has become the first state to exempt physicians from prior authorizations for meeting insurer benchmarks.

The law was passed in June and will take effect in September. It excuses physicians from having to obtain prior authorization if, during the previous 6 months, 90% of their treatments met medical necessity criteria by the health insurer. Through this law, doctors in the state will spend less time getting approvals for treatments for their patients.

Automatic approval of authorizations for treatments – or what the Texas Medical Association calls a “gold card” – “allows patients to get the care they need in a more timely fashion,” says Debra Patt, MD, an Austin, Tex.–based oncologist and former chair of the council on legislation for the TMA.

About 87% of Texas physicians reported a “drastic increase over the past 5 years in the burden of prior authorization on their patients and their practices,” per a 2020 survey by the TMA. Nearly half (48%) of Texas physicians have hired staff whose work focuses on processing requests for prior authorization, according to the survey.

Jack Resneck Jr., MD, a San Francisco–based dermatologist and president-elect of the American Medical Association, said other states have investigated ways to ease the impact of prior authorizations on physicians, but no other state has passed such a law.

Administrative burdens plague physicians around the country. The Medscape Physician Compensation Report 2021 found that physicians spend on average 15.6 hours per week on paperwork and administrative duties.
 

Better outcomes, less anxiety for patients

Dr. Patt, who testified in support of the law’s passage in the Texas legislature, says automatic approval of authorizations “is better for patients because it reduces their anxiety about whether they’re able to get the treatments they need now, and they will have better outcomes if they’re able to receive more timely care.”

Recently, a chemotherapy treatment Dr. Patt prescribed for one of her patients was not authorized by an insurer. The result is “a lot of anxiety and potentially health problems” for the patient.

She expects that automatic approval for treatments will be based on prescribing patterns during the preceding 6 months. “It means that when I order a test today, the [health insurer] looks back at my record 6 months previously,” she said. Still, Dr. Patt awaits guidance from the Texas Department of Insurance, which regulates health insurers in the state, regarding the law.

Dr. Resneck said the pharmacy counter is where most patients encounter prior authorization delays. “That’s when the pharmacist looks at them and says: ‘Actually, this isn’t covered by your health insurer’s formulary,’ or it isn’t covered fully on their formulary.”

One of Dr. Resneck’s patients had a life-altering case of eczema that lasted many years. Because of the condition, the patient couldn’t work or maintain meaningful bonds with family members. A biologic treatment transformed his patient’s life. The patient was able to return to work and to reengage with family, said Dr. Resneck. But a year after his patient started the treatment, the health insurer wouldn’t authorize the treatment because the patient wasn’t experiencing the same symptoms.

The patient didn’t have the same symptoms because the biologic treatment worked, said Dr. Resneck.

Kristine Grow, a spokesperson for America’s Health Insurance Plans, a national association for health insurers, said: “The use of prior authorization is relatively small – typically, less than 15% – and can help ensure safer opioid prescribing, help prevent dangerous drug interactions, and help protect patients from unnecessary exposure to potentially harmful radiation for inappropriate diagnostic imaging. Numerous studies show that Americans frequently receive inappropriate care, and 25% of unnecessary treatments are associated with complications or adverse events.”

Medical management tools, such as prior authorization, are “an important way” to deliver “safe, high-quality care” to patients, she added.
 

Potential for harm?

Sadeea Abbasi, MD, a practicing physician at Cedars-Sinai in the gastroenterology clinical office in Santa Monica, Calif., can attest that these practices are harmful for her patients.

“Prior authorization requirements have been on the rise across various medical specialties. For GI, we have seen an increase of required approvals for procedures like upper endoscopy, colonoscopy, and wireless capsule endoscopy and in medications prescribed, including biologic infusions for inflammatory bowel disease.”

Dr. Abbasi added: “One of the largest concerns I have with this growing ‘cost-savings’ trend is the impact it has on clinical outcomes. I have seen patients suffer with symptoms while waiting for a decision on a prior authorization for a medication. My patients have endured confusion and chaos when arriving for imaging appointments, only to learn the insurance has not reached a decision on whether the study is approved. When patients learn their procedure has been delayed, they have to reschedule the appointment, take another day off work, coordinate transportation and most importantly, postpone subsequent treatments to alleviate symptoms.”

According to an AMA survey, almost all physicians (94%) said prior authorization delays care and 79% percent have had patients abandon their recommended treatment because of issues related to prior authorization. This delay causes potentially irreversible damage to patients’ digestive system and increases the likelihood of hospitalization. This is a huge issue for America’s seniors: Medicare Advantage (MA) plans, which represent 24.1 million of the 62 million Medicare beneficiaries, the increase in prior authorization requests has been substantial.
 

State and federal efforts to curb prior authorization

In addition to efforts to curb prior authorization in other states, the AMA and nearly 300 other stakeholders, including the American Gastroenterological Association, support the Improving Seniors’ Timely Access to Care Act (H.R. 3173). The legislation includes a provision related to “gold carding,” said Robert Mills, an AMA spokesperson.

The bill aims to establish transparency requirements and standards for prior authorization processes related to MA plans. The requirements and standards for MA plans include the following:

• Establishing an electronic prior authorization program that meets specific standards, such as the ability to provide real-time decisions in response to requests for items and services that are routinely approved.
• Publishing on an annual basis specific prior authorization information, including the percentage of requests approved and the average response time.
• Ensuring prior authorization requests are reviewed by qualified medical personnel.
• Meeting standards set by the Centers for Medicare & Medicaid Services related to the quality and timeliness of prior authorization determinations.

This legislation was introduced in the U.S. House of Representatives in May by representatives Suzan DelBene (D-Wash.); Mike Kelly (R-Pa.); Ami Bera, MD (D-Calif.); and Larry Bucshon (R-Ind.), after which it was referred to the House Committee on Energy and Commerce and the House Committee on Ways and Means for consideration.

Gaining support for this legislation is a priority for AGA and as such the legislation will be featured as a top policy request at AGA’s upcoming fall Advocacy Day on Sept. 23. The AGA encourages all physicians to contact their lawmakers, urging for support of the bill in the 117th Congress.

In addition to AGA’s advocacy efforts on prior authorization reform, the Regulatory Relief Coalition, a group of national physician specialty organizations, advocates for regulatory burden reduction in Medicare so that physicians can spend more time treating patients. The physician community has banded together to address prior authorization burdens in our field and improve delivery of patient care. Learn more about prior authorization burdens and the various advocacy efforts being pursued.

With additional reporting by staff from this news organization.

In what could be a model for other states, Texas has become the first state to exempt physicians from prior authorizations for meeting insurer benchmarks.

The law was passed in June and will take effect in September. It excuses physicians from having to obtain prior authorization if, during the previous 6 months, 90% of their treatments met medical necessity criteria by the health insurer. Through this law, doctors in the state will spend less time getting approvals for treatments for their patients.

Automatic approval of authorizations for treatments – or what the Texas Medical Association calls a “gold card” – “allows patients to get the care they need in a more timely fashion,” says Debra Patt, MD, an Austin, Tex.–based oncologist and former chair of the council on legislation for the TMA.

About 87% of Texas physicians reported a “drastic increase over the past 5 years in the burden of prior authorization on their patients and their practices,” per a 2020 survey by the TMA. Nearly half (48%) of Texas physicians have hired staff whose work focuses on processing requests for prior authorization, according to the survey.

Jack Resneck Jr., MD, a San Francisco–based dermatologist and president-elect of the American Medical Association, said other states have investigated ways to ease the impact of prior authorizations on physicians, but no other state has passed such a law.

Administrative burdens plague physicians around the country. The Medscape Physician Compensation Report 2021 found that physicians spend on average 15.6 hours per week on paperwork and administrative duties.
 

Better outcomes, less anxiety for patients

Dr. Patt, who testified in support of the law’s passage in the Texas legislature, says automatic approval of authorizations “is better for patients because it reduces their anxiety about whether they’re able to get the treatments they need now, and they will have better outcomes if they’re able to receive more timely care.”

Recently, a chemotherapy treatment Dr. Patt prescribed for one of her patients was not authorized by an insurer. The result is “a lot of anxiety and potentially health problems” for the patient.

She expects that automatic approval for treatments will be based on prescribing patterns during the preceding 6 months. “It means that when I order a test today, the [health insurer] looks back at my record 6 months previously,” she said. Still, Dr. Patt awaits guidance from the Texas Department of Insurance, which regulates health insurers in the state, regarding the law.

Dr. Resneck said the pharmacy counter is where most patients encounter prior authorization delays. “That’s when the pharmacist looks at them and says: ‘Actually, this isn’t covered by your health insurer’s formulary,’ or it isn’t covered fully on their formulary.”

One of Dr. Resneck’s patients had a life-altering case of eczema that lasted many years. Because of the condition, the patient couldn’t work or maintain meaningful bonds with family members. A biologic treatment transformed his patient’s life. The patient was able to return to work and to reengage with family, said Dr. Resneck. But a year after his patient started the treatment, the health insurer wouldn’t authorize the treatment because the patient wasn’t experiencing the same symptoms.

The patient didn’t have the same symptoms because the biologic treatment worked, said Dr. Resneck.

Kristine Grow, a spokesperson for America’s Health Insurance Plans, a national association for health insurers, said: “The use of prior authorization is relatively small – typically, less than 15% – and can help ensure safer opioid prescribing, help prevent dangerous drug interactions, and help protect patients from unnecessary exposure to potentially harmful radiation for inappropriate diagnostic imaging. Numerous studies show that Americans frequently receive inappropriate care, and 25% of unnecessary treatments are associated with complications or adverse events.”

Medical management tools, such as prior authorization, are “an important way” to deliver “safe, high-quality care” to patients, she added.
 

Potential for harm?

Sadeea Abbasi, MD, a practicing physician at Cedars-Sinai in the gastroenterology clinical office in Santa Monica, Calif., can attest that these practices are harmful for her patients.

“Prior authorization requirements have been on the rise across various medical specialties. For GI, we have seen an increase of required approvals for procedures like upper endoscopy, colonoscopy, and wireless capsule endoscopy and in medications prescribed, including biologic infusions for inflammatory bowel disease.”

Dr. Abbasi added: “One of the largest concerns I have with this growing ‘cost-savings’ trend is the impact it has on clinical outcomes. I have seen patients suffer with symptoms while waiting for a decision on a prior authorization for a medication. My patients have endured confusion and chaos when arriving for imaging appointments, only to learn the insurance has not reached a decision on whether the study is approved. When patients learn their procedure has been delayed, they have to reschedule the appointment, take another day off work, coordinate transportation and most importantly, postpone subsequent treatments to alleviate symptoms.”

According to an AMA survey, almost all physicians (94%) said prior authorization delays care and 79% percent have had patients abandon their recommended treatment because of issues related to prior authorization. This delay causes potentially irreversible damage to patients’ digestive system and increases the likelihood of hospitalization. This is a huge issue for America’s seniors: Medicare Advantage (MA) plans, which represent 24.1 million of the 62 million Medicare beneficiaries, the increase in prior authorization requests has been substantial.
 

State and federal efforts to curb prior authorization

In addition to efforts to curb prior authorization in other states, the AMA and nearly 300 other stakeholders, including the American Gastroenterological Association, support the Improving Seniors’ Timely Access to Care Act (H.R. 3173). The legislation includes a provision related to “gold carding,” said Robert Mills, an AMA spokesperson.

The bill aims to establish transparency requirements and standards for prior authorization processes related to MA plans. The requirements and standards for MA plans include the following:

• Establishing an electronic prior authorization program that meets specific standards, such as the ability to provide real-time decisions in response to requests for items and services that are routinely approved.
• Publishing on an annual basis specific prior authorization information, including the percentage of requests approved and the average response time.
• Ensuring prior authorization requests are reviewed by qualified medical personnel.
• Meeting standards set by the Centers for Medicare & Medicaid Services related to the quality and timeliness of prior authorization determinations.

This legislation was introduced in the U.S. House of Representatives in May by representatives Suzan DelBene (D-Wash.); Mike Kelly (R-Pa.); Ami Bera, MD (D-Calif.); and Larry Bucshon (R-Ind.), after which it was referred to the House Committee on Energy and Commerce and the House Committee on Ways and Means for consideration.

Gaining support for this legislation is a priority for AGA and as such the legislation will be featured as a top policy request at AGA’s upcoming fall Advocacy Day on Sept. 23. The AGA encourages all physicians to contact their lawmakers, urging for support of the bill in the 117th Congress.

In addition to AGA’s advocacy efforts on prior authorization reform, the Regulatory Relief Coalition, a group of national physician specialty organizations, advocates for regulatory burden reduction in Medicare so that physicians can spend more time treating patients. The physician community has banded together to address prior authorization burdens in our field and improve delivery of patient care. Learn more about prior authorization burdens and the various advocacy efforts being pursued.

With additional reporting by staff from this news organization.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Among patients hospitalized for COVID-19, those who had been taking statins had a substantially lower risk of death in a new large observational study.

Results showed that use of statins prior to admission was linked to a greater than 40% reduction in mortality and a greater than 25% reduction in risk of developing a severe outcome.

The findings come an analysis of data from the American Heart Association’s COVID-19 Cardiovascular Disease Registry on more than 10,000 patients hospitalized with COVID-19 at 104 hospitals across the United States published in PLoS One.

While several other studies have suggested benefits of statins in COVID-19, this is by far the largest study so far on this topic.

“I would say this is the most reliable study on statins in COVID-19 to date, with the results adjusted for many confounders, including socioeconomic factors and insurance type,” lead author Lori B. Daniels, MD, told this news organization. “However, it still an observational study and therefore falls short of a randomized study. But I would think a randomized study of statins in COVID-19 is probably not feasible, so this study provides excellent data at an observational level.”

After propensity matching for cardiovascular disease, results showed that most of the benefit of statins occurred in patients with known cardiovascular disease.

“While most patients taking statins will have cardiovascular disease, there are also many patients who take these drugs who don’t have heart disease but do have cardiovascular risk factors, such as those with raised cholesterol, or a family history of cardiovascular disease. For [such patients], the effect of statins was also in the same direction but it was not significant. This doesn’t exclude an effect,” noted Dr. Daniels, who is professor of medicine and director of cardiovascular intensive care at the University of California, San Diego.

“We are not saying that everyone should rush out and take a statin if they do not have risk factors for cardiovascular in order to lower their risk of dying from COVID. But if individuals do have an indication for a statin and are not taking one of these dugs this is another good reason to start taking them now,” she added.

The investigators embarked on the study because, although previous observational studies have found that statins may reduce the severity of COVID-19 infection, these studies have been limited in size with mostly single-center or regional studies, and some results have been conflicting. They therefore conducted the current, much larger analysis, in the AHA COVID-19 CVD Registry which systematically collected hospitalized patient–level data in a broad and diverse hospital and patient population across the United States.

For the analysis, the researchers analyzed data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 U.S. hospitals enrolled in the AHA registry to evaluate the associations between statin use and outcomes.

Most patients (71%) had either cardiovascular disease, hypertension, or both. Prior to admission, 42% of subjects used statins, with 7% being on statins alone and 35% on statins plus antihypertensives. Death (or discharge to hospice) occurred in 2,212 subjects (21%).

Results showed that outpatient use of statins, either alone or with antihypertensives, was associated with a 41% reduced risk of death (odds ratio, 0.59; 95% confidence interval, 0.50-0.69), after adjusting for demographic characteristics, underlying conditions, insurance status, hospital site, and concurrent medications. Statin use was also associated with a roughly 25% lower adjusted odds of developing severe disease.

Noting that patients on statins are also likely to be on antihypertensive medication, the researchers found that the statin benefit on mortality was seen in both patients taking a statin alone (OR, 0.54) and in those taking statins with an antihypertensive medication (OR, 0.60).

Use of antihypertensive drugs was associated with a smaller, albeit still substantial, 27% lower odds of death (OR, 0.73; 95% CI, 0.62-0.87).

In propensity-matched analyses, use of statins and/or antihypertensives was tied to a 32% reduced risk of death among those with a history of CVD and/or hypertension (OR, 0.68; 95% CI, 0.58-0.81). An observed 16% reduction in odds of death with statins and/or antihypertensive drugs among those without cardiovascular disease and/or hypertension was not statistically significant (OR, 0.84; 95% CI, 0.58-1.22).
 

Stabilizing the underlying disease

The researchers pointed out that the results of the propensity matching analysis are consistent with the hypothesis that the major benefit of these medications accrues from treating and/or stabilizing underlying disease.

“Although it is well known that statins improve long-term outcomes among patients with or at elevated risk for cardiovascular disease, the association with a large short-term benefit which accrues in the setting of hospitalization for COVID-19 is a new and intriguing finding,” they said.

They cited several “plausible mechanisms whereby statins could directly mitigate outcomes in COVID-19 beyond treating underlying disease conditions,” including anti-inflammatory effects and a direct inhibitory effect on the SARS-CoV-2 virus.

Dr. Daniels elaborated more on the potential mechanism at play in an interview: “I think what is happening is that the statin is stabilizing the coronary disease so patients are less likely to die from MI or stroke, and this gives them more time and strength to recover from COVID-19.”

She added: “Statins may also have some direct anti-COVID effects such as an anti-inflammatory actions, but I would guess that this is probably not the primary effect behind what we’re seeing here.”
 

‘Important clinical implications’

The authors say their findings have “important clinical implications.”

They noted that early in the pandemic there was speculation that certain medications, including statins, and the ACE inhibitor/angiotensin receptor blocker (ARB) classes of antihypertensives may confer an increased susceptibility to COVID-19 positivity and/or severity.

“Our study reinforces the AHA and others’ recommendations that not only is it safe to remain on these medications, but they may substantially reduce risk of severe COVID-19 and especially death from COVID-19, particularly statins, and particularly among those with associated underlying conditions,” the authors stressed.

Dr. Daniels added that, although statins are very safe drugs, there are always some patients who prefer not to take medication even if indicated, and others who may have borderline indications and decide not to take a statin at present.

“This study may persuade these patients that taking a statin is the right thing to do. It may give those patients on the cusp of thinking about taking one of these drugs a reason to go ahead,” she said.
 

‘Provocative but not definitive’

Commenting on the study, Robert Harrington, MD, professor of medicine and chair of the department of medicine at Stanford (Calif.) University, said: “These are interesting observational data but as such have all the limitations of nonrandomized comparisons despite the best attempts to adjust for a variety of potential confounders. For example, is this an effect of statins (perhaps through some anti-inflammatory mechanism) or is it more an effect that can be attributed to the patients who are prescribed and taking a statin, compared with those who are not?”

He added: “The primary clinical benefit of statins, based on many large randomized clinical trials, seems to be derived from their LDL lowering effect. Observational studies have suggested potential benefits from anti-inflammatory effects of statins, but the randomized trials have not confirmed these observations. So, the current data are interesting, even provocative, but ultimately hypothesis generating rather than definitive.”

Also commenting on the study, Steven Nissen, MD, professor of medicine at the Cleveland Clinic, said: “While statins have many established benefits, their role in preventing COVID-19 complications is very speculative. Like all observational studies, the current study must be viewed as hypothesis generating, not definitive evidence of benefit. There are many potential confounders. I’m skeptical.”

The authors of this study received no specific funding for this work and report no competing interests. Dr. Harrington was AHA president when the COVID registry was created and he is still a member of the AHA board, which has oversight over the project.

Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.

The GRADE trial ran for roughly 5 years at 36 U.S. centers and was designed to answer the question of which is the best second-line agent for patients with type 2 diabetes already taking metformin. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions. 

The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.

The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.

For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.

During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
 

Too soon for take-aways, or are the data already obsolete?

“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.

Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.

“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”

“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.

But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.

“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.

Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.

A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.

Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.

The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”

Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.

“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”

In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.

Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.

They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.

Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
 

A study with lots of data

The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m², average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m². The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.

Patients were then randomized to one of the four agents as add-on treatment.

Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.

The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.

Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin. 

A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.

For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.

For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance. 

Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.

And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.

Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)

And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
 

Four drugs performed equally well for some outcomes

Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.

The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.

But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.

GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.

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

Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.

The GRADE trial ran for roughly 5 years at 36 U.S. centers and was designed to answer the question of which is the best second-line agent for patients with type 2 diabetes already taking metformin. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions. 

The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.

The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.

For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.

During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
 

Too soon for take-aways, or are the data already obsolete?

“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.

Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.

“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”

“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.

But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.

“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.

Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.

A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.

Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.

The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”

Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.

“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”

In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.

Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.

They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.

Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
 

A study with lots of data

The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m², average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m². The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.

Patients were then randomized to one of the four agents as add-on treatment.

Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.

The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.

Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin. 

A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.

For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.

For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance. 

Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.

And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.

Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)

And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
 

Four drugs performed equally well for some outcomes

Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.

The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.

But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.

GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.

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

Liraglutide and insulin glargine outperformed glimepiride and sitagliptin as single add-on agents to metformin for treating patients with type 2 diabetes in a multicenter U.S. trial that randomized just over 5,000 patients.

The GRADE trial ran for roughly 5 years at 36 U.S. centers and was designed to answer the question of which is the best second-line agent for patients with type 2 diabetes already taking metformin. Results were reported at the virtual American Diabetes Association (ADA) 81st Scientific Sessions. 

The comparison included two oral medications – the sulfonylurea glimepiride and dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin – and two injectable medications – insulin glargine and glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide.

The primary endpoint was change in A1c level and overall glycemic control. Secondary endpoints include changes in weight, as well as cardiovascular, renal, gastrointestinal, and other complications.

For the primary endpoint – keeping A1c levels below 7% – liraglutide and the basal insulin glargine both did this best and were almost equivalent.

During the average 5-year follow-up, the rates of patients progressing to a confirmed A1c of 7% or higher were 67% among patients randomized to insulin glargine, 68% maintained on liraglutide, 72% taking the sulfonylurea glimepiride, and 77% taking sitagliptin, reported John M. Lachin, ScD, a biostatistician at George Washington University, Washington.
 

Too soon for take-aways, or are the data already obsolete?

“The ultimate goal of GRADE is to help clinicians select the therapies that will work best for individual patients, as diabetes care is not a one-size-fits all approach,” noted David M. Nathan, MD, chair of the study and director of the Diabetes Center at Massachusetts General Hospital, in an ADA press release.

Dr. Nathan, as well as several other members of the GRADE trial steering committee who presented results, repeatedly cautioned that the findings were preliminary because they represent 90% of outcomes, with the remaining 10% still to be adjudicated.

“We undertook this study to fill a gap in the guidelines,” said investigator Deborah J. Wexler, MD, clinical director of the Diabetes Center at Massachusetts General Hospital in Boston. “I would like to have all the results in ... before I comment on how the guidelines should change.”

“The metabolic data are solid, but the cardiovascular disease data are preliminary,” warned Dr. Nathan.

But that didn’t stop some from drawing their own conclusions, with Julio Rosenstock, MD, who comoderated the session but was not involved with the study, giving his own opinion.

“A pleasant surprise was the performance of basal insulin,” he said, calling the findings “a vindication” for basal insulin as a treatment for the types of patients with type 2 diabetes that enrolled in the study.

Steven E. Kahn, MB, ChB, another GRADE co-investigator agreed. “Based on the results, guidelines should say that you add insulin early on,” he observed.

A generic basal insulin and a generic sulfonylurea are both reasonable options, after metformin, for patients with limited resources, added Dr. Kahn, an endocrinologist and professor at the University of Washington, Seattle.

Dr. Rosenstock, director of the Dallas Diabetes Research Center, also saw the results as an indictment of agents in the DDP-4 inhibitor class, such as sitagliptin.

The DPP-4 inhibitors generate $9 billion a year, he said, wondering whether it “is justifiable to put them on the same level as other agents?”

Meanwhile the assigned discussant, David R. Matthews, DPhil, a professor of diabetes medicine at the University of Oxford, England – while congratulating the investigators on certain aspects of the study – said it ultimately fell short because it didn’t include an arm with an SGLT2 inhibitor.

“We should kick the authors for missing out on SGLT2 inhibitors,” Dr. Matthews said. “The omission means that the GRADE data are already obsolescent.”

In reply, Dr. Nathan admitted “we feel bad we did not include” an SGLT2 inhibitor, but he vigorously defended the dilemma faced by the trial’s organizers.

Oral SGLT2 inhibitors were not “well-established drugs” for type 2 diabetes when enrollment launched in 2013, and the researchers were wary of including what could turn out to be a problematic agent soon after controversy over the safety of agents in the thiazolidinedione drug class (such as rosiglitazone), he explained.

They also realized that adding a fifth drug to the study would necessitate doubling enrollment size, which would have undercut the funding plans already in place.

Dr. Matthews also derided GRADE as being underpowered to adequately address the impact of the tested agents on major adverse cardiovascular events (MACE) and hospitalizations for heart failure and too U.S.-centric to be generalizable elsewhere.
 

A study with lots of data

The roughly 5,000 patients enrolled in GRADE were an average age of 57 years old, 64% were men, 66% were White, and 20% were Black. They had had type 2 diabetes, on average, for 4.2 years. Mean body mass index at entry was about 34 kg/m², average A1c was 7.5%, and average estimated glomerular filtration rate was 95 mL/min/1.73m². The trial included a 6-12 week run-in period during which background metformin treatment was optimized and led to average A1c levels less than 7%.

Patients were then randomized to one of the four agents as add-on treatment.

Both liraglutide and insulin glargine performed well on many of the numerous metrics in the data-rich trial, largely funded by two branches of the National Institutes of Health, with commercial involvement limited to free supplies of the study drugs.

The secondary metabolic outcome, of disease progressing to a confirmed A1c of 7.5%, was reached by 39% of patients taking insulin glargine, significantly lower than the rate of 46% among patients taking liraglutide, and that rate, in turn, was significantly below the 50% rate among patients taking glimepiride and the 55% rate of those taking sitagliptin.

Mean doses of the second-line agents after 4 years of treatment were 38.3 units/day for glargine, 3.5 mg/day for glimepiride, 1.3 mg/day for subcutaneous liraglutide, and 82.9 mg/day for sitagliptin. 

A trio of cardiovascular outcomes showed one significant benefit of liraglutide over the other three drugs for the endpoint of any cardiovascular event, which included not only major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, or stroke), but also several other event types, including heart failure requiring hospitalization, unstable angina requiring hospitalization, revascularization or any arterial repairs, stent thrombosis, or transient ischemic attack.

For the endpoint of any cardiovascular event, the rate was 5.8% for patients taking liraglutide, significantly less than the rate of 7.6% of those taking insulin glargine, 8.0% for glimepiride, and 8.6% for sitagliptin, reported John B. Buse, MD, PhD, professor, chief of endocrinology, and director of the Diabetes Center at the University of North Carolina at Chapel Hill.

For each of the other two main cardiovascular endpoints – MACE and hospitalization for heart failure – liraglutide had a numeric advantage over the other three drugs but failed to reach significance. 

Patients taking liraglutide also had a smaller but not significantly different point estimate for all-cause death, at 2.1%, compared with 3.1%-3.4% in the other three groups.

And, Dr. Nathan emphasized, the cardiovascular disease data are still considered preliminary.

Liraglutide scored a pair of additional outcome victories. Its use resulted in a significantly lower rate of patients who progressed during follow-up to either needing antihypertensive medications or having their blood pressure rise above 140/90 mm Hg compared with the other three drugs. (At baseline, average blood pressure for all patients was 128/77 mm Hg.)

And after 4 years, patients taking liraglutide lost an average of about 4 kg (8.8 lb) from their baseline weight (which averaged about 100 kg [220 lb]), roughly the same as patients taking sitagliptin but significantly better than with glimepiride or insulin glargine. Patients taking glargine gained a small amount of weight on average during their first couple of years of treatment, roughly 1 kg, but returned to around their baseline weight by the end of 4 years.
 

Four drugs performed equally well for some outcomes

Finally, the four drugs had similar results for some outcomes. This included their effects on renal function, distal sensory polyneuropathy, and low-density lipoprotein (LDL) cholesterol.

The four agents also had roughly similar safety profiles, with rates of serious adverse events all falling within the tight range of 33%-37%.

But the rate of severe hypoglycemic episodes that required assistance to treat showed significant separation, ranging from 2.3% for glimepiride, 1.4% for glargine, 0.9% for liraglutide, and 0.7% for sitagliptin. Gastrointestinal symptoms occurred in about 50% of patients in three of the treatment groups but were significantly higher in those taking liraglutide, affecting 60%.

GRADE received no commercial funding. Dr. Wexler has reported serving on data monitoring committees for Novo Nordisk. Dr. Buse has reported being a consultant for and holding stock in numerous companies. Dr. Rosenstock has reported being an advisor or consultant to Applied Therapeutics, Boehringer Ingelheim, Hanmi Pharmaceutical, Intarcia Therapeutics, Lilly, Novo Nordisk, Oramed, and Sanofi and has received research support from numerous companies. Dr. Kahn has reported being an advisor to or speaker on behalf of Bayer, Boehringer Ingelheim, Casma Therapeutics, Intarcia Therapeutics, Lilly, Merck, Novo Nordisk, Pfizer, and Third Rock Ventures. Dr. Matthews has reported receiving lecture and advisor fees from Merck, Novartis, Novo Nordisk, Sanofi Aventis, and Servier. Dr. Lachin and Dr. Nathan have reported no relevant financial relationships.

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

Pregnant women with a history of bariatric surgery have better cardiovascular adaptation to pregnancy compared with women who have similar early-pregnancy body mass index (BMI) but no history of weight loss surgery, new data suggest.

“Pregnant women who have had bariatric surgery demonstrate better cardiovascular adaptation through lower blood pressure, heart rate, and cardiac output, more favorable diastolic indices, and better systolic function,” reported Deesha Patel, MBBS MRCOG, specialist registrar, Chelsea and Westminster Hospital, London.

“Because the groups were matched for early pregnancy BMI, it’s unlikely that the results are due to weight loss alone but indicate that the metabolic alterations as a result of the surgery, via the enterocardiac axis, play an important role,” Dr. Patel continued.

The findings were presented at the Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress.

Although obesity is known for its inflammatory and toxic effects on the cardiovascular system, it is not clear to what extent the various treatment options for obesity modify these risks in the long term, said Hutan Ashrafian, MD, clinical lecturer in surgery, Imperial College London.

“It is even less clear how anti-obesity interventions affect the cardiovascular system in pregnancy,” Dr. Ashrafian told this news organization.

“This very novel study in pregnant mothers having undergone the most successful and consistent intervention for severe obesity – bariatric or metabolic surgery – gives new clues as to the extent that bariatric procedures can alter cardiovascular risk in pregnant mothers,” continued Dr. Ashrafian, who was not involved in the study.

The results show how bariatric surgery has favorable effects on cardiac adaptation in pregnancy and in turn “might offer protection from pregnancy-related cardiovascular pathology such as preeclampsia,” explained Dr. Ashrafian. “This adds to the known effects of cardiovascular protection of bariatric surgery through the enterocardiac axis, which may explain a wider range of effects that can be translated within pregnancy and possibly following pregnancy in the postpartum era and beyond.”
 

A history of bariatric surgery versus no surgery

The prospective, longitudinal study compared 41 women who had a history of bariatric surgery with 41 women who had not undergone surgery. Patients’ characteristics were closely matched for age, BMI (34.5 kg/m2 and 34.3 kg/m2 in the surgery and bariatric surgery groups, respectively) and race. Hypertensive disorders in the post-surgery group were significantly less common compared with the no-surgery group (0% vs. 9.8%).

During the study, participants underwent cardiovascular assessment at 12-14 weeks, 20-24 weeks, and 30-32 weeks of gestation. The assessment included measurement of blood pressure and heart rate, transthoracic echocardiography, and 2D speckle tracking, performed offline to assess global longitudinal and circumferential strain.

Blood pressure readings across the three trimesters were consistently lower in the women who had undergone bariatric surgery compared with those in the no-surgery group, and all differences were statistically significant. Likewise, heart rate and cardiac output across the three trimesters were lower in the post-surgery cohort. However, there was no difference in stroke volume between the two groups.

As for diastolic function, there were more favorable indices in the post-surgery group with a higher E/A ratio, a marker of left ventricle filling (P < .001), and lower left atrial volume (P < .05), Dr. Patel reported.

With respect to systolic function, there was no difference in ejection fraction, but there was lower global longitudinal strain (P < .01) and global circumferential strain in the post-bariatric group (P = .02), suggesting better systolic function.

“Strain is a measure of differences in motion and velocity between regions of the myocardium through the cardiac cycle and can detect subclinical changes when ejection fraction is normal,” she added.

“This is a fascinating piece of work. The author should be congratulated on gathering so many [pregnant] women who had had bariatric surgery. The work gives a unique glimpse into metabolic syndrome,” said Philip Toozs-Hobson, MD, who moderated the session.

“We are increasingly recognizing the impact [of bariatric surgery] on metabolic syndrome, and the fact that this study demonstrates that there is more to it than just weight is important,” continued Dr. Toosz-Hobson, who is a consultant gynecologist at Birmingham Women’s Hospital NHS Foundation Trust, United Kingdom.
 

Cardiovascular benefits of bariatric surgery

Bariatric surgery has been associated with loss of excess body weight of up to 55% and with approximately 40% reduction in all-cause mortality in the general population. The procedure also reduces the risk for heart disease, diabetes, and cancer.

The cardiovascular benefits of bariatric surgery include reduced hypertension, remodeling of the heart with a reduction in left ventricular mass, and an improvement in diastolic and systolic function.

“Traditionally, the cardiac changes were thought to be due to weight loss and blood pressure reduction, but it is now conceivable that the metabolic components contribute to the reverse modeling via changes to the enterocardiac axis involving changes to gut hormones,” said Dr. Patel. These hormones include secretin, glucagon, and vasoactive intestinal peptide, which are known to have inotropic effects, as well as adiponectin and leptin, which are known to have cardiac effects, she added.

“Pregnancy following bariatric surgery is associated with a reduced risk of hypertensive disorders, as well as a reduced risk of gestational diabetes, large-for-gestational-age neonates, and a small increased risk of small-for-gestational-age neonates,” said Dr. Patel.

Dr. Patel and Dr. Toosz-Hobson have disclosed no relevant financial relationships.

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

Pregnant women with a history of bariatric surgery have better cardiovascular adaptation to pregnancy compared with women who have similar early-pregnancy body mass index (BMI) but no history of weight loss surgery, new data suggest.

“Pregnant women who have had bariatric surgery demonstrate better cardiovascular adaptation through lower blood pressure, heart rate, and cardiac output, more favorable diastolic indices, and better systolic function,” reported Deesha Patel, MBBS MRCOG, specialist registrar, Chelsea and Westminster Hospital, London.

“Because the groups were matched for early pregnancy BMI, it’s unlikely that the results are due to weight loss alone but indicate that the metabolic alterations as a result of the surgery, via the enterocardiac axis, play an important role,” Dr. Patel continued.

The findings were presented at the Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress.

Although obesity is known for its inflammatory and toxic effects on the cardiovascular system, it is not clear to what extent the various treatment options for obesity modify these risks in the long term, said Hutan Ashrafian, MD, clinical lecturer in surgery, Imperial College London.

“It is even less clear how anti-obesity interventions affect the cardiovascular system in pregnancy,” Dr. Ashrafian told this news organization.

“This very novel study in pregnant mothers having undergone the most successful and consistent intervention for severe obesity – bariatric or metabolic surgery – gives new clues as to the extent that bariatric procedures can alter cardiovascular risk in pregnant mothers,” continued Dr. Ashrafian, who was not involved in the study.

The results show how bariatric surgery has favorable effects on cardiac adaptation in pregnancy and in turn “might offer protection from pregnancy-related cardiovascular pathology such as preeclampsia,” explained Dr. Ashrafian. “This adds to the known effects of cardiovascular protection of bariatric surgery through the enterocardiac axis, which may explain a wider range of effects that can be translated within pregnancy and possibly following pregnancy in the postpartum era and beyond.”
 

A history of bariatric surgery versus no surgery

The prospective, longitudinal study compared 41 women who had a history of bariatric surgery with 41 women who had not undergone surgery. Patients’ characteristics were closely matched for age, BMI (34.5 kg/m2 and 34.3 kg/m2 in the surgery and bariatric surgery groups, respectively) and race. Hypertensive disorders in the post-surgery group were significantly less common compared with the no-surgery group (0% vs. 9.8%).

During the study, participants underwent cardiovascular assessment at 12-14 weeks, 20-24 weeks, and 30-32 weeks of gestation. The assessment included measurement of blood pressure and heart rate, transthoracic echocardiography, and 2D speckle tracking, performed offline to assess global longitudinal and circumferential strain.

Blood pressure readings across the three trimesters were consistently lower in the women who had undergone bariatric surgery compared with those in the no-surgery group, and all differences were statistically significant. Likewise, heart rate and cardiac output across the three trimesters were lower in the post-surgery cohort. However, there was no difference in stroke volume between the two groups.

As for diastolic function, there were more favorable indices in the post-surgery group with a higher E/A ratio, a marker of left ventricle filling (P < .001), and lower left atrial volume (P < .05), Dr. Patel reported.

With respect to systolic function, there was no difference in ejection fraction, but there was lower global longitudinal strain (P < .01) and global circumferential strain in the post-bariatric group (P = .02), suggesting better systolic function.

“Strain is a measure of differences in motion and velocity between regions of the myocardium through the cardiac cycle and can detect subclinical changes when ejection fraction is normal,” she added.

“This is a fascinating piece of work. The author should be congratulated on gathering so many [pregnant] women who had had bariatric surgery. The work gives a unique glimpse into metabolic syndrome,” said Philip Toozs-Hobson, MD, who moderated the session.

“We are increasingly recognizing the impact [of bariatric surgery] on metabolic syndrome, and the fact that this study demonstrates that there is more to it than just weight is important,” continued Dr. Toosz-Hobson, who is a consultant gynecologist at Birmingham Women’s Hospital NHS Foundation Trust, United Kingdom.
 

Cardiovascular benefits of bariatric surgery

Bariatric surgery has been associated with loss of excess body weight of up to 55% and with approximately 40% reduction in all-cause mortality in the general population. The procedure also reduces the risk for heart disease, diabetes, and cancer.

The cardiovascular benefits of bariatric surgery include reduced hypertension, remodeling of the heart with a reduction in left ventricular mass, and an improvement in diastolic and systolic function.

“Traditionally, the cardiac changes were thought to be due to weight loss and blood pressure reduction, but it is now conceivable that the metabolic components contribute to the reverse modeling via changes to the enterocardiac axis involving changes to gut hormones,” said Dr. Patel. These hormones include secretin, glucagon, and vasoactive intestinal peptide, which are known to have inotropic effects, as well as adiponectin and leptin, which are known to have cardiac effects, she added.

“Pregnancy following bariatric surgery is associated with a reduced risk of hypertensive disorders, as well as a reduced risk of gestational diabetes, large-for-gestational-age neonates, and a small increased risk of small-for-gestational-age neonates,” said Dr. Patel.

Dr. Patel and Dr. Toosz-Hobson have disclosed no relevant financial relationships.

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

Pregnant women with a history of bariatric surgery have better cardiovascular adaptation to pregnancy compared with women who have similar early-pregnancy body mass index (BMI) but no history of weight loss surgery, new data suggest.

“Pregnant women who have had bariatric surgery demonstrate better cardiovascular adaptation through lower blood pressure, heart rate, and cardiac output, more favorable diastolic indices, and better systolic function,” reported Deesha Patel, MBBS MRCOG, specialist registrar, Chelsea and Westminster Hospital, London.

“Because the groups were matched for early pregnancy BMI, it’s unlikely that the results are due to weight loss alone but indicate that the metabolic alterations as a result of the surgery, via the enterocardiac axis, play an important role,” Dr. Patel continued.

The findings were presented at the Royal College of Obstetricians and Gynecologists 2021 Virtual World Congress.

Although obesity is known for its inflammatory and toxic effects on the cardiovascular system, it is not clear to what extent the various treatment options for obesity modify these risks in the long term, said Hutan Ashrafian, MD, clinical lecturer in surgery, Imperial College London.

“It is even less clear how anti-obesity interventions affect the cardiovascular system in pregnancy,” Dr. Ashrafian told this news organization.

“This very novel study in pregnant mothers having undergone the most successful and consistent intervention for severe obesity – bariatric or metabolic surgery – gives new clues as to the extent that bariatric procedures can alter cardiovascular risk in pregnant mothers,” continued Dr. Ashrafian, who was not involved in the study.

The results show how bariatric surgery has favorable effects on cardiac adaptation in pregnancy and in turn “might offer protection from pregnancy-related cardiovascular pathology such as preeclampsia,” explained Dr. Ashrafian. “This adds to the known effects of cardiovascular protection of bariatric surgery through the enterocardiac axis, which may explain a wider range of effects that can be translated within pregnancy and possibly following pregnancy in the postpartum era and beyond.”
 

A history of bariatric surgery versus no surgery

The prospective, longitudinal study compared 41 women who had a history of bariatric surgery with 41 women who had not undergone surgery. Patients’ characteristics were closely matched for age, BMI (34.5 kg/m2 and 34.3 kg/m2 in the surgery and bariatric surgery groups, respectively) and race. Hypertensive disorders in the post-surgery group were significantly less common compared with the no-surgery group (0% vs. 9.8%).

During the study, participants underwent cardiovascular assessment at 12-14 weeks, 20-24 weeks, and 30-32 weeks of gestation. The assessment included measurement of blood pressure and heart rate, transthoracic echocardiography, and 2D speckle tracking, performed offline to assess global longitudinal and circumferential strain.

Blood pressure readings across the three trimesters were consistently lower in the women who had undergone bariatric surgery compared with those in the no-surgery group, and all differences were statistically significant. Likewise, heart rate and cardiac output across the three trimesters were lower in the post-surgery cohort. However, there was no difference in stroke volume between the two groups.

As for diastolic function, there were more favorable indices in the post-surgery group with a higher E/A ratio, a marker of left ventricle filling (P < .001), and lower left atrial volume (P < .05), Dr. Patel reported.

With respect to systolic function, there was no difference in ejection fraction, but there was lower global longitudinal strain (P < .01) and global circumferential strain in the post-bariatric group (P = .02), suggesting better systolic function.

“Strain is a measure of differences in motion and velocity between regions of the myocardium through the cardiac cycle and can detect subclinical changes when ejection fraction is normal,” she added.

“This is a fascinating piece of work. The author should be congratulated on gathering so many [pregnant] women who had had bariatric surgery. The work gives a unique glimpse into metabolic syndrome,” said Philip Toozs-Hobson, MD, who moderated the session.

“We are increasingly recognizing the impact [of bariatric surgery] on metabolic syndrome, and the fact that this study demonstrates that there is more to it than just weight is important,” continued Dr. Toosz-Hobson, who is a consultant gynecologist at Birmingham Women’s Hospital NHS Foundation Trust, United Kingdom.
 

Cardiovascular benefits of bariatric surgery

Bariatric surgery has been associated with loss of excess body weight of up to 55% and with approximately 40% reduction in all-cause mortality in the general population. The procedure also reduces the risk for heart disease, diabetes, and cancer.

The cardiovascular benefits of bariatric surgery include reduced hypertension, remodeling of the heart with a reduction in left ventricular mass, and an improvement in diastolic and systolic function.

“Traditionally, the cardiac changes were thought to be due to weight loss and blood pressure reduction, but it is now conceivable that the metabolic components contribute to the reverse modeling via changes to the enterocardiac axis involving changes to gut hormones,” said Dr. Patel. These hormones include secretin, glucagon, and vasoactive intestinal peptide, which are known to have inotropic effects, as well as adiponectin and leptin, which are known to have cardiac effects, she added.

“Pregnancy following bariatric surgery is associated with a reduced risk of hypertensive disorders, as well as a reduced risk of gestational diabetes, large-for-gestational-age neonates, and a small increased risk of small-for-gestational-age neonates,” said Dr. Patel.

Dr. Patel and Dr. Toosz-Hobson have disclosed no relevant financial relationships.

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