Mitchel L. Zoler, PhD

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

As inclisiran, a first-in-class LDL-cholesterol lowering drug, enters the U.S. market following Food and Drug Administration approval in December 2021, several issues muddy how popular inclisiran will be in actual practice. That’s despite stellar phase 3 trial evidence for safety, tolerability, and a potent lipid-lowering effect.

The active ingredient of inclisiran (Leqvio) is a small interfering RNA (siRNA) molecule that shuts down production of the PCSK9 (proprotein convertase subtilisin/kexin type 9) protein, an enzyme that’s made and functions primarily in the liver and degrades cellular receptors for LDL cholesterol. Inhibiting PCSK9 production means LDL-cholesterol receptors accumulate and boost the ability of liver cells to pull more LDL cholesterol out of blood.

PCSK9 inhibition is the most potent LDL-cholesterol lowering method now available, and it works well in patients who have maxed out LDL reduction by diet and statin treatment. The siRNA of inclisiran is tweaked to target the molecule to the surface of liver cells following subcutaneous injection. Other modifications of the siRNA give it stability that allows twice-a-year dosing, although patients receive a third injection during their first year to hasten a maximum treatment effect.

Inclisiran’s FDA approval relied on results from three pivotal trials that together enrolled 3,660 patients with either atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH), and LDL-cholesterol levels of at least 70 mg/dL in those with established ASCVD, or at least 100 mg/dL in other patients. (HeFH and ASCVD are the drug’s approved indications.) Pooled data from the three trials showed that inclisiran was safe and well tolerated during 18 months and produced an average LDL-cholesterol reduction after 510 days (1.4 years) of about 51% compared to baseline after correction for placebo effects (J Am Coll Cardiol. 2021 Mar 9;77 [9]:1182-93).

These data showed inclisiran was about as safe and effective for reducing LDL-cholesterol as agents from another class of PCSK9 inhibitors that rely on injected antibodies to inactivate PCSK9. Two agents from this class, alirocumab (Praluent) and evolocumab (Repatha), both came on the U.S. market in 2015. Although their performance in routine practice during the ensuing 6-plus years has been as safe and effective as what they showed in their respective registration trials, they have faced a rocky uptake road that’s been primarily hindered by the hefty price tag that both drugs carry.
 

Prior-authorization blues

When they first came out, evolocumab and alirocumab were burdened by annual drug costs of roughly $14,000, a fact that led to widespread prior-authorization and copay barriers set up by U.S. insurers. Although these barriers gradually lessened over time, in part aided by a substantial price cut for both drugs that led to annual drug costs more in the range of $6,000/year, they remain relatively pricey and are still not easy to start in patients because of prior-authorization requirements, said clinicians.

Recent penetration of the older PCSK9 inhibitors into eligible U.S. patients “is only about 1%-2%, based on the latest data,” said Michael H. Davidson, MD, a lipid specialist and director of Preventive Cardiology at the University of Chicago.

“We have these great, effective drugs, but they haven’t really made an impact over the past 5 years,” because of very limited uptake, a situation Dr. Davidson called “very disappointing,” during an interview.

Given this recent history, inclisiran, another expensive PCSK9 inhibitor, may face similar coverage pushback as it hits the U.S. market with a retail price, announced by its manufacturer Novartis, of $3,250/dose. This means that patients who start the drug and receive their initial dose, a second dose after 3 months, and then additional doses every 6 months, rack up a drug cost of close to $10,000 the first year on the drug and $6,500 each subsequent year.

This treatment schedule highlights the major logistical difference that distinguishes inclisiran from the antibody-based PCSK9 inhibitors, which are given by repeated subcutaneous injection every 2 or 4 weeks, usually with patients self-injecting the drugs at home. The less-frequent dosing schedule for inclisiran prompted the drug’s developers to schedule injections by a clinician in an office setting in the pivotal trials, which led to labeling for inclisiran that specifies administration only by a health care professional.
 

The ‘buy-and-bill’ coverage model

This difference in drug administration between inclisiran and the antibody-based PCSK9 inhibitors set up Novartis to promote insurance reimbursement for inclisiran using a “buy-and-bill” paradigm that was first developed for oncology drugs and which may provide a loophole around the prior-authorization roadblocks that hindered early uptake of the antibody-based PCSK9 inhibitors.

It’s also an approach that has made U.S. clinicians unsure how it will play out in practice. Infrequent inclisiran dosing may also boost patient compliance.

“Adherence is the greatest challenge in preventive cardiology, and thus inclisiran has the potential to be a game changer,” commented Christie M. Ballantyne, MD, professor and chief of cardiology at Baylor College of Medicine, Houston.

“Will it be easier for physicians to write a prescription and for patients to get the medication without a demanding and frustrating prior-authorization process?” he wondered during an interview. “I’m waiting to see how this unfolds, especially in systems where pharmacy is not fully integrated with the outpatient setting. In some ways, this is as big of an experiment as was development of the drug,” Dr. Ballantyne said.

Although the prior-authorization hoops for evolocumab and alirocumab have become easier to jump through, “most physicians don’t have the resources to handle it and don’t bother,” noted Dr. Davidson, and he’s concerned that infrastructure challenges will also hamper the buy-and-bill strategy for inclisiran.

He also expressed skepticism that the prior-authorization barrier will disappear. “Payers don’t want to open a large population to a very expensive drug without some gatekeeping,” he said, while acknowledging that in late January 2022 he did not yet have personal experience administering inclisiran or navigating its insurance reimbursement.
 

Boosting patient compliance

Dr. Davidson agreed that the prospect for enhanced patient compliance with inclisiran was intriguing and had already drawn the interest of some of his patients.

“There is a lot of appeal” to a treatment that’s only given once every 6 months, he said. “Compliance is a major issue, and this is less work for patients.”

“The biggest possible attraction of inclisiran is that it is given twice a year, but whether this plays out as anticipated in the real world need to be seen,” cautioned Vijay Nambi, MD, a cardiologist at the Michael E. DeBakey VA Hospital, Houston, and at Baylor College of Medicine who has written about inclisiran. He noted that while two doses a year is “on paper very attractive,” this scheme opens the door to missed or delayed appointments because of vacations, other patient travel, or events like a pandemic.

“The biggest pro for inclisiran is the dosing schedule,” said Chandni Bardolia, PharmD, a drug information specialist at Tabula Rasa Healthcare, Moorestown, N.J., who has analyzed and written about inclisiran and other lipid-lowering medications. “Twice yearly dosing following initiation will be a huge benefit to improve adherence and reduce the number of injections.”

However, inclisiran’s attractive dosing schedule as well as its safety and potent efficacy do not tell the whole story, she highlighted in an interview.

Inclisiran’s clinical evidence still cooking

“I see inclisiran as a last-line drug, mainly because the current alternatives have more safety and efficacy data,” Dr. Bardolia said.

Inclisiran’s “cost and the fact that there are other agents with clinical outcome data already available [alirocumab and evolocumab] means inclisiran is not a first-line agent after statins,” agreed Dr. Nambi.

The FDA based its inclisiran approval entirely on the drug’s demonstrated safety and LDL-lowering efficacy. The cardiovascular outcomes trial for inclisiran, ORION-4, with about 15,000 enrolled patients, started in 2018 and remains in progress with full results expected in 2026.

The lack of clinical outcomes data for inclisiran is a major limitation, said Neil J. Stone, MD, a cardiologist and professor at Northwestern University, Chicago, and vice chair of the panel that wrote the most recent cholesterol guideline for the American College of Cardiology and American Heart Association.

“My greatest concern is the lack of outcome trial data. That’s very important,” Dr. Stone said in an interview.

But others minimize this limitation given the overwhelming evidence that links lower levels of LDL-cholesterol to reduced clinical events.

Most clinicians “support lower LDL as a surrogate” for reduced clinical events, “just like blood pressure and hemoglobin A1c,” noted Dr. Davidson, although he conceded that a “substantial minority wants to wait to see inclisiran’s outcome benefits.”
 

It’s all about price

While opinions are mixed on the need for clinical outcomes data, experts are more uniform in seeing drug prices that run to several thousands per year as the main uptake issue.

“We need to look at the cost-efficacy with inclisiran, and we need benefit data to determine this,” said Dr. Stone.

“Outcomes data are central to characterizing value. I imagine that costs will impact adoption and dissemination” of inclisiran, commented Paul L. Hess, MD, a cardiologist at the Rocky Mountain Regional VA Medical Center, Denver.

Patient interest in less frequent dosing will be important for driving use, but “ultimately cost will be the most important driving factor,” for inclisiran uptake, commented Robert H. Eckel, MD, an endocrinologist affiliated with the University of Colorado School of Medicine, Aurora.

Dr. Davidson has ties to New Amsterdam Pharma and Amgen, which markets evolocumab (Repatha). Dr. Ballantyne is a consultant to numerous companies, including Amgen and Regeneron, which market alirocumab (Praluent). Dr. Nambi has been a site investigator for studies sponsored by Amgen, and by Merck, which markets the LDL-cholesterol drug ezetimibe (Zetia) and is developing an oral PCSK9 inhibitor (he said that the views he expressed are his own and don’t represent that of the department of Veterans Affairs or Baylor.) Dr. Bardolia had no disclosures beyond her employment at Tabula Rasa Healthcare. Dr. Stone, Dr. Hess, and Dr. Eckel had no relevant disclosures.


 

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

The drumbeat of U.S. recalls continues for various lots of extended-release metformin because of contamination with unacceptably high levels of a nitrosamine that pose a cancer risk.

On Dec. 28, 2021, Viona Pharmaceuticals voluntarily recalled 33 lots of metformin hydrochloride extended-release tablets, USP 750 mg to the retail level, as a precautionary measure, because of possible contamination with N-nitrosodimethylamine (NDMA).

Metformin is used as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes mellitus. Patients who have received impacted lots of metformin are advised to continue taking their medication and contact their physician for advice regarding an alternative treatment

The product can be identified as white to off-white, capsule shaped, uncoated tablets, debossed with “Z,” “C” on one side and “20” on the other side, and come in bottles of 100 tablets, which have been distributed nationwide. The 33 batch numbers are listed in a company statement.

The affected product was manufactured by Cadila Healthcare, Ahmedabad, India, for U.S. distribution by Viona.

In its statement, Viona said: “NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.”

This recall is being conducted “with the knowledge of the U.S. Food and Drug Administration,” it added.

Consumers with questions regarding this recall can contact the recall processor Eversana Life Science Services by phone at 1-888-304-5022, option 1; Monday-Friday, 8:00 a.m.–7:00 p.m. CT. Customers with medical-related questions who wish to report an adverse event or quality issues about the products being recalled should contact Viona Pharmaceuticals by phone at 888-304-5011, Monday-Friday, 8:30 p.m.–5:30 p.m., EST.
 

Latest in a long line of metformin recalls

This is the second time in 2021 that Viona has voluntarily recalled extended-release metformin tablets, 750 mg, because of potential contamination with NDMA. It recalled two lots in June, as reported by this news organization.

And in January 2021, Nostrum Laboratories recalled another lot of metformin extended-release 750-mg tablets, following on from a prior recall in November 2020.

These recalls follows 258 distinct U.S. lot recalls tracked by the FDA during the past 2 years because of unacceptably high NDMA levels in lots of metformin hydrochloride extended-release tablets.

The FDA has issued several statements about NDMA contamination of metformin formulations over the past 2 years, including a review of the methods used to detect NDMA and a summary of the information the agency had collected on excessive levels of NDMA in metformin.

According to the FDA’s 2020 summary, the agency has not yet determined how or why high levels of NDMA turn up so often in multiple batches of metformin hydrochloride extended-release tablets. However, published research attributed the contamination to certain methods of manufacturing metformin tablets.

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

The drumbeat of U.S. recalls continues for various lots of extended-release metformin because of contamination with unacceptably high levels of a nitrosamine that pose a cancer risk.

On Dec. 28, 2021, Viona Pharmaceuticals voluntarily recalled 33 lots of metformin hydrochloride extended-release tablets, USP 750 mg to the retail level, as a precautionary measure, because of possible contamination with N-nitrosodimethylamine (NDMA).

Metformin is used as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes mellitus. Patients who have received impacted lots of metformin are advised to continue taking their medication and contact their physician for advice regarding an alternative treatment

The product can be identified as white to off-white, capsule shaped, uncoated tablets, debossed with “Z,” “C” on one side and “20” on the other side, and come in bottles of 100 tablets, which have been distributed nationwide. The 33 batch numbers are listed in a company statement.

The affected product was manufactured by Cadila Healthcare, Ahmedabad, India, for U.S. distribution by Viona.

In its statement, Viona said: “NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.”

This recall is being conducted “with the knowledge of the U.S. Food and Drug Administration,” it added.

Consumers with questions regarding this recall can contact the recall processor Eversana Life Science Services by phone at 1-888-304-5022, option 1; Monday-Friday, 8:00 a.m.–7:00 p.m. CT. Customers with medical-related questions who wish to report an adverse event or quality issues about the products being recalled should contact Viona Pharmaceuticals by phone at 888-304-5011, Monday-Friday, 8:30 p.m.–5:30 p.m., EST.
 

Latest in a long line of metformin recalls

This is the second time in 2021 that Viona has voluntarily recalled extended-release metformin tablets, 750 mg, because of potential contamination with NDMA. It recalled two lots in June, as reported by this news organization.

And in January 2021, Nostrum Laboratories recalled another lot of metformin extended-release 750-mg tablets, following on from a prior recall in November 2020.

These recalls follows 258 distinct U.S. lot recalls tracked by the FDA during the past 2 years because of unacceptably high NDMA levels in lots of metformin hydrochloride extended-release tablets.

The FDA has issued several statements about NDMA contamination of metformin formulations over the past 2 years, including a review of the methods used to detect NDMA and a summary of the information the agency had collected on excessive levels of NDMA in metformin.

According to the FDA’s 2020 summary, the agency has not yet determined how or why high levels of NDMA turn up so often in multiple batches of metformin hydrochloride extended-release tablets. However, published research attributed the contamination to certain methods of manufacturing metformin tablets.

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

The drumbeat of U.S. recalls continues for various lots of extended-release metformin because of contamination with unacceptably high levels of a nitrosamine that pose a cancer risk.

On Dec. 28, 2021, Viona Pharmaceuticals voluntarily recalled 33 lots of metformin hydrochloride extended-release tablets, USP 750 mg to the retail level, as a precautionary measure, because of possible contamination with N-nitrosodimethylamine (NDMA).

Metformin is used as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes mellitus. Patients who have received impacted lots of metformin are advised to continue taking their medication and contact their physician for advice regarding an alternative treatment

The product can be identified as white to off-white, capsule shaped, uncoated tablets, debossed with “Z,” “C” on one side and “20” on the other side, and come in bottles of 100 tablets, which have been distributed nationwide. The 33 batch numbers are listed in a company statement.

The affected product was manufactured by Cadila Healthcare, Ahmedabad, India, for U.S. distribution by Viona.

In its statement, Viona said: “NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables.”

This recall is being conducted “with the knowledge of the U.S. Food and Drug Administration,” it added.

Consumers with questions regarding this recall can contact the recall processor Eversana Life Science Services by phone at 1-888-304-5022, option 1; Monday-Friday, 8:00 a.m.–7:00 p.m. CT. Customers with medical-related questions who wish to report an adverse event or quality issues about the products being recalled should contact Viona Pharmaceuticals by phone at 888-304-5011, Monday-Friday, 8:30 p.m.–5:30 p.m., EST.
 

Latest in a long line of metformin recalls

This is the second time in 2021 that Viona has voluntarily recalled extended-release metformin tablets, 750 mg, because of potential contamination with NDMA. It recalled two lots in June, as reported by this news organization.

And in January 2021, Nostrum Laboratories recalled another lot of metformin extended-release 750-mg tablets, following on from a prior recall in November 2020.

These recalls follows 258 distinct U.S. lot recalls tracked by the FDA during the past 2 years because of unacceptably high NDMA levels in lots of metformin hydrochloride extended-release tablets.

The FDA has issued several statements about NDMA contamination of metformin formulations over the past 2 years, including a review of the methods used to detect NDMA and a summary of the information the agency had collected on excessive levels of NDMA in metformin.

According to the FDA’s 2020 summary, the agency has not yet determined how or why high levels of NDMA turn up so often in multiple batches of metformin hydrochloride extended-release tablets. However, published research attributed the contamination to certain methods of manufacturing metformin tablets.

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

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

[email protected]

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

[email protected]

A pair of updated scoring models for estimating a patient’s risk for contrast-associated acute kidney injury during and immediately after percutaneous coronary intervention worked better than a widely used prior version in initial validation testing using data collected at a single U.S. tertiary-care hospital.

Mount Sinai Medical Center

While the two new risk scores looked promising, they need further, external validation with additional, diverse patient cohorts, Roxana Mehran, MD, cautioned at the American Heart Association scientific sessions.

“Don’t change anything until we externally validate this,” urged Dr. Mehran, professor and director of the Center for Interventional Cardiovascular Research and Clinical Trials at Icahn School of Medicine at Mount Sinai in New York. External validation of the two new risk scores is in progress with planned reporting of the results in 2022, she said in an interview.

One of the two new algorithms, which both predict a patient’s risk for developing acute kidney injury (AKI) as a result of receiving iodinated contrast media within 48 hours of a percutaneous coronary intervention (PCI), relies on eight easily available variables taken from a patient’s medical record just prior to undergoing PCI: age, type of coronary disease (ranging from asymptomatic or stable angina to ST-segment elevation MI), estimated glomerular filtration rate, left ventricular ejection fraction, diabetes, hemoglobin, basal glucose, and heart failure.

This risk score accounted for 72% (a C-statistic of 0.72) of the observed AKI episodes during the derivation phase, which used data from 14,616 consecutive Mount Sinai patients who underwent PCI during January 2012–December 2017.

Internal validation using data from 5,606 consecutive Mount Sinai patients who underwent PCI during January 2018–December 2020 showed that the eight-item formula accounted for 84% of all incident AKI events occurring during or within 48 hours of a PCI procedure.
 

Accounting for periprocedural variables

A second risk score included the eight preprocedural variables plus four additional periprocedural variables: complex PCI anatomy, contrast volume during the procedure, development of a periprocedural bleed, and having slow or no reflow into affected coronaries (less than TIMI grade 3 flow) immediately after the procedure. The second model produced a C-statistic of 0.74 during derivation and accounted for 86% of incident AKI events in the validation analysis.

The data Dr. Mehran reported appeared in The Lancet .

She and her coauthors designed these two new algorithms to replace a “widely used” and externally validated risk score that Dr. Mehran and associates introduced in 2004. Despite its merits, the 17-year-old scoring formula has limitations including “low discrimination” with a C-statistic of 0.67, derivation from data that’s now 20 years old, and exclusion of patients with ST-elevation MIs, the authors said in the new report.

Dr. Mehran encouraged interventional cardiologists to use both new risk scores (once externally validated) when possible.

The eight-item preprocedural model “gives clinicians an idea about a patient’s risk [for incident AKI] before they go into the catheterization laboratory,” and then they can further refine the risk assessment during the procedure based on the four periprocedural risk factors, she explained. The goal is to target “tailored preventive strategies” to patients identified by the scoring algorithms as being at high risk for AKI.
 

A role for preventive measures

Preventive strategies to consider for higher-risk patients include limiting the administered volume of iodinated contrast media, increasing hydration, and avoiding nephrotoxic agents, Dr. Mehran said. The two new risk-assessment tools will “allow for better evaluation of PCI patients” when testing “innovative strategies and treatments” designed to help avoid contrast-associated AKI.

“The focus to date has been on measures to protect renal function from contrast media, based on indirect data,” Estelle C. Nijssen, MSc, and Joachim E. Wildberger, MD, wrote in an editorial that accompanied the published report. “The effect of prophylactic measures on longer-term averse outcomes is still unclear,” they noted. “Perhaps our focus should shift from contrast and renal function to the heart, the role of which has probably been undervalued in this setting,” wrote Ms. Nijssen, a researcher at Maastricht (The Netherlands) University, and Dr. Wildberger, professor and chairman of the department of radiology at Maastricht University.

The editorial’s authors noted that the two new risk scores have the advantage of relying on variables that are “readily available in clinical practice.” But they also noted several limitations, such as the model’s development from largely low-risk patients who had a low, roughly 30% prevalence of chronic kidney disease. During 9 full years studied, 2012-2020, the annual incidence of AKI showed a downward trend, with an incidence of just over 3% in 2020.

Dr. Mehran attributed this decline in AKI to “great work identifying high-risk patients” and using the prophylactic measures she cited. But even when occurring at relatively low incidence, “AKI is still an important complication that is associated with mortality post PCI,” she stressed.

Establishing a safe contrast dose

“The study is great, and helps reinforce the risk factors that are most important to consider when risk stratifying patients prior to PCI,” said Neal Yuan, MD, a cardiologist at the University of California, San Francisco, who has studied contrast-associated AKI in patients who undergo PCI. The report from Dr. Mehran also “confirms in a large cohort the association between contrast-associated AKI and death,” and describes “an easy method for calculating risk,” he said in an interview.

Dr. Yuan agreed on the need for external validation, and once adequately validated he called for incorporation of the risk score into EHRs. Another important issue for future study is “how much [AKI] risk is too much risk,” he said.

The risk factors identified in Dr. Mehran’s report “are some of the same ones identified in previous studies. Even though this was a more contemporary dataset, there is not a ton of new [findings]; it mainly strengthens findings from prior studies.”

Results published by Dr. Yuan and his associates in 2020 used data from more than 20,000 U.S. patients who underwent PCI to try to identify a generally safe upper limit for the dose of iodinated contrast.

The main purpose for performing AKI risk stratification on PCI patients is to “identify high-risk patients and use preventive strategies when treating these patients.” Current AKI preventive strategies “mainly fall into intravascular volume expansion, and reduced contrast.” What’s less clear is “how to operationalize reduced contrast,” he said.

The report by Dr. Yuan showed that “about 10% of PCI patients were at very high risk” for contrast-associated AKI “no matter what is done.” In contrast, about two-thirds of PCI patients “could receive lots of contrast and still be very unlikely to develop AKI,” Dr. Yuan said.

He voiced some skepticism about the willingness of many clinicians to routinely use a formal risk score to assess their patients scheduled for PCI.

Most operators “approximate AKI risk based on variables such as age and creatinine level, but few take time to put the variables into a calculator to get an exact risk number.” In a “small survey” he ran, he found that these rough approximations often ignore important risk factors like hemoglobin level. This inertia by clinicians against routinely using a risk score could be addressed, at least in part, by integrating the risk score into an EHR for automatic calculation, Dr. Yuan suggested.

Dr. Mehran noted that the risk score that she introduced in 2004 is used “in many EHRs to identify high-risk patients.”

The current study received no commercial or external funding. Dr. Mehran has been a consultant to Boston Scientific, Cine-Med Research, CIRM, and Janssen, and she holds equity in Applied Therapeutics, Elixir Medical, and STEL. Dr. Wildberger had no relevant disclosures. Ms. Nijssen and Dr. Yuan had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Patients with cardiac implantable electronic devices (CIEDs) who received treatment with an sodium-glucose cotransporter 2 inhibitor had significantly fewer atrial arrhythmia events, compared with those who never received such a drug, in a prospective analysis of nearly 14,000 patients with a device who were followed for an average of nearly 2 years.

The findings suggest that use of an agent from the class of SGLT2 inhibitors “is associated with a pronounced reduction in atrial arrhythmia burden and all-cause mortality in patients with a CIED in a real-world setting,” said Ilan Goldenberg, MD, at the American Heart Association scientific sessions. “These data indicate possible antiarrhythmic properties of SGLT2 inhibitors that are incremental to the beneficial effects of the drug on heart failure outcomes,” added Dr. Goldenberg, director of the Clinical Cardiovascular Research Center at the University of Rochester (N.Y.).

In a propensity score–matched analysis that included more than 5,000 of the enrolled patients with a CIED, treatment with an SGLT2 inhibitor was tied to a significant 23% relative reduction in atrial arrhythmia events and a 44% relative drop in all-cause death, he reported.
 

Effect mediated by reduced left atrial pressure?

“Other heart failure drugs have shown some decrease in the rate of sudden cardiac death, but this is the first [heart failure] drug to associate with a reduction in atrial arrhythmias,” Dr. Goldenberg noted. “We think that a reduction in left atrial pressure” produced by treatment with an SGLT2 inhibitor “may be linked to the reduction in atrial arrhythmias.”

The study did not show an association of SGLT2-inhibitor use and a change in ventricular arrhythmias, compared with patients with CIEDs who did not receive an agent from this class.

The findings suggest “expanding the possible indications for SGLT2 inhibitors,” commented Harriette G.C. Van Spall, MD, a cardiologist at McMaster University, Hamilton, Ont., who moderated the session where Dr. Goldenberg gave his report.

The study included 13,890 consecutive, prospectively enrolled patients who received a CIED during January 2015–April 2020 at any of five hospitals operated by either of two tertiary health care systems, one run by the University of Rochester and the second based at Sheba Medical Center in Tel HaShomer, Israel. The devices that made patients eligible for the study included permanent pacemakers, implantable cardioverter defibrillators, cardiac resynchronization therapy devices, and implantable cardiac monitors. A blinded adjudication committee composed of electrophysiologists identified the arrhythmic episodes.

At entry into the study (the time of device implantation), 12,992 patients were not receiving an SGLT2 inhibitor (94%) and 898 (6%) were receiving a drug from this class. Of those, 39% were on dapagliflozin (Farxiga), 35% were on empagliflozin (Jardiance), and 26% were on canagliflozin (Invokana).

Patients receiving an SGLT2 inhibitor at baseline were on average substantially younger than the patients not on this drug class (59 years vs. 69 years); they had a substantially higher prevalence of diabetes (78% vs. 25%), and ischemic cardiomyopathy (63% vs. 39%). Patients on an SGLT2 inhibitor at baseline also had more modestly higher prevalence rates of prior heart failure (38% vs. 31%), and hypertension (69% vs. 63%). Prevalence of a history of atrial fibrillation (AFib) was nearly the same in both groups: 31% in patients on an SGLT2 inhibitor and 35% in those not on these drugs.

The study’s primary endpoint was the total number of arrhythmia events during follow-up of 24,442 patient-years, during which patients exhibited 19,633 atrial arrhythmia events and 3,231 ventricular arrhythmia events.
 

1% absolute reduction in atrial arrhythmias

A multivariate analysis of the entire population – adjusted for baseline differences in age, diabetes, sex, and history of AFib – showed that treatment with an SGLT2 inhibitor at baseline was linked with a significant 24% relative reduction in incident atrial arrhythmia events, a significant 24% reduction in both atrial and ventricular arrhythmia events, and a 42% relative reduction in all-cause deaths, compared with no SGLT2-inhibitor treatment.

The only analyzed endpoint that showed no significant between-group difference was incidence of ventricular arrhythmias, which was a relative 7% lower in the SGLT2-inhibitor group.

On an absolute basis, treatment with an SGLT2 inhibitor was tied to about a 1% lower rate of atrial arrhythmia events per year, a reduction from a 2.5% rate in those not on an SGLT2 inhibitor to about a 1.5% rate in those taking this drug class.

A second, confirmatory analysis used propensity score matching to identify 5,323 patients not on an SGLT2 inhibitor at baseline who closely matched the 898 patients on an SGLT2 inhibitor. The multivariate modeling for this analysis also adjusted for age, diabetes, sex, and history of AFib.

The results of these analyses closely matched the calculations that used the entire study population. Relative to patients not on an SGLT2 inhibitor those on a drug from this class had 23% fewer atrial arrhythmias, 44% fewer total death, and 22% fewer atrial or ventricular arrhythmias, all significant differences. However, ventricular arrhythmias only reduced by a relative 5%, a nonsignificant difference.

In the propensity score–matched analysis, the absolute reduction in atrial arrhythmias in those on an SGLT2 inhibitor at baseline was roughly 1.3% fewer per year, compared with those not on this drug class.

The study was funded by an unrestricted grant to the University of Rochester from AstraZeneca, the company that markets the SGLT2 inhibitor dapagliflozin (Farxiga). Dr. Goldenberg and Dr. Van Spall had no disclosures.

[email protected]

Roughly 5% of adults with type 2 diabetes achieve remission of their disease, often unbeknownst to the patient and without aggressive weight-loss interventions, according to a new analysis of data from more than 160,000 people in a national diabetes registry in Scotland.

“One of our key new findings is that a reasonably large proportion of people [with type 2 diabetes] were able to achieve remission in routine care, without undergoing bariatric surgery and prior to the introduction of very-low-calorie interventions in routine care,” said Mireille Captieux, MBChB, lead author of the report, in an interview.

The findings “support previous reports that weight loss is associated with type 2 diabetes remission,” said Dr. Captieux, a diabetes researcher at the University of Edinburgh (Scotland).

In her analysis, two of the strongest correlates of remission related to weight loss.

First, a history of bariatric surgery, which included a scant 488 people (0.3% of the study cohort), was associated with a 13-fold increase in the rate of remission, compared with those who did not undergo bariatric surgery. Second, weight loss of 15 kg (33 lb) or more at the time of remission detection in 2019, in comparison with their weight at initial diabetes diagnosis, was linked with a greater than fourfold increase in the rate of remission, compared with those who did not have this amount of weight loss.

But “even losing a small amount of weight increased the chances of remission,” highlights Dr. Captieux. “This finding offers a counterbalance to the pessimistic assumption that almost all people find it very difficult to lose weight.”
 

Hopeful message, but which people achieve diabetes remission?

“What’s encouraging here is that you have people who probably did not do anything radical, and yet they went into remission. The next step is to find out who these people are and what they did to go into remission,” commented Julia Lawton, PhD, a professor of health and social science at the University of Edinburgh whose research focuses on how patients with diabetes manage their disorder.

“If we can understand who the patients are who can achieve remission without taking extreme measures, it could help people in the health professions get beyond their presumptions about who is, or is not, a good candidate for achieving diabetes remission,” said Dr. Lawton, who was not involved with the study.

The message from this study is “very hopeful,” Dr. Lawton said in an interview. “How can we make this opportunity [for diabetes remission] available to more people? What can we learn from these patients that we could then apply to other patients?”

Dr. Captieux agrees. Given her findings, an important next step is to find out more about the population in remission to better understand “their perspectives on the challenges and benefits of supporting weight loss.

“Obesity is a complex issue, and therefore weight loss interventions that target individual actions and behaviors are much more likely to be effective if they are accompanied by multiple interventions at different levels,” Dr. Captieux said.

In addition, “more evidence is needed to assess the sustainability of diabetes remission and the effect of different durations of remission for a clinically relevant definition.”
 

Duration, definition of diabetes remission

Dr. Captieux noted that the new international consensus definition of type 2 diabetes remission – which specifies a minimum 3-month duration of glycemic control to qualify as remission – means that people with diabetes “may frequently oscillate” between remission and active disease.

This makes it important to better define the effect of duration of diabetes remission regarding various diabetes complications.

Another issue raised by the new findings is the importance of distinguishing people who lose weight because of a healthier diet and increased activity from those who lose weight because of chronic illness or frailty that’s followed by long-term adverse outcomes.

If these two populations are not distinguished in an observational cohort study – such as the one run by Dr. Captieux and her associates – then the people with chronic illness might appear to have worse outcomes following diabetes remission.

Dr. Captieux and her coauthors used data collected in the Scottish Care Information–Diabetes registry, which includes almost all people diagnosed with diabetes in Scotland. They focused on people with diabetes who had first been diagnosed with diabetes during 2004-2018, who were at least 30 years old at the time of their initial diagnosis, and who had received care in the national health system during 2019.

This yielded a study cohort of 162,316 people, of whom 7,710 (4.8%) were identified by the researchers as being in remission in 2019.

Patients in remission were defined as those whose hemoglobin A1c level was less than 6.5% at their index reading in 2019 and whose A1c level could be documented as being lower than 6.5% for at least 1 year prior to the 2019 measurement.

In a primary logistic regression analysis, the authors identified five variables that were significantly linked with remission: age of at least 65 years (the association was even stronger for age older than 75 years), a lower A1c level at the time of initial diabetes diagnosis, weight loss, prior bariatric surgery, and no prior treatment with a glucose-lowering therapy.

The strongest association was with having had no prior treatment with a glucose-lowering therapy in 2019. People who met this criterion were nearly 15 times more likely to be in remission in 2019, compared with those who had received at least one of these agents.

The study received no commercial funding. Dr. Captieux and Dr. Lawton have disclosed no relevant financial relationships.

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

Roughly 5% of adults with type 2 diabetes achieve remission of their disease, often unbeknownst to the patient and without aggressive weight-loss interventions, according to a new analysis of data from more than 160,000 people in a national diabetes registry in Scotland.

“One of our key new findings is that a reasonably large proportion of people [with type 2 diabetes] were able to achieve remission in routine care, without undergoing bariatric surgery and prior to the introduction of very-low-calorie interventions in routine care,” said Mireille Captieux, MBChB, lead author of the report, in an interview.

The findings “support previous reports that weight loss is associated with type 2 diabetes remission,” said Dr. Captieux, a diabetes researcher at the University of Edinburgh (Scotland).

In her analysis, two of the strongest correlates of remission related to weight loss.

First, a history of bariatric surgery, which included a scant 488 people (0.3% of the study cohort), was associated with a 13-fold increase in the rate of remission, compared with those who did not undergo bariatric surgery. Second, weight loss of 15 kg (33 lb) or more at the time of remission detection in 2019, in comparison with their weight at initial diabetes diagnosis, was linked with a greater than fourfold increase in the rate of remission, compared with those who did not have this amount of weight loss.

But “even losing a small amount of weight increased the chances of remission,” highlights Dr. Captieux. “This finding offers a counterbalance to the pessimistic assumption that almost all people find it very difficult to lose weight.”
 

Hopeful message, but which people achieve diabetes remission?

“What’s encouraging here is that you have people who probably did not do anything radical, and yet they went into remission. The next step is to find out who these people are and what they did to go into remission,” commented Julia Lawton, PhD, a professor of health and social science at the University of Edinburgh whose research focuses on how patients with diabetes manage their disorder.

“If we can understand who the patients are who can achieve remission without taking extreme measures, it could help people in the health professions get beyond their presumptions about who is, or is not, a good candidate for achieving diabetes remission,” said Dr. Lawton, who was not involved with the study.

The message from this study is “very hopeful,” Dr. Lawton said in an interview. “How can we make this opportunity [for diabetes remission] available to more people? What can we learn from these patients that we could then apply to other patients?”

Dr. Captieux agrees. Given her findings, an important next step is to find out more about the population in remission to better understand “their perspectives on the challenges and benefits of supporting weight loss.

“Obesity is a complex issue, and therefore weight loss interventions that target individual actions and behaviors are much more likely to be effective if they are accompanied by multiple interventions at different levels,” Dr. Captieux said.

In addition, “more evidence is needed to assess the sustainability of diabetes remission and the effect of different durations of remission for a clinically relevant definition.”
 

Duration, definition of diabetes remission

Dr. Captieux noted that the new international consensus definition of type 2 diabetes remission – which specifies a minimum 3-month duration of glycemic control to qualify as remission – means that people with diabetes “may frequently oscillate” between remission and active disease.

This makes it important to better define the effect of duration of diabetes remission regarding various diabetes complications.

Another issue raised by the new findings is the importance of distinguishing people who lose weight because of a healthier diet and increased activity from those who lose weight because of chronic illness or frailty that’s followed by long-term adverse outcomes.

If these two populations are not distinguished in an observational cohort study – such as the one run by Dr. Captieux and her associates – then the people with chronic illness might appear to have worse outcomes following diabetes remission.

Dr. Captieux and her coauthors used data collected in the Scottish Care Information–Diabetes registry, which includes almost all people diagnosed with diabetes in Scotland. They focused on people with diabetes who had first been diagnosed with diabetes during 2004-2018, who were at least 30 years old at the time of their initial diagnosis, and who had received care in the national health system during 2019.

This yielded a study cohort of 162,316 people, of whom 7,710 (4.8%) were identified by the researchers as being in remission in 2019.

Patients in remission were defined as those whose hemoglobin A1c level was less than 6.5% at their index reading in 2019 and whose A1c level could be documented as being lower than 6.5% for at least 1 year prior to the 2019 measurement.

In a primary logistic regression analysis, the authors identified five variables that were significantly linked with remission: age of at least 65 years (the association was even stronger for age older than 75 years), a lower A1c level at the time of initial diabetes diagnosis, weight loss, prior bariatric surgery, and no prior treatment with a glucose-lowering therapy.

The strongest association was with having had no prior treatment with a glucose-lowering therapy in 2019. People who met this criterion were nearly 15 times more likely to be in remission in 2019, compared with those who had received at least one of these agents.

The study received no commercial funding. Dr. Captieux and Dr. Lawton have disclosed no relevant financial relationships.

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

Roughly 5% of adults with type 2 diabetes achieve remission of their disease, often unbeknownst to the patient and without aggressive weight-loss interventions, according to a new analysis of data from more than 160,000 people in a national diabetes registry in Scotland.

“One of our key new findings is that a reasonably large proportion of people [with type 2 diabetes] were able to achieve remission in routine care, without undergoing bariatric surgery and prior to the introduction of very-low-calorie interventions in routine care,” said Mireille Captieux, MBChB, lead author of the report, in an interview.

The findings “support previous reports that weight loss is associated with type 2 diabetes remission,” said Dr. Captieux, a diabetes researcher at the University of Edinburgh (Scotland).

In her analysis, two of the strongest correlates of remission related to weight loss.

First, a history of bariatric surgery, which included a scant 488 people (0.3% of the study cohort), was associated with a 13-fold increase in the rate of remission, compared with those who did not undergo bariatric surgery. Second, weight loss of 15 kg (33 lb) or more at the time of remission detection in 2019, in comparison with their weight at initial diabetes diagnosis, was linked with a greater than fourfold increase in the rate of remission, compared with those who did not have this amount of weight loss.

But “even losing a small amount of weight increased the chances of remission,” highlights Dr. Captieux. “This finding offers a counterbalance to the pessimistic assumption that almost all people find it very difficult to lose weight.”
 

Hopeful message, but which people achieve diabetes remission?

“What’s encouraging here is that you have people who probably did not do anything radical, and yet they went into remission. The next step is to find out who these people are and what they did to go into remission,” commented Julia Lawton, PhD, a professor of health and social science at the University of Edinburgh whose research focuses on how patients with diabetes manage their disorder.

“If we can understand who the patients are who can achieve remission without taking extreme measures, it could help people in the health professions get beyond their presumptions about who is, or is not, a good candidate for achieving diabetes remission,” said Dr. Lawton, who was not involved with the study.

The message from this study is “very hopeful,” Dr. Lawton said in an interview. “How can we make this opportunity [for diabetes remission] available to more people? What can we learn from these patients that we could then apply to other patients?”

Dr. Captieux agrees. Given her findings, an important next step is to find out more about the population in remission to better understand “their perspectives on the challenges and benefits of supporting weight loss.

“Obesity is a complex issue, and therefore weight loss interventions that target individual actions and behaviors are much more likely to be effective if they are accompanied by multiple interventions at different levels,” Dr. Captieux said.

In addition, “more evidence is needed to assess the sustainability of diabetes remission and the effect of different durations of remission for a clinically relevant definition.”
 

Duration, definition of diabetes remission

Dr. Captieux noted that the new international consensus definition of type 2 diabetes remission – which specifies a minimum 3-month duration of glycemic control to qualify as remission – means that people with diabetes “may frequently oscillate” between remission and active disease.

This makes it important to better define the effect of duration of diabetes remission regarding various diabetes complications.

Another issue raised by the new findings is the importance of distinguishing people who lose weight because of a healthier diet and increased activity from those who lose weight because of chronic illness or frailty that’s followed by long-term adverse outcomes.

If these two populations are not distinguished in an observational cohort study – such as the one run by Dr. Captieux and her associates – then the people with chronic illness might appear to have worse outcomes following diabetes remission.

Dr. Captieux and her coauthors used data collected in the Scottish Care Information–Diabetes registry, which includes almost all people diagnosed with diabetes in Scotland. They focused on people with diabetes who had first been diagnosed with diabetes during 2004-2018, who were at least 30 years old at the time of their initial diagnosis, and who had received care in the national health system during 2019.

This yielded a study cohort of 162,316 people, of whom 7,710 (4.8%) were identified by the researchers as being in remission in 2019.

Patients in remission were defined as those whose hemoglobin A1c level was less than 6.5% at their index reading in 2019 and whose A1c level could be documented as being lower than 6.5% for at least 1 year prior to the 2019 measurement.

In a primary logistic regression analysis, the authors identified five variables that were significantly linked with remission: age of at least 65 years (the association was even stronger for age older than 75 years), a lower A1c level at the time of initial diabetes diagnosis, weight loss, prior bariatric surgery, and no prior treatment with a glucose-lowering therapy.

The strongest association was with having had no prior treatment with a glucose-lowering therapy in 2019. People who met this criterion were nearly 15 times more likely to be in remission in 2019, compared with those who had received at least one of these agents.

The study received no commercial funding. Dr. Captieux and Dr. Lawton have disclosed no relevant financial relationships.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
 

An end to ‘renalism’

“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.   

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.

EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.

“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
 

More CKD-independent effects of empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.

“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

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

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

[email protected]

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

[email protected]

Main results from the landmark EMPEROR-Preserved trial, reported in August, established for the first time that treatment with a drug, the sodium-glucose cotransporter 2 inhibitor empagliflozin, could clearly benefit patients with heart failure with preserved ejection fraction (HFpEF).

The only caveat was that EMPEROR-Preserved enrolled patients with a left ventricular ejection fraction of at least 41%, while “true” HFpEF means patients with heart failure and an LVEF of at least 50%, according to recent definitions. About one-third of the 5,988 patients enrolled in EMPEROR-Preserved had an LVEF of 41%-49%, heart failure with mildly reduced ejection fraction.

Secondary analysis from the EMPEROR-Preserved trial has now resolved this ambiguity by showing that, among the 4,005 patients (67%) enrolled in the trial with an LVEF of at least 50%, treatment with empagliflozin (Jardiance) reduced the study’s primary endpoint – cardiovascular death or first hospitalization for heart failure – by a significant 17%, relative to patients who received placebo, dismissing any doubt about the relevance of the overall finding to the subgroup of patients with unmitigated HFpEF.

“This is the first large-scale trial to document meaningful and significant improvements associated with drug therapy in patients with ‘true’ HFpEF,” Stefan D. Anker, MD, said in presenting the results at the American Heart Association scientific sessions.

Streamlining heart failure treatment

The demonstration that empagliflozin is an effective – and safe – treatment for patients with HFpEF not only provides a new treatment for a disorder that until now had no evidence-based intervention, but also streamlines the management approach for treating patients with heart failure with an agent from empagliflozin’s class, the SGLT2 inhibitors, commented Mary Norine Walsh, MD, medical director of the heart failure and cardiac transplantation programs at Ascension St. Vincent Heart Center in Indianapolis.

That’s because empagliflozin has shown significant and consistent benefit across essentially the full range of LVEFs seen in patients with heart failure based on its performance in EMPEROR-Preserved as well as in a mirror-image trial, EMPEROR-Reduced, run in patients with heart failure with reduced ejection fraction.

“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients” with an SGLT2 inhibitor, noted Dr. Walsh, a designated discussant for the report. “Clinicians who are busy can now refer less to LVEF than to the patient’s phenotype.”
 

Treatment prevents hospitalization for heart failure

The more-detailed data reported by Dr. Anker also strengthened the case that the benefit from empagliflozin in patients with an LVEF of at least 50% mostly came from a reduction in hospitalizations for heart failure (HHF), which dropped following start of empagliflozin treatment by a relative 22%, compared with placebo for first HHF, a significant decline, and by a relative 17% for total HHF, a reduction that missed significance in this secondary analysis. The other half of the primary endpoint, cardiovascular death, declined by a nonsignificant 11% with empagliflozin treatment, compared with placebo in patients with clear-cut HFpEF.

The significant reduction in first HHF is, by itself, sufficient reason to use empagliflozin (or possibly a different SGLT2 inhibitor) in patients with HFpEF, maintained Clyde W. Yancy, MD, professor and chief of cardiology at Northwestern Medicine in Chicago.

“Attenuated HHF is a meaningful outcome,” stressed Dr. Yancy, also a discussant for the study. “This is the first time we’ve had evidence supporting that we can change the natural history of patients with HFpEF. While we still need to find interventions that save lives, we cannot overlook that this treatment can improve morbidity, and we cannot overlook that patient quality of life is better.”
 

Further benefits in patients with an LVEF of at least 50%

Dr. Anker, professor of cardiology and metabolism at Charité Medical University in Berlin, also reported results from several other analyses that further defined the effect of empagliflozin on clinical outcomes of patients with “true” HFpEF:

• The impact of empagliflozin, compared with placebo, for reducing both the study’s combined, primary outcome as well as total HHF was statistically consistent across all strata of LVEF, from 50% to greater than 70%. However, both outcome measures also showed a puzzling loss of benefit among patients with an LVEF of 65%-69%. In prior reports, a researcher on the EMPEROR-Preserved team, Milton Packer, MD, speculated that some patients in this LVEF stratum might not actually have had heart failure but instead had a different disorder that mimicked heart failure in clinical presentation, such as atrial fibrillation.
• Patients’ quality of life as measured by the Kansas City Cardiomyopathy Questionnaire showed a consistent benefit from empagliflozin treatment, compared with placebo, both in patients with an LVEF of at least 50% as well as in those with an LVEF of 41%-49%. In both subgroups the adjusted mean difference from placebo was significant and about 1.5 points.
• Patients showed a significant improvement in average New York Heart Association functional class while on treatment, and a strong trend toward less deterioration in functional class while on treatment.
• Deterioration of renal function on treatment slowed by an average 1.24 mL/min per 1.73 m² per year in patients on empagliflozin, compared with placebo, in the subgroup with an LVEF of at least 50%.

Dr. Anker also reported the primary outcome and component results for the subgroup of patients with a baseline LVEF of 41%-49%. These patients had what looked like a “bigger magnitude” of effect from treatment, he noted, showing a significant 29% relative decline in the primary endpoint, compared with placebo-treated patients, and a significant 42% relative drop in first HHF and a significant 43% relative decline in total HHF, compared with placebo.

The primary analysis from EMPEROR-Preserved, which included all 5,988 randomized patients with heart failure and an LVEF of 41% or greater, showed a significant reduction in the combined, primary endpoint with empagliflozin treatment of 21%, compared with control patients during a median follow-up of about 26 months. The absolute rate reduction of the combined primary endpoint was 3.3% during 26-months’ follow-up. Statistical tests have shown no heterogeneity of this effect by diabetes status (49% of patients had diabetes), nor by renal function down to an estimated glomerular filtration rate at entry as low as 20 mL/min per 1.73 m².

EMPEROR-Preserved was sponsored by Boehringer Ingelheim and Lilly, the two companies that market empagliflozin (Jardiance). Dr. Anker has been a consultant to Boehringer Ingelheim as well as to Abbott Vascular, Bayer, Brahms, Cardiac Dimensions, Cordio, Novartis, Servier, and Vifor. Dr. Walsh and Dr. Yancy had no disclosures.

[email protected]

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

Daily treatment with oral daprodustat was noninferior to standard erythropoiesis-stimulating agents (ESAs) for both increasing hemoglobin levels and for cardiovascular safety in patients with chronic kidney disease (CKD), both in those who are dialysis dependent and those who are not, in a pair of phase 3, randomized trials that together included more than 6,800 patients.

“Daprodustat could represent an oral alternative to ESAs for treating anemia of CKD in both dialysis and nondialysis patients,” said Ajay K. Singh, MBBS, who presented results from both studies at the annual meeting of the American Society of Nephrology.

Concurrently, reports on the trial with dialysis-dependent patients, ASCEND-D, and on the trial with non–dialysis-dependent patients, ASCEND-ND, appeared online in the New England Journal of Medicine.

Singh highlighted that the results prove the noninferiority of oral daprodustat to the injected ESAs – epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) – used as the comparator agents in the two trials for the adjudicated safety outcome of major adverse cardiovascular events (MACE). In addition, results from the two studies also showed “no safety signals that pop out, and no new safety signals observed,” he said.

Those were telling assessments, given that two other agents from the same drug class – the hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) roxadustat and vadadustat – have been hobbled by safety concerns that cropped up in their pivotal trials.
 

A class with a history of safety concerns

The HIF-PHI roxadustat received an overwhelming negative reaction from an advisory committee to the Food and Drug Administration in July 2021 because of safety concerns, although it was approved in the European Union.

And results from a phase 3 trial of the HIF-PHI agent vadadustat reported in April, showed that, in patients with non–dialysis-dependent CKD treated with vadadustat the MACE incidence failed to meet the trial’s criterion for noninferiority, compared with patients treated with the ESA darbepoetin alfa.

In contrast, the safety of daprodustat, based on the results reported so far “is looking really good,” commented Jay B. Wish, MD, a nephrologist and professor at Indiana University in Indianapolis who was not involved with the study.

“You never know what’s behind the curtain, but what’s out there [for daprodustat] seems very encouraging,” Dr. Wish said in an interview.

He cited in particular the data reported by Dr. Singh on thromboembolic events and vascular access thrombosis, adverse effects that were especially problematic for roxadustat. The report by Dr. Singh specifically called out these numbers and showed numerical reductions in these rates, compared with ESA-treated patients among those on dialysis, and small increases among those on daprodustat, compared with ESA treatment among those not on dialysis.

In ASCEND-ND, nonfatal thromboembolic events during median follow-up of 1.9 years occurred 97 times (in 3.0% of patients) among 1,917 patients treated with daprodustat and 65 times (in 2.4% of patients) among 1,935 patients treated with darbepoetin alfa, reported Dr. Singh, a nephrologist at Brigham and Women’s Hospital in Boston. Vascular access thrombosis in ASCEND-ND occurred 69 times in 2.1% of patients on daprodustat and 42 times in 1.5% of patients who received the ESA.

Drugs from the HIF-PHI class for anemia in patients with CKD “have now been evaluated in a number of phase 3, randomized, controlled trials. Initial results in patients with dialysis-dependent CKD are promising, but in patients with non–dialysis-dependent CKD questions about indications and safety warrant further investigations,” Patrick Parfrey, MD, commented in an editorial that accompanied the ASCEND-D and ASCEND-ND reports.
 

Safety signals seen for cancers and erosions

Dr. Parfrey cited two particular safety findings, both seen in ASCEND-ND. One was a numerically higher rate of cancer-related death, or tumor progression or recurrence, among the daprodustat recipients (3.7%), compared with the controls who received an ESA in the ASCEND-ND trial (2.5%), representing a significant relative risk of 1.47.

In contrast, in ASCEND-D this cancer safety measure showed a reduced relative risk with daprodustat of 0.92 relative to the ESA comparators.

“The safety of HIF-PHIs from the cancer perspective will require longer follow-up, individual patient meta-analysis ... and postmarketing surveillance,” wrote Dr. Parfrey, a nephrologist and professor at Memorial University, St. John’s, Nfld.

Elevated cancer rates are a hypothetical concern with agents from the HIF-PHI class because of their potential for increasing angiogenesis that could support tumor growth, said Dr. Wish.

Dr. Parfrey also cited another safety signal in ASCEND-ND, a higher rate of esophageal or gastric erosions on daprodustat (3.6%), compared with those on darbepoetin alfa (2.1%), with a significant relative risk of 1.7.

Again, this signal was absent in ASCEND-D, where esophageal or gastric erosions were more common in the patients on an ESA, with a relative risk reduction in favor of daprodustat of 0.74.

But even if these cancer and erosion effects in nondialysis patients on daprodustat are real, “these things don’t sink a drug. You deal with them in the drug’s label,” commented Dr. Wish.

During the FDA’s advisory committee meeting on roxadustat, agency staffers especially cited apparent excess rates of thrombosis and seizures associated with the drug. In both ASCEND-D and ASCEND-ND the rate of seizures in both treatment arms was less than 1%.

Dr. Wish speculated that the differences seen between roxadustat and daprodustat are likely more related to the design of their respective studies rather than real drug differences within the class.

Perhaps most importantly, the roxadustat trials in patients with CKD and not requiring dialysis compared the drug against placebo, while in ASCEND-ND the comparator was darbepoetin alfa. He also suggested that patients on dialysis receiving roxadustat may have been “overdosed,” resulting in faster increases in hemoglobin and higher peak levels.
 

Big potential for oral anemia treatment

In general, having an oral alternative for treating anemia in patients with CKD will be a significant advance, said Dr. Wish, especially for patients not on dialysis as well as for the rapidly growing number of patients who receive dialysis at home.

U.S. patients with CKD who do not require dialysis “often don’t get treated for anemia because it is so cumbersome” to use ESAs on patients not treated at a centralized clinic, said Dr. Wish, medical director of the outpatient dialysis unit at Indiana University Hospital, Indianapolis. “It’s a logistical nightmare.”

On the other hand, Wish did not see nearly as great a need for an oral therapy for anemia in patients treated at a dialysis clinic.

Patients who receive an ESA during their three-times weekly dialysis session usually do very well. “It’s not broken, and does not need to get fixed,” Dr. Wish said.

ASCEND-D and ASCEND-ND were sponsored by GlaxoSmithKline, the company developing daprodustat. Dr. Singh has been a consultant to GlaxoSmithKline and owns stock in Gilead. Dr. Wish has been a consultant to GlaxoSmithKline, as well as an adviser to AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medica, and he has been a speaker on behalf of AstraZeneca and Akebia.

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

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]