Pharmacology

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

The U.S. Food and Drug Administration (FDA) has approved daratumumab + hyaluronidase-fihj (Darzalex Faspro) and carfilzomib (Kyprolis) plus dexamethasone (Kd) for patients with relapsed or refractory multiple myeloma who have had one to three prior lines of therapy.

Using the newly approved combination in this setting is a time-saver for patients and clinics, observed an investigator.

“The approval of subcutaneous daratumumab in combination with Kd will help clinicians address unmet patient needs by reducing the administration time from hours to just minutes and reducing the frequency of infusion-related reactions, as compared to the intravenous daratumumab formulation in combination with Kd,” said Ajai Chari, MD, of Mount Sinai Cancer Clinical Trials Office in New York City in a Janssen press statement.

Efficacy data for the new approval come from a single-arm cohort of PLEIADES, a multicohort, open-label trial. The cohort included 66 patients with relapsed or refractory multiple myeloma who had received one or more prior lines of therapy. Patients received daratumumab + hyaluronidase-fihj subcutaneously in combination with carfilzomib and dexamethasone.

The main efficacy outcome measure was overall response rate, which was 84.8%. At a median follow-up of 9.2 months, the median duration of response had not been reached.

The response rate with the new combination, which features a subcutaneous injection, was akin to those with the older combination, which features the more time-consuming IV administration and was FDA approved, according to the company press release.

The most common adverse reactions (≥20%) occurring in patients treated with Darzalex Faspro, Kyprolis, and dexamethasone were upper respiratory tract infections, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea, and edema peripheral.

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

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]

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

Merck’s antiviral pill for COVID-19, molnupiravir, appears to be far less effective than early results from the clinical trial first suggested.

According to an analysis by scientists at the Food and Drug Administration, the experimental pill cut the risk of hospitalization or death from COVID-19 by about 30%, compared to a placebo, and the pill showed no benefit for people with antibodies against COVID-19 from prior infection.

The updated analysis showed 48 hospitalizations or deaths among study participants who were randomly assigned to take the antiviral drug, compared to 68 among those who took a placebo.

Those results come from the full set of 1,433 patients who were randomized in the clinical trial, which just became available last week.

Initial results from the first 775 patients enrolled in the clinical trial, which were issued in a company news release in October, had said the drug cut the risk of hospitalization or death for patients at high risk of severe disease by about 50%.

Merck has been producing millions of doses of molnupiravir, which is the first antiviral pill to treat COVID-19 infections. The United Kingdom’s drug regulator authorized use of the medication in early November. The company said it expected to distribute the medication globally by the end of 2021.

In October, two Indian drug companies halted late-stage clinical trials of a generic version of molnupiravir after the studies failed to find any benefit to patients with moderate COVID-19. Trials in patients with milder symptoms are still ongoing.

On Nov. 27, the New England Journal of Medicine postponed its planned early release of the molnupiravir study results, citing “new information.”

The medication is designed to be given as four pills taken every 12 hours for 5 days. It’s most effective when taken within the first few days of new symptoms, something that requires convenient and affordable testing.

The new results seem to put molnupiravir far below the effectiveness of existing treatments.

The infused monoclonal antibody cocktail REGEN-COV, which the FDA has already authorized for emergency use, is about 85% effective at preventing hospitalization or death in patients who are at risk for severe COVID-19 outcomes, and it appears to be just as effective in people who already have antibodies against COVID-19, which is why it is being given to both vaccinated and unvaccinated patients, the FDA said.

In early November, Pfizer said its experimental antiviral pill Paxlovid cut the risk of hospitalization or death by 89%.

In briefing documents posted ahead of an advisory committee meeting Nov. 30, the FDA highlights other potential safety issues with the Merck drug, which works by causing the virus to make mistakes as it copies itself, eventually causing the virus to mutate itself to death.

The agency has asked the advisory committee to weigh in on the right patient population for the drug: Should pregnant women get it? Could the drug harm a developing fetus?

Should vaccinated people with breakthrough infections get it? Would it work for them? People with reduced immune function are more likely to get a breakthrough infection. They’re also more likely to shed virus for a longer period of time, making them perfect incubators for variants. What could happen if we give this type of patient a drug that increases mutations?

And what about mutations caused by the medication? Could they increase the potential for more variants? The agency concluded the risk of this happening was low.

In animal studies, the drug impacted bone formation. For this reason, the agency has agreed with the drug company that molnupiravir should not be given to anyone under the age of 18.

Aside from these concerns, the FDA says there were no major safety issues among people who took part in the clinical trial, though they acknowledge that number is small.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

There is a significant inverse relationship between concentrations of circulating 25-hydroxy-vitamin D (25[OH]D) and all-cause mortality, but only in people with vitamin D deficiency, suggests a new large-scale analysis.

Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.

However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.

The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.

In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.

They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”

They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”

However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
 

Prior RCTS underpowered to detect effects of vitamin D supplements

“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.

They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”

The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”

They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.

To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.

They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.

Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.

The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.

Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.

Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.

The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
 

Up to 7% of study participants were vitamin D deficient

The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.

Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.

However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.

There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).

Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.

They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”

Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”

They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”

The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

The Food and Drug Administration has approved the first treatment for posttransplant cytomegalovirus (CMV) that is resistant to other drugs. The treatment, maribavir (Livtencity), is approved for adults and children 12 years and older who weigh at least 35 kg (77 pounds).

There are an estimated 200,000 adult transplants every year globally. CMV, a type of herpes virus, is one of the most common infections in transplant patients, occurring in 16%-56% of solid organ transplant recipients and 30%-70% of hematopoietic stem cell transplant recipients, according to Takeda Pharmaceutical Company Limited, the company that manufactures Livtencity. For immunosuppressed transplant patients, CMV infection can lead to complications that include loss of the transplanted or organ or even death.

“Cytomegalovirus infections that are resistant or do not respond to available drugs are of even greater concern,” John Farley, MD, MPH, the director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Today’s approval helps meet a significant unmet medical need by providing a treatment option for this patient population.”

Livtencity, which is taken orally, works by preventing the activity of the enzyme responsible for virus replication. The approval, announced Nov. 23, was based on a phase 3 clinical trial that compared Livtencity with conventional antiviral treatments in the achievement of CMV DNA concentration levels below what is measurable in transplant patients with CMV infection that is refractory or treatment-resistant. After 8 weeks, of the 235 patients who received Livtencity, 56% achieved this primary endpoint, compared with 24% of the 117 patients who received conventional antiviral treatments, the press release says.

The most reported adverse reactions of Livtencity were taste disturbance, nausea, diarrhea, vomiting, and fatigue.

“We are grateful for the contributions of the patients and clinicians who participated in our clinical trials, as well as the dedication of our scientists and researchers,” Ramona Sequeira, president of the Takeda’s U.S. Business Unit and Global Portfolio Commercialization, said in a statement. “People undergoing transplants have a lengthy and complex health care journey; with the approval of this treatment, we’re proud to offer these individuals a new oral antiviral to fight CMV infection and disease.”

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

A head-to-head comparison of immune checkpoint inhibitors atezolizumab and nivolumab and the chemotherapy drug docetaxel in patients with advanced non–small cell lung cancer (NSCLC), finds that atezolizumab was associated with a significantly longer overall survival than docetaxel and was on par with nivolumab.

The findings were reported in JAMA Network Open.

“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.

Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.

This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.

Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.

This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.

Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.

“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”

Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.

This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.

A head-to-head comparison of immune checkpoint inhibitors atezolizumab and nivolumab and the chemotherapy drug docetaxel in patients with advanced non–small cell lung cancer (NSCLC), finds that atezolizumab was associated with a significantly longer overall survival than docetaxel and was on par with nivolumab.

The findings were reported in JAMA Network Open.

“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.

Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.

This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.

Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.

This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.

Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.

“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”

Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.

This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.

A head-to-head comparison of immune checkpoint inhibitors atezolizumab and nivolumab and the chemotherapy drug docetaxel in patients with advanced non–small cell lung cancer (NSCLC), finds that atezolizumab was associated with a significantly longer overall survival than docetaxel and was on par with nivolumab.

The findings were reported in JAMA Network Open.

“Until recently, chemotherapy with platinum doublet was the standard first-line option for most patients with advanced NSCLC who did not have these genetic drivers or were not tested for them and remains the first choice in many parts of the world,” wrote the authors of the study which was led by Sreeram Ramagopalan, PhD, of F. Hoffmann-La Roche in Switzerland which funded the study.

Atezolizumab (Tecentriq, Genentech), which was approved in October by the U.S. Food and Drug Administration, is a monoclonal antibody that targets programmed cell death ligand 1 (PD-L1). It is also approved as monotherapy for patients with advanced NSCLC whose disease progressed despite treatment with platinum-based chemotherapy.

This is the first-known analysis that compares atezolizumab, nivolumab (Opdivo, Bristol Myers Squibb), and docetaxel (Taxotere, Sanofi) in patients outside of clinical trials, said Vivek Subbiah, MD, of MD Anderson Cancer Center and the study’s first author. “We have several new immune checkpoint inhibitors approved for treatment for NSCLC. Head-to-head comparison of the effectiveness of these agents in the real world are lacking,” he said.

Treatment with immune checkpoint inhibitors has shown improvement in the survival of patients with advanced NSCLC who failed chemotherapy treatment.

This study included 3,336 patients (mean age 67 years, 54.6% men) with advanced NSCLC who were treated with platinum-based chemotherapy. Data were collected from more than 1,000 clinics in the United States. Of the patients, 206 received atezolizumab, 500 received docetaxel, and 2,630 received nivolumab.

Patients were followed between May 2011 and March 2020. Atezolizumab and nivolumab showed a similar overall survival in these patients, but atezolizumab showed a longer overall survival, compared with docetaxel.

“Compared with docetaxel, atezolizumab was associated with significantly longer survival in the overall population and across all subgroups analyzed,” including patients with stage IIIB or IV cancer at diagnosis and nonsquamous NSCLC, the authors wrote. “Atezolizumab was associated with longer overall survival compared with docetaxel and was on par with nivolumab, supporting current clinical guidelines for systemic therapy for patients with advanced NSCLC in the U.S.”

Limitations of the study included its observational design and a small number of patients receiving atezolizumab. The authors suggested that studies using larger sample sizes are needed.

This study was funded by F. Hoffmann-La Roche. Genentech is a subsidiary of F. Hoffmann-La Roche.

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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

Adding lithium to usual care does not decrease the risk of suicide-related events in those with major depressive disorder (MDD) or bipolar disorder (BD) who have survived a recent suicidal event, new research shows.

The results of a randomized, double-blind, placebo-controlled trial in veterans showed no apparent advantage of the drug in preventing self-injury, suicide attempts, or urgent hospitalization to prevent suicide.

“Lithium is an important therapy for bipolar disorders and depression subsets. Our study indicates that, in patients who are actively followed and treated in a system of care that the VA provides, simply adding lithium to their existing management, including medications, is unlikely to be effective for preventing a broad range of suicide-related events,” study investigator Ryan Ferguson, MPH, ScD, Boston Cooperative Studies Coordinating Center, VA Boston Healthcare System, told this news organization.

The study was published online JAMA Psychiatry.
 

Surprising findings

The results were somewhat surprising, Dr. Ferguson added. “Lithium showed little or no effect in our study, compared to observational data and results from previous trials. Many clinicians and practice guidelines had assumed that lithium was an effective agent in preventing suicide,” he said.

However, the authors of an accompanying editorial urge caution in concluding that lithium has no antisuicidal effects.

This “rigorously designed and conducted trial has much to teach but cannot be taken as evidence that lithium treatment is ineffective regarding suicidal risk,” write Ross Baldessarini, MD, and Leonardo Tondo, MD, department of psychiatry, Harvard Medical School, Boston.

Study participants were veterans with MDD or BD receiving care at one of 29 Veterans Administration medical centers who survived a recent suicide-related event. In addition to usual care, they were randomly assigned to receive oral extended-release lithium carbonate starting at 600 mg/day or matching placebo for 52 weeks.

The primary outcome was time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide.

The trial was stopped for futility after 519 veterans (mean age, 42.8 years; 84% male) were randomly assigned to receive lithium (n = 255) or placebo (n = 264). At 3 months, mean lithium concentrations were 0.54 mEq/L for patients with BD and 0.46 mEq/L for those with MDD.

There was no significant difference in the primary outcome (hazard ratio, 1.10; 95% confidence interval, 0.77-1.55; P = .61).

A total of 127 participants (24.5%) had suicide-related outcomes – 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and three in the placebo group. There were no unanticipated drug-related safety concerns.
 

Caveats, cautionary notes

The researchers note that the study did not reach its original recruitment goal. “One of the barriers to recruitment was the perception of many of the clinicians caring for potential participants that the effectiveness of lithium was already established; in fact, this perception was supported by the VA/U.S. Department of Defense Clinical Practice Guideline,” they point out.

They also note that most veterans in the study had depression rather than BD, which is the most common indication for lithium use. Most also had substance use disorders, posttraumatic stress disorder, or both, which could influence outcomes.

As a result of small numbers, it wasn’t possible to evaluate outcomes for patients with BD, test whether outcomes differed among patients with BD and MDD, or assess whether comorbidities attenuated the effects of lithium.

The study’s protocol increased participants’ contacts with the VA, which also may have affected outcomes, the researchers note.

In addition, high rates of attrition and low rates of substantial adherence to lithium meant only about half (48.1%) of the study population achieved target serum lithium concentrations.

Editorial writers Dr. Baldessarini and Dr. Tondo note that the low circulating concentrations of lithium and the fact that adherence to assigned treatment was considered adequate in only 17% of participants are key limitations of the study.

“In general, controlled treatment trials aimed at detecting suicide preventive effects are difficult to design, perform, and interpret,” they point out.

Evidence supporting an antisuicidal effect of lithium treatment includes nearly three dozen observational trials that have shown fewer suicides or attempts with lithium treatment, as well as “marked, temporary” increases in suicidal behavior soon after stopping lithium treatment.

Dr. Baldessarini and Dr. Tondo note the current findings “cannot be taken as evidence that lithium lacks antisuicidal effects. An ironic final note is that recruiting participants to such trials may be made difficult by an evidently prevalent belief that the question of antisuicidal effects of lithium is already settled, which it certainly is not,” they write.

Dr. Ferguson “agrees that more work needs to be done to understand the antisuicidal effect of lithium.

The study received financial and material support from a grant from the Cooperative Studies Program, Office of Research and Development, U.S. Department of Veterans Affairs. Dr. Ferguson has disclosed no relevant financial relationships. A complete list of author disclosures is available with the original article.

Dr. Baldessarini and Dr. Tondo have disclosed no relevant financial relationships. Their editorial was supported by grants from the Bruce J. Anderson Foundation, the McLean Private Donors Fund for Psychiatric Research, and the Aretaeus Foundation of Rome.

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.

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.

Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.

Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.

Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.

There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”

EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.

“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.

The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.

Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”

Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.

“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”

EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.

At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.

The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.

Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.

They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.

EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.

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

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

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

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

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

Lowering blood pressure – known to prevent the vascular complications of type 2 diabetes – can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – so-called renin-angiotensin system (RAS) blockers – showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Mr. Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, U.K., and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the U.K. Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, U.K., said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, U.K., similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”
 

RAS blockers associated with lower diabetes risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9,883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction, 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure lowering treatments with drugs, and possibly device therapies,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes; however, the causality of that association is uncertain, the authors note.
 

Results fill gap in evidence for guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St. George’s, University of London, told the U.K. Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Mr. Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.
 

Authors of U.S. hypertension guidelines should follow lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension; however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Dr. Cavender and Dr. Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the U.S. to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Dr. Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Dr. Wirka and Dr. George have reported no relevant financial relationships. Dr. McConway is a trustee of the SMC and member of its advisory committee. Dr. Gill is employed part-time by Novo Nordisk.

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