Heart Failure

The striking gains in functional capacity and quality of life conferred by baroreflex activation therapy in patients with heart failure, as shown in the pivotal phase 3 clinical trial for this novel intervention, were at least as great in women as in men, JoAnn Lindenfeld, MD, said at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Mitchel L. Zoler/MDedge News

The results of the multicenter, prospective, randomized BeAT-HF trial led to marketing approval of the BaroStim Neo system for improvement in symptoms of heart failure with reduced ejection fraction (HFrEF) by the Food and Drug Administration in August 2019. Dr. Lindenfeld presented a fresh breakdown of the results by gender which showed, intriguingly, that the improvement in all study endpoints was consistently numerically greater in the women – sometimes startlingly so – although these gender differences in response didn’t achieve statistical significance. The 6-month randomized trial was underpowered for drawing definitive conclusions on that score, with a study population of only 53 women and 211 men. So the investigator remained circumspect.

“We think that what this study shows us is that women have at least equivalent improvement as men in this population. I don’t think we can conclude from this study yet that it’s better, but it’s certainly in all these parameters as least as good. And I think this is a population in which we’ve seen that improving symptoms and functional capacity is very important,” said Dr. Lindenfeld, professor of medicine and director of advanced heart failure/cardiac transplantation at Vanderbilt University, Nashville, Tenn.

The FDA approval was restricted to patients like those enrolled in BeAT-HF: that is, individuals with New York Heart Association functional class III heart failure, a left ventricular ejection fraction of 35% or less while on stable optimal medical therapy, and ineligibility for cardiac resynchronization therapy according to current guidelines. Seventy-eight percent of BeAT-HF participants had an implantable cardioverter-defibrillator.

Participants were randomized to baroreflex activation therapy (BAT) plus optimal medical therapy or to optimal medical therapy alone. The three coprimary endpoints were change from baseline to 6 months in 6-minute hall walk distance (6MHW), scores on the Minnesota Living with Heart Failure Questionnaire (MLHF), and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

In the overall study population, 6MHW increased by 60 m in the BAT group and decreased by 8 m in controls; MLHF scores dropped by 14 and 6 points, respectively; and NT-proBNP fell by an average of 25% with BAT while rising by 3% in controls.

Very often, just a 5-point reduction in MLHF score is considered a clinically meaningful improvement in quality of life, the cardiologist noted.

The gender-based analysis is where things got particularly interesting.

The investigators defined a clinically relevant response as a greater than 10% increase from baseline on the 6MHW, at least a one-class improvement in NYHA class, or a reduction of 5 points or more on the MLHF. Among subjects in the BAT group, 70% of women and 60% of men met the clinically relevant response standard in terms of 6MHW, as did 70% of women and 64% of men for improvement in NYHA class, and 78% of women and 66% of men for MLHF score.

Eighty-seven percent of women and 68% of men on BAT had a clinically relevant response on at least one of these endpoints, as did about 28% of controls. Moreover, 31% of women in the BAT group were clinically relevant responders on at least two endpoints, compared with 19% of BAT men and 4% and 9% of controls.
 

Women dominate super-responder category

In order to be classified as a super responder, a patient had to demonstrate a greater than 20% increase in 6MHW, improvement in NYHA class I status, or at least a 10-point improvement in MLHF score. Ninety-one percent of women on BAT achieved super-responder status for at least one of these endpoints, compared with 76% of men. Forty-three percent of women and 24% of men in the BAT group were super responders in at least two domains, as were 8% and 11% of female and male controls, Dr. Lindenfeld continued.

Discussant Ewa Anita Jankowska, MD, PhD, deemed the BeAT-HF results on the therapeutic benefits of this autonomic modulation strategy “quite convincing.”

“We need to acknowledge that in recent years we have been spoiled a bit by the huge trials in heart failure where the ultimate goal was a reduction in mortality. But I think this is the time when we should think about the patients who want to live – here, now – with a better life. Patients expect symptomatic benefits. There is a substantial group of patients who are symptomatic even though they receive quite extensive neurohormonal blockage and who are not suitable for CRT. This study demonstrates that, for this group of patients, BAT can bring really significant symptomatic benefits,” she said.

“If you think about a treatment that provides patients who are NYHA class III an increase in 6MHW of 60 meters, that’s really something. And 20% of patients went from NYHA class III to class I – that’s really something, too,” added Dr. Jankowska, professor of medicine and head of the laboratory of applied research on the cardiovascular system at Wroclaw (Poland) University.

How baroreflex activation therapy works

The BaroStim system consists of a 2-mm unipolar electrode on a 7-mm backer that is placed over the carotid sinus. It is supported by a small generator with a 4- to 5-year battery life implanted under the collarbone, along with radiofrequency telemetry capability and programming flexibility.

Stimulation of the carotid baroreceptor promotes an integrated autonomic nervous system response which enhances parasympathetic activity and inhibits sympathetic nervous system activity. The result, as shown in numerous earlier proof-of-concept studies, is a reduced heart rate, decreased ventricular remodeling, enhanced diuresis, increased vasodilation, a drop in elevated blood pressure, and decreased renin secretion – all achieved nonpharmacologically.

The study was sponsored by CVRx. Dr. Lindenfeld reported serving as a consultant to CVRx, Abbott, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Impulse Dynamics, and VWave.

bjancin@mdedge.com

The striking gains in functional capacity and quality of life conferred by baroreflex activation therapy in patients with heart failure, as shown in the pivotal phase 3 clinical trial for this novel intervention, were at least as great in women as in men, JoAnn Lindenfeld, MD, said at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Mitchel L. Zoler/MDedge News

The results of the multicenter, prospective, randomized BeAT-HF trial led to marketing approval of the BaroStim Neo system for improvement in symptoms of heart failure with reduced ejection fraction (HFrEF) by the Food and Drug Administration in August 2019. Dr. Lindenfeld presented a fresh breakdown of the results by gender which showed, intriguingly, that the improvement in all study endpoints was consistently numerically greater in the women – sometimes startlingly so – although these gender differences in response didn’t achieve statistical significance. The 6-month randomized trial was underpowered for drawing definitive conclusions on that score, with a study population of only 53 women and 211 men. So the investigator remained circumspect.

“We think that what this study shows us is that women have at least equivalent improvement as men in this population. I don’t think we can conclude from this study yet that it’s better, but it’s certainly in all these parameters as least as good. And I think this is a population in which we’ve seen that improving symptoms and functional capacity is very important,” said Dr. Lindenfeld, professor of medicine and director of advanced heart failure/cardiac transplantation at Vanderbilt University, Nashville, Tenn.

The FDA approval was restricted to patients like those enrolled in BeAT-HF: that is, individuals with New York Heart Association functional class III heart failure, a left ventricular ejection fraction of 35% or less while on stable optimal medical therapy, and ineligibility for cardiac resynchronization therapy according to current guidelines. Seventy-eight percent of BeAT-HF participants had an implantable cardioverter-defibrillator.

Participants were randomized to baroreflex activation therapy (BAT) plus optimal medical therapy or to optimal medical therapy alone. The three coprimary endpoints were change from baseline to 6 months in 6-minute hall walk distance (6MHW), scores on the Minnesota Living with Heart Failure Questionnaire (MLHF), and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

In the overall study population, 6MHW increased by 60 m in the BAT group and decreased by 8 m in controls; MLHF scores dropped by 14 and 6 points, respectively; and NT-proBNP fell by an average of 25% with BAT while rising by 3% in controls.

Very often, just a 5-point reduction in MLHF score is considered a clinically meaningful improvement in quality of life, the cardiologist noted.

The gender-based analysis is where things got particularly interesting.

The investigators defined a clinically relevant response as a greater than 10% increase from baseline on the 6MHW, at least a one-class improvement in NYHA class, or a reduction of 5 points or more on the MLHF. Among subjects in the BAT group, 70% of women and 60% of men met the clinically relevant response standard in terms of 6MHW, as did 70% of women and 64% of men for improvement in NYHA class, and 78% of women and 66% of men for MLHF score.

Eighty-seven percent of women and 68% of men on BAT had a clinically relevant response on at least one of these endpoints, as did about 28% of controls. Moreover, 31% of women in the BAT group were clinically relevant responders on at least two endpoints, compared with 19% of BAT men and 4% and 9% of controls.
 

Women dominate super-responder category

In order to be classified as a super responder, a patient had to demonstrate a greater than 20% increase in 6MHW, improvement in NYHA class I status, or at least a 10-point improvement in MLHF score. Ninety-one percent of women on BAT achieved super-responder status for at least one of these endpoints, compared with 76% of men. Forty-three percent of women and 24% of men in the BAT group were super responders in at least two domains, as were 8% and 11% of female and male controls, Dr. Lindenfeld continued.

Discussant Ewa Anita Jankowska, MD, PhD, deemed the BeAT-HF results on the therapeutic benefits of this autonomic modulation strategy “quite convincing.”

“We need to acknowledge that in recent years we have been spoiled a bit by the huge trials in heart failure where the ultimate goal was a reduction in mortality. But I think this is the time when we should think about the patients who want to live – here, now – with a better life. Patients expect symptomatic benefits. There is a substantial group of patients who are symptomatic even though they receive quite extensive neurohormonal blockage and who are not suitable for CRT. This study demonstrates that, for this group of patients, BAT can bring really significant symptomatic benefits,” she said.

“If you think about a treatment that provides patients who are NYHA class III an increase in 6MHW of 60 meters, that’s really something. And 20% of patients went from NYHA class III to class I – that’s really something, too,” added Dr. Jankowska, professor of medicine and head of the laboratory of applied research on the cardiovascular system at Wroclaw (Poland) University.

How baroreflex activation therapy works

The BaroStim system consists of a 2-mm unipolar electrode on a 7-mm backer that is placed over the carotid sinus. It is supported by a small generator with a 4- to 5-year battery life implanted under the collarbone, along with radiofrequency telemetry capability and programming flexibility.

Stimulation of the carotid baroreceptor promotes an integrated autonomic nervous system response which enhances parasympathetic activity and inhibits sympathetic nervous system activity. The result, as shown in numerous earlier proof-of-concept studies, is a reduced heart rate, decreased ventricular remodeling, enhanced diuresis, increased vasodilation, a drop in elevated blood pressure, and decreased renin secretion – all achieved nonpharmacologically.

The study was sponsored by CVRx. Dr. Lindenfeld reported serving as a consultant to CVRx, Abbott, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Impulse Dynamics, and VWave.

bjancin@mdedge.com

The striking gains in functional capacity and quality of life conferred by baroreflex activation therapy in patients with heart failure, as shown in the pivotal phase 3 clinical trial for this novel intervention, were at least as great in women as in men, JoAnn Lindenfeld, MD, said at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

Mitchel L. Zoler/MDedge News

The results of the multicenter, prospective, randomized BeAT-HF trial led to marketing approval of the BaroStim Neo system for improvement in symptoms of heart failure with reduced ejection fraction (HFrEF) by the Food and Drug Administration in August 2019. Dr. Lindenfeld presented a fresh breakdown of the results by gender which showed, intriguingly, that the improvement in all study endpoints was consistently numerically greater in the women – sometimes startlingly so – although these gender differences in response didn’t achieve statistical significance. The 6-month randomized trial was underpowered for drawing definitive conclusions on that score, with a study population of only 53 women and 211 men. So the investigator remained circumspect.

“We think that what this study shows us is that women have at least equivalent improvement as men in this population. I don’t think we can conclude from this study yet that it’s better, but it’s certainly in all these parameters as least as good. And I think this is a population in which we’ve seen that improving symptoms and functional capacity is very important,” said Dr. Lindenfeld, professor of medicine and director of advanced heart failure/cardiac transplantation at Vanderbilt University, Nashville, Tenn.

The FDA approval was restricted to patients like those enrolled in BeAT-HF: that is, individuals with New York Heart Association functional class III heart failure, a left ventricular ejection fraction of 35% or less while on stable optimal medical therapy, and ineligibility for cardiac resynchronization therapy according to current guidelines. Seventy-eight percent of BeAT-HF participants had an implantable cardioverter-defibrillator.

Participants were randomized to baroreflex activation therapy (BAT) plus optimal medical therapy or to optimal medical therapy alone. The three coprimary endpoints were change from baseline to 6 months in 6-minute hall walk distance (6MHW), scores on the Minnesota Living with Heart Failure Questionnaire (MLHF), and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

In the overall study population, 6MHW increased by 60 m in the BAT group and decreased by 8 m in controls; MLHF scores dropped by 14 and 6 points, respectively; and NT-proBNP fell by an average of 25% with BAT while rising by 3% in controls.

Very often, just a 5-point reduction in MLHF score is considered a clinically meaningful improvement in quality of life, the cardiologist noted.

The gender-based analysis is where things got particularly interesting.

The investigators defined a clinically relevant response as a greater than 10% increase from baseline on the 6MHW, at least a one-class improvement in NYHA class, or a reduction of 5 points or more on the MLHF. Among subjects in the BAT group, 70% of women and 60% of men met the clinically relevant response standard in terms of 6MHW, as did 70% of women and 64% of men for improvement in NYHA class, and 78% of women and 66% of men for MLHF score.

Eighty-seven percent of women and 68% of men on BAT had a clinically relevant response on at least one of these endpoints, as did about 28% of controls. Moreover, 31% of women in the BAT group were clinically relevant responders on at least two endpoints, compared with 19% of BAT men and 4% and 9% of controls.
 

Women dominate super-responder category

In order to be classified as a super responder, a patient had to demonstrate a greater than 20% increase in 6MHW, improvement in NYHA class I status, or at least a 10-point improvement in MLHF score. Ninety-one percent of women on BAT achieved super-responder status for at least one of these endpoints, compared with 76% of men. Forty-three percent of women and 24% of men in the BAT group were super responders in at least two domains, as were 8% and 11% of female and male controls, Dr. Lindenfeld continued.

Discussant Ewa Anita Jankowska, MD, PhD, deemed the BeAT-HF results on the therapeutic benefits of this autonomic modulation strategy “quite convincing.”

“We need to acknowledge that in recent years we have been spoiled a bit by the huge trials in heart failure where the ultimate goal was a reduction in mortality. But I think this is the time when we should think about the patients who want to live – here, now – with a better life. Patients expect symptomatic benefits. There is a substantial group of patients who are symptomatic even though they receive quite extensive neurohormonal blockage and who are not suitable for CRT. This study demonstrates that, for this group of patients, BAT can bring really significant symptomatic benefits,” she said.

“If you think about a treatment that provides patients who are NYHA class III an increase in 6MHW of 60 meters, that’s really something. And 20% of patients went from NYHA class III to class I – that’s really something, too,” added Dr. Jankowska, professor of medicine and head of the laboratory of applied research on the cardiovascular system at Wroclaw (Poland) University.

How baroreflex activation therapy works

The BaroStim system consists of a 2-mm unipolar electrode on a 7-mm backer that is placed over the carotid sinus. It is supported by a small generator with a 4- to 5-year battery life implanted under the collarbone, along with radiofrequency telemetry capability and programming flexibility.

Stimulation of the carotid baroreceptor promotes an integrated autonomic nervous system response which enhances parasympathetic activity and inhibits sympathetic nervous system activity. The result, as shown in numerous earlier proof-of-concept studies, is a reduced heart rate, decreased ventricular remodeling, enhanced diuresis, increased vasodilation, a drop in elevated blood pressure, and decreased renin secretion – all achieved nonpharmacologically.

The study was sponsored by CVRx. Dr. Lindenfeld reported serving as a consultant to CVRx, Abbott, AstraZeneca, Boehringer Ingelheim, Edwards Lifesciences, Impulse Dynamics, and VWave.

bjancin@mdedge.com

It’s bad news for patients with newly diagnosed type 2 diabetes when they then develop heart failure during the next few years.

Patients with incident type 2 diabetes (T2D) who soon after also had heart failure appear faced a dramatically elevated mortality risk, higher than the incremental risk from any other cardiovascular or renal comorbidity that appeared following diabetes onset, in an analysis of more than 150,000 Danish patients with incident type 2 diabetes during 1998-2015.

The 5-year risk of death in patients who developed heart failure during the first 5 years following an initial diagnosis of T2D was about 48%, about threefold higher than in patients with newly diagnosed T2D who remained free of heart failure or any of the other studied comorbidities, Bochra Zareini, MD, and associates reported in a study published in Circulation: Cardiovascular Quality and Outcomes. The studied patients had no known cardiovascular or renal disease at the time of their first T2D diagnosis.

“Our study reports not only on the absolute 5-year risk” of mortality, “but also takes into consideration when patients developed” a comorbidity. “What is surprising and worrying is the very high risk of death following heart failure and the potential life years lost when compared to T2D patients who do not develop heart failure,” said Dr. Zareini, a cardiologist at Herlev and Gentofte University Hospital in Copenhagen. “The implications of our study are to create awareness and highlight the importance of early detection of heart failure development in patients with T2D.” The results also showed that “heart failure is a common cardiovascular disease” in patients with newly diagnosed T2D, she added in an interview.

The data she and her associates reported came from a retrospective analysis of 153,403 Danish citizens in national health records who received a prescription for an antidiabetes drug for the first time during 1998-2015, excluding patients with a prior diagnosis of heart failure, ischemic heart disease (IHD), stroke, peripheral artery disease (PAD), chronic kidney disease (CKD), or gestational diabetes. They followed these patients for a median of just under 10 years, during which time 45% of the cohort had an incident diagnosis of at least one of these cardiovascular and renal conditions, based on medical-record entries from hospitalization discharges or ambulatory contacts.

Nearly two-thirds of the T2D patients with an incident comorbidity during follow-up had a single new diagnosis, a quarter had two new comorbidities appear during follow-up, and 13% developed at least three new comorbidities.
 

Heart failure, least common but deadliest comorbidity

The most common of the tracked comorbidities was IHD, which appeared in 8% of the T2D patients within 5 years and in 13% after 10 years. Next most common was stroke, affecting 3% of patients after 5 years and 5% after 10 years. CKD occurred in 2.2% after 5 years and in 4.0% after 10 years, PAD occurred in 2.1% after 5 years and in 3.0% at 10 years, and heart failure occurred in 1.6% at 5 years and in 2.2% after 10 years.

But despite being the least common of the studied comorbidities, heart failure was by far the most deadly, roughly tripling the 5-year mortality rate, compared with T2D patients with no comorbidities, regardless of exactly when it first appeared during the first 5 years after the initial T2D diagnosis. The next most deadly comorbidities were stroke and PAD, which each roughly doubled mortality, compared with the patients who remained free of any studied comorbidity. CKD boosted mortality by 70%-110%, depending on exactly when it appeared during the first 5 years of follow-up, and IHD, while the most frequent comorbidity was also the most benign, increasing mortality by about 30%.

The most deadly combinations of two comorbidities were when heart failure appeared with either CKD or with PAD; each of these combinations boosted mortality by 300%-400% when it occurred during the first few years after a T2D diagnosis.

The findings came from “a very big and unselected patient group of patients, making our results highly generalizable in terms of assessing the prognostic consequences of heart failure,” Dr. Zareini stressed.
 

Management implications

The dangerous combination of T2D and heart failure has been documented for several years, and prompted a focused statement in 2019 about best practices for managing these patients (Circulation. 2019 Aug 3;140[7]:e294-324). “Heart failure has been known for some time to predict poorer outcomes in patients with T2D. Not much surprising” in the new findings reported by Dr. Zareini and associates, commented Robert H. Eckel, MD, a cardiovascular endocrinologist at the University of Colorado at Denver, Aurora. Heart failure “rarely acts alone, but in combination with other forms of heart or renal disease,” he noted in an interview.

Earlier studies may have “overlooked” heart failure’s importance compared with other comorbidities because they often “only investigated one cardiovascular disease in patients with T2D,” Dr. Zareini noted. In recent years the importance of heart failure occurring in patients with T2D also gained heightened significance because of the growing role of the sodium-glucose cotransporter 2 (SGLT2) inhibitor drug class in treating patients with T2D and the documented ability of these drugs to significantly reduce hospitalizations for heart failure (J Am Coll Cardiol. 2020 Apr 28;75[16]:1956-74). Dr. Zareini and associates put it this way in their report: “Heart failure has in recent years been recognized as an important clinical endpoint ... in patients with T2D, in particular, after the results from randomized, controlled trials of SGLT2 inhibitors showed benefit on cardiovascular death and heart failure hospitalizations.”

Despite this, the new findings “do not address treatment with SGLT2 inhibitors in patients with T2D, nor can we use our data to address which patients should not be treated,” with this drug class, which instead should rely on “current evidence and expert consensus,” she said.

“Guidelines favor SGLT2 inhibitors or [glucagonlike peptide–1] receptor agonists in patients with a history of or high risk for major adverse coronary events,” and SGLT2 inhibitors are also “preferable in patients with renal disease,” Dr. Eckel noted.

Other avenues also exist for minimizing the onset of heart failure and other cardiovascular diseases in patients with T2D, Dr. Zareini said, citing modifiable risks that lead to heart failure that include hypertension, “diabetic cardiomyopathy,” and ISD. “Clinicians must treat all modifiable risk factors in patients with T2D in order to improve prognosis and limit development of cardiovascular and renal disease.”

The study received no commercial funding. Dr. Zareini and Dr. Eckel had no disclosures.

mzoler@mdedge.com

SOURCE: Zareini B et al. Circ Cardiovasc Qual Outcomes. 2020 Jun 23. doi: 10.1161/CIRCOUTCOMES.119.006260.

It’s bad news for patients with newly diagnosed type 2 diabetes when they then develop heart failure during the next few years.

Patients with incident type 2 diabetes (T2D) who soon after also had heart failure appear faced a dramatically elevated mortality risk, higher than the incremental risk from any other cardiovascular or renal comorbidity that appeared following diabetes onset, in an analysis of more than 150,000 Danish patients with incident type 2 diabetes during 1998-2015.

The 5-year risk of death in patients who developed heart failure during the first 5 years following an initial diagnosis of T2D was about 48%, about threefold higher than in patients with newly diagnosed T2D who remained free of heart failure or any of the other studied comorbidities, Bochra Zareini, MD, and associates reported in a study published in Circulation: Cardiovascular Quality and Outcomes. The studied patients had no known cardiovascular or renal disease at the time of their first T2D diagnosis.

“Our study reports not only on the absolute 5-year risk” of mortality, “but also takes into consideration when patients developed” a comorbidity. “What is surprising and worrying is the very high risk of death following heart failure and the potential life years lost when compared to T2D patients who do not develop heart failure,” said Dr. Zareini, a cardiologist at Herlev and Gentofte University Hospital in Copenhagen. “The implications of our study are to create awareness and highlight the importance of early detection of heart failure development in patients with T2D.” The results also showed that “heart failure is a common cardiovascular disease” in patients with newly diagnosed T2D, she added in an interview.

The data she and her associates reported came from a retrospective analysis of 153,403 Danish citizens in national health records who received a prescription for an antidiabetes drug for the first time during 1998-2015, excluding patients with a prior diagnosis of heart failure, ischemic heart disease (IHD), stroke, peripheral artery disease (PAD), chronic kidney disease (CKD), or gestational diabetes. They followed these patients for a median of just under 10 years, during which time 45% of the cohort had an incident diagnosis of at least one of these cardiovascular and renal conditions, based on medical-record entries from hospitalization discharges or ambulatory contacts.

Nearly two-thirds of the T2D patients with an incident comorbidity during follow-up had a single new diagnosis, a quarter had two new comorbidities appear during follow-up, and 13% developed at least three new comorbidities.
 

Heart failure, least common but deadliest comorbidity

The most common of the tracked comorbidities was IHD, which appeared in 8% of the T2D patients within 5 years and in 13% after 10 years. Next most common was stroke, affecting 3% of patients after 5 years and 5% after 10 years. CKD occurred in 2.2% after 5 years and in 4.0% after 10 years, PAD occurred in 2.1% after 5 years and in 3.0% at 10 years, and heart failure occurred in 1.6% at 5 years and in 2.2% after 10 years.

But despite being the least common of the studied comorbidities, heart failure was by far the most deadly, roughly tripling the 5-year mortality rate, compared with T2D patients with no comorbidities, regardless of exactly when it first appeared during the first 5 years after the initial T2D diagnosis. The next most deadly comorbidities were stroke and PAD, which each roughly doubled mortality, compared with the patients who remained free of any studied comorbidity. CKD boosted mortality by 70%-110%, depending on exactly when it appeared during the first 5 years of follow-up, and IHD, while the most frequent comorbidity was also the most benign, increasing mortality by about 30%.

The most deadly combinations of two comorbidities were when heart failure appeared with either CKD or with PAD; each of these combinations boosted mortality by 300%-400% when it occurred during the first few years after a T2D diagnosis.

The findings came from “a very big and unselected patient group of patients, making our results highly generalizable in terms of assessing the prognostic consequences of heart failure,” Dr. Zareini stressed.
 

Management implications

The dangerous combination of T2D and heart failure has been documented for several years, and prompted a focused statement in 2019 about best practices for managing these patients (Circulation. 2019 Aug 3;140[7]:e294-324). “Heart failure has been known for some time to predict poorer outcomes in patients with T2D. Not much surprising” in the new findings reported by Dr. Zareini and associates, commented Robert H. Eckel, MD, a cardiovascular endocrinologist at the University of Colorado at Denver, Aurora. Heart failure “rarely acts alone, but in combination with other forms of heart or renal disease,” he noted in an interview.

Earlier studies may have “overlooked” heart failure’s importance compared with other comorbidities because they often “only investigated one cardiovascular disease in patients with T2D,” Dr. Zareini noted. In recent years the importance of heart failure occurring in patients with T2D also gained heightened significance because of the growing role of the sodium-glucose cotransporter 2 (SGLT2) inhibitor drug class in treating patients with T2D and the documented ability of these drugs to significantly reduce hospitalizations for heart failure (J Am Coll Cardiol. 2020 Apr 28;75[16]:1956-74). Dr. Zareini and associates put it this way in their report: “Heart failure has in recent years been recognized as an important clinical endpoint ... in patients with T2D, in particular, after the results from randomized, controlled trials of SGLT2 inhibitors showed benefit on cardiovascular death and heart failure hospitalizations.”

Despite this, the new findings “do not address treatment with SGLT2 inhibitors in patients with T2D, nor can we use our data to address which patients should not be treated,” with this drug class, which instead should rely on “current evidence and expert consensus,” she said.

“Guidelines favor SGLT2 inhibitors or [glucagonlike peptide–1] receptor agonists in patients with a history of or high risk for major adverse coronary events,” and SGLT2 inhibitors are also “preferable in patients with renal disease,” Dr. Eckel noted.

Other avenues also exist for minimizing the onset of heart failure and other cardiovascular diseases in patients with T2D, Dr. Zareini said, citing modifiable risks that lead to heart failure that include hypertension, “diabetic cardiomyopathy,” and ISD. “Clinicians must treat all modifiable risk factors in patients with T2D in order to improve prognosis and limit development of cardiovascular and renal disease.”

The study received no commercial funding. Dr. Zareini and Dr. Eckel had no disclosures.

mzoler@mdedge.com

SOURCE: Zareini B et al. Circ Cardiovasc Qual Outcomes. 2020 Jun 23. doi: 10.1161/CIRCOUTCOMES.119.006260.

It’s bad news for patients with newly diagnosed type 2 diabetes when they then develop heart failure during the next few years.

Patients with incident type 2 diabetes (T2D) who soon after also had heart failure appear faced a dramatically elevated mortality risk, higher than the incremental risk from any other cardiovascular or renal comorbidity that appeared following diabetes onset, in an analysis of more than 150,000 Danish patients with incident type 2 diabetes during 1998-2015.

The 5-year risk of death in patients who developed heart failure during the first 5 years following an initial diagnosis of T2D was about 48%, about threefold higher than in patients with newly diagnosed T2D who remained free of heart failure or any of the other studied comorbidities, Bochra Zareini, MD, and associates reported in a study published in Circulation: Cardiovascular Quality and Outcomes. The studied patients had no known cardiovascular or renal disease at the time of their first T2D diagnosis.

“Our study reports not only on the absolute 5-year risk” of mortality, “but also takes into consideration when patients developed” a comorbidity. “What is surprising and worrying is the very high risk of death following heart failure and the potential life years lost when compared to T2D patients who do not develop heart failure,” said Dr. Zareini, a cardiologist at Herlev and Gentofte University Hospital in Copenhagen. “The implications of our study are to create awareness and highlight the importance of early detection of heart failure development in patients with T2D.” The results also showed that “heart failure is a common cardiovascular disease” in patients with newly diagnosed T2D, she added in an interview.

The data she and her associates reported came from a retrospective analysis of 153,403 Danish citizens in national health records who received a prescription for an antidiabetes drug for the first time during 1998-2015, excluding patients with a prior diagnosis of heart failure, ischemic heart disease (IHD), stroke, peripheral artery disease (PAD), chronic kidney disease (CKD), or gestational diabetes. They followed these patients for a median of just under 10 years, during which time 45% of the cohort had an incident diagnosis of at least one of these cardiovascular and renal conditions, based on medical-record entries from hospitalization discharges or ambulatory contacts.

Nearly two-thirds of the T2D patients with an incident comorbidity during follow-up had a single new diagnosis, a quarter had two new comorbidities appear during follow-up, and 13% developed at least three new comorbidities.
 

Heart failure, least common but deadliest comorbidity

The most common of the tracked comorbidities was IHD, which appeared in 8% of the T2D patients within 5 years and in 13% after 10 years. Next most common was stroke, affecting 3% of patients after 5 years and 5% after 10 years. CKD occurred in 2.2% after 5 years and in 4.0% after 10 years, PAD occurred in 2.1% after 5 years and in 3.0% at 10 years, and heart failure occurred in 1.6% at 5 years and in 2.2% after 10 years.

But despite being the least common of the studied comorbidities, heart failure was by far the most deadly, roughly tripling the 5-year mortality rate, compared with T2D patients with no comorbidities, regardless of exactly when it first appeared during the first 5 years after the initial T2D diagnosis. The next most deadly comorbidities were stroke and PAD, which each roughly doubled mortality, compared with the patients who remained free of any studied comorbidity. CKD boosted mortality by 70%-110%, depending on exactly when it appeared during the first 5 years of follow-up, and IHD, while the most frequent comorbidity was also the most benign, increasing mortality by about 30%.

The most deadly combinations of two comorbidities were when heart failure appeared with either CKD or with PAD; each of these combinations boosted mortality by 300%-400% when it occurred during the first few years after a T2D diagnosis.

The findings came from “a very big and unselected patient group of patients, making our results highly generalizable in terms of assessing the prognostic consequences of heart failure,” Dr. Zareini stressed.
 

Management implications

The dangerous combination of T2D and heart failure has been documented for several years, and prompted a focused statement in 2019 about best practices for managing these patients (Circulation. 2019 Aug 3;140[7]:e294-324). “Heart failure has been known for some time to predict poorer outcomes in patients with T2D. Not much surprising” in the new findings reported by Dr. Zareini and associates, commented Robert H. Eckel, MD, a cardiovascular endocrinologist at the University of Colorado at Denver, Aurora. Heart failure “rarely acts alone, but in combination with other forms of heart or renal disease,” he noted in an interview.

Earlier studies may have “overlooked” heart failure’s importance compared with other comorbidities because they often “only investigated one cardiovascular disease in patients with T2D,” Dr. Zareini noted. In recent years the importance of heart failure occurring in patients with T2D also gained heightened significance because of the growing role of the sodium-glucose cotransporter 2 (SGLT2) inhibitor drug class in treating patients with T2D and the documented ability of these drugs to significantly reduce hospitalizations for heart failure (J Am Coll Cardiol. 2020 Apr 28;75[16]:1956-74). Dr. Zareini and associates put it this way in their report: “Heart failure has in recent years been recognized as an important clinical endpoint ... in patients with T2D, in particular, after the results from randomized, controlled trials of SGLT2 inhibitors showed benefit on cardiovascular death and heart failure hospitalizations.”

Despite this, the new findings “do not address treatment with SGLT2 inhibitors in patients with T2D, nor can we use our data to address which patients should not be treated,” with this drug class, which instead should rely on “current evidence and expert consensus,” she said.

“Guidelines favor SGLT2 inhibitors or [glucagonlike peptide–1] receptor agonists in patients with a history of or high risk for major adverse coronary events,” and SGLT2 inhibitors are also “preferable in patients with renal disease,” Dr. Eckel noted.

Other avenues also exist for minimizing the onset of heart failure and other cardiovascular diseases in patients with T2D, Dr. Zareini said, citing modifiable risks that lead to heart failure that include hypertension, “diabetic cardiomyopathy,” and ISD. “Clinicians must treat all modifiable risk factors in patients with T2D in order to improve prognosis and limit development of cardiovascular and renal disease.”

The study received no commercial funding. Dr. Zareini and Dr. Eckel had no disclosures.

mzoler@mdedge.com

SOURCE: Zareini B et al. Circ Cardiovasc Qual Outcomes. 2020 Jun 23. doi: 10.1161/CIRCOUTCOMES.119.006260.

Potentially preventable inpatient admissions accounted for almost 9% of all adult hospital costs in 2017, according to the Agency for Healthcare Research and Quality.

That year, there were 27.4 million inpatient visits by adults with a total cost of $380.1 billion, although obstetric stays were not included in the analysis. Of those inpatient admissions, 3.5 million (12.9%) were deemed to be “avoidable, in part, through timely and quality primary and preventive care,” Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, said in a recent AHRQ statistical brief.

The charges for those 3.5 million visits came to $33.7 billion, or 8.9% of aggregate hospital costs in 2017, based on data from the AHRQ Healthcare Cost and Utilization Project’s state inpatient databases.

“Determining the volume and costs of potentially preventable inpatient stays can identify where potential cost savings might be found associated with reducing these hospitalizations overall and among specific subpopulations,” the investigators pointed out.

Of the seven conditions that are potentially avoidable, heart failure was the most expensive, producing more than 1.1 million inpatient admissions at a cost of $11.2 billion. Diabetes was next with a cost of almost $7.4 billion, followed by chronic obstructive pulmonary disease (COPD) at nearly $7.3 billion, they said.

Those three conditions, along with hypertension and asthma in younger adults, brought the total cost of the preventable-stay equation’s chronic side to $27.3 billion in 2017, versus $6.4 billion for the two acute conditions, community-acquired pneumonia and urinary tract infections, said Dr. McDermott of IBM Watson Health and Dr. Jiang of the AHRQ.

The rate of potentially avoidable stays for chronic conditions was higher for men (1,112/100,000 population) than for women (954/100,000), but women had a higher rate for acute conditions, 346 vs. 257, which made the overall rates similar (1,369 for men and 1,300 for women), they reported.

Differences by race/ethnicity were more striking. The rate of potentially avoidable stays for blacks was 2,573/100,000 in 2017, compared with 1,315 for Hispanics, 1,173 for whites, and 581 for Asians/Pacific Islanders. The considerable margins between those figures, however, were far eclipsed by the “other” category, which had 4,911 stays per 100,000, the researchers said.

Large disparities also can be seen when looking at community-level income. Communities with income in the lowest quartile had a preventable-hospitalization rate of 2,013/100,000, and the rate dropped with each successive quartile until it reached 878/100,000 for the highest-income communities, according to the report.

“High hospital admission rates for these conditions may indicate areas where changes to the healthcare delivery system could be implemented to improve patient outcomes and lower costs,” Dr. McDermott and Dr. Jiang wrote.

rfranki@mdedge.com

SOURCE: McDermott KW and Jiang HJ. HCUP Statistical Brief #259. June 2020.

Potentially preventable inpatient admissions accounted for almost 9% of all adult hospital costs in 2017, according to the Agency for Healthcare Research and Quality.

That year, there were 27.4 million inpatient visits by adults with a total cost of $380.1 billion, although obstetric stays were not included in the analysis. Of those inpatient admissions, 3.5 million (12.9%) were deemed to be “avoidable, in part, through timely and quality primary and preventive care,” Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, said in a recent AHRQ statistical brief.

The charges for those 3.5 million visits came to $33.7 billion, or 8.9% of aggregate hospital costs in 2017, based on data from the AHRQ Healthcare Cost and Utilization Project’s state inpatient databases.

“Determining the volume and costs of potentially preventable inpatient stays can identify where potential cost savings might be found associated with reducing these hospitalizations overall and among specific subpopulations,” the investigators pointed out.

Of the seven conditions that are potentially avoidable, heart failure was the most expensive, producing more than 1.1 million inpatient admissions at a cost of $11.2 billion. Diabetes was next with a cost of almost $7.4 billion, followed by chronic obstructive pulmonary disease (COPD) at nearly $7.3 billion, they said.

Those three conditions, along with hypertension and asthma in younger adults, brought the total cost of the preventable-stay equation’s chronic side to $27.3 billion in 2017, versus $6.4 billion for the two acute conditions, community-acquired pneumonia and urinary tract infections, said Dr. McDermott of IBM Watson Health and Dr. Jiang of the AHRQ.

The rate of potentially avoidable stays for chronic conditions was higher for men (1,112/100,000 population) than for women (954/100,000), but women had a higher rate for acute conditions, 346 vs. 257, which made the overall rates similar (1,369 for men and 1,300 for women), they reported.

Differences by race/ethnicity were more striking. The rate of potentially avoidable stays for blacks was 2,573/100,000 in 2017, compared with 1,315 for Hispanics, 1,173 for whites, and 581 for Asians/Pacific Islanders. The considerable margins between those figures, however, were far eclipsed by the “other” category, which had 4,911 stays per 100,000, the researchers said.

Large disparities also can be seen when looking at community-level income. Communities with income in the lowest quartile had a preventable-hospitalization rate of 2,013/100,000, and the rate dropped with each successive quartile until it reached 878/100,000 for the highest-income communities, according to the report.

“High hospital admission rates for these conditions may indicate areas where changes to the healthcare delivery system could be implemented to improve patient outcomes and lower costs,” Dr. McDermott and Dr. Jiang wrote.

rfranki@mdedge.com

SOURCE: McDermott KW and Jiang HJ. HCUP Statistical Brief #259. June 2020.

Potentially preventable inpatient admissions accounted for almost 9% of all adult hospital costs in 2017, according to the Agency for Healthcare Research and Quality.

That year, there were 27.4 million inpatient visits by adults with a total cost of $380.1 billion, although obstetric stays were not included in the analysis. Of those inpatient admissions, 3.5 million (12.9%) were deemed to be “avoidable, in part, through timely and quality primary and preventive care,” Kimberly W. McDermott, PhD, and H. Joanna Jiang, PhD, said in a recent AHRQ statistical brief.

The charges for those 3.5 million visits came to $33.7 billion, or 8.9% of aggregate hospital costs in 2017, based on data from the AHRQ Healthcare Cost and Utilization Project’s state inpatient databases.

“Determining the volume and costs of potentially preventable inpatient stays can identify where potential cost savings might be found associated with reducing these hospitalizations overall and among specific subpopulations,” the investigators pointed out.

Of the seven conditions that are potentially avoidable, heart failure was the most expensive, producing more than 1.1 million inpatient admissions at a cost of $11.2 billion. Diabetes was next with a cost of almost $7.4 billion, followed by chronic obstructive pulmonary disease (COPD) at nearly $7.3 billion, they said.

Those three conditions, along with hypertension and asthma in younger adults, brought the total cost of the preventable-stay equation’s chronic side to $27.3 billion in 2017, versus $6.4 billion for the two acute conditions, community-acquired pneumonia and urinary tract infections, said Dr. McDermott of IBM Watson Health and Dr. Jiang of the AHRQ.

The rate of potentially avoidable stays for chronic conditions was higher for men (1,112/100,000 population) than for women (954/100,000), but women had a higher rate for acute conditions, 346 vs. 257, which made the overall rates similar (1,369 for men and 1,300 for women), they reported.

Differences by race/ethnicity were more striking. The rate of potentially avoidable stays for blacks was 2,573/100,000 in 2017, compared with 1,315 for Hispanics, 1,173 for whites, and 581 for Asians/Pacific Islanders. The considerable margins between those figures, however, were far eclipsed by the “other” category, which had 4,911 stays per 100,000, the researchers said.

Large disparities also can be seen when looking at community-level income. Communities with income in the lowest quartile had a preventable-hospitalization rate of 2,013/100,000, and the rate dropped with each successive quartile until it reached 878/100,000 for the highest-income communities, according to the report.

“High hospital admission rates for these conditions may indicate areas where changes to the healthcare delivery system could be implemented to improve patient outcomes and lower costs,” Dr. McDermott and Dr. Jiang wrote.

rfranki@mdedge.com

SOURCE: McDermott KW and Jiang HJ. HCUP Statistical Brief #259. June 2020.

Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.

Courtesy Joslin Diabetes Center

Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m², was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.

The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m², end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m²), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).

The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m² per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
 

Finding and treating ‘fast decliners’

The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.

The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”

Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m² per year (median of 5.1 mL/min per 1.73 m² per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m² per year) among the other patients.
 

Overcoming dapagliflozin’s initial eGFR reduction

The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.

The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m² and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m² the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m², the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.

The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.

The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.

In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).

DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.

mzoler@mdedge.com

SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.

Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.

Courtesy Joslin Diabetes Center

Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m², was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.

The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m², end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m²), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).

The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m² per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
 

Finding and treating ‘fast decliners’

The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.

The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”

Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m² per year (median of 5.1 mL/min per 1.73 m² per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m² per year) among the other patients.
 

Overcoming dapagliflozin’s initial eGFR reduction

The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.

The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m² and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m² the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m², the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.

The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.

The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.

In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).

DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.

mzoler@mdedge.com

SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.

Treatment of patients with type 2 diabetes with the SGLT2 inhibitor dapagliflozin led to a significant drop in the occurrence of ‘fast decline’ of renal function in more than 15,000 patients enrolled in the drug’s main cardiovascular outcome trial, another example of the potent renal protective effects of agents from this drug class.

Courtesy Joslin Diabetes Center

Among patients with type 2 diabetes enrolled in the DECLARE-TIMI 58 trial, the incidence of a fast decline in renal function, defined as a drop in estimated glomerular filtration rate (eGFR) of at least 3 mL/min per 1.73 m², was 27% among patients treated with dapagliflozin and 37% in control patients who received placebo, a statistically significant difference for this post-hoc analysis, Itamar Raz, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

This finding, which adds to a long list of other renal function parameters reported to have been improved by treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors, “emphasizes the value of SGLT2 inhibitors as an important component of both prevention and treatment of chronic kidney disease among patients with type 2 diabetes,” said Dr. Raz, a diabetes researcher and professor of medicine at Hadassah University Hospital in Jerusalem.

The primary, prespecified renal outcomes in DECLARE-TIMI 58 were a cardiorenal composite outcome of sustained decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m², end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR of less than 15 mL/min per 1.73 m²), or death from renal or cardiovascular causes; and a second prespecified renal-specific composite outcome that was the same except for excluding death from cardiovascular causes. The results showed that the cardiorenal outcome dropped by a statistically significant 24% with dapagliflozin treatment relative to control patients, and the renal-specific outcome fell by a statistically significant 47% with dapagliflozin relative to control patients (Lancet Diab Endocrinol. 2019 Aug 1;7[8];606-17).

The new findings on the incidence of fast decline in renal function help to further flesh out the scope of renal benefit exerted by SGLT2 inhibitors like dapagliflozin in patients with type 2 diabetes, said experts. Fast decline is a relatively recently devised measure of a high-risk, precipitous loss of renal function that has been defined as a drop of either 3 or 5 mL/min per 1.73 m² per year (Kidney Int. 2017 Jun;91[6]:1300-11); for this analysis Dr. Raz and his associates used the less stringent definition.
 

Finding and treating ‘fast decliners’

The new report from Dr. Raz “confirms the original [renal] findings and looks to expand them to a particularly high risk group: the fast decliners,” commented Robert A. Gabbay, MD, chief science & medical officer of the ADA. “In some ways, the group of patients that we need to find a better treatment for most are those whose GFR declines quickly. We don’t always know who they are until after the fact, and studies have been looking for markers that might prospectively identify them,” he said in an interview.

The new analysis showed that dapagliflozin “was effective in this subgroup of patients. Furthermore, it didn’t matter if they had significant baseline disease or not. Even people with normal kidney function [at baseline] who were still fast decliners fared better with the drug than without it. This suggests that, if it can be confirmed in a prospective study, dapagliflozin might be effective very early in the course of treatment if we can identify who will be the fast decliners.”

Dr. Raz and his associates had the data necessary to calculate the rates of eGFR decline during the full follow-up period for 15,012 of the 17,160 patients enrolled in DECLARE-TIMI 58, and they found that 4,788 (32%) were fast decliners and 10,224 had a slower rate of renal deterioration. The average annual decline in eGFR during the period from 6 months after study entry through 4 years was 6.3 mL/min per 1.73 m² per year (median of 5.1 mL/min per 1.73 m² per year) among the fast decliners, and zero (median of 0.6 mL/min per 1.73 m² per year) among the other patients.
 

Overcoming dapagliflozin’s initial eGFR reduction

The researchers focused on the 6-month to 4-year period of treatment as more representative of the impact of dapagliflozin because the SGLT2 inhibitors have an established pattern of triggering an initial, moderate decline in eGFR over roughly the first 6 months on the drug, which is similar to what happens to patients who start treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

“Some patients get as much as a 10% decline in eGFR” when SGLT2 inhibitor treatment starts, but “patients do better over time even with this initial hit,” the same way they do on drugs that act on the renin-angiotensin system, explained Silvio E. Inzucchi, MD, an endocrinologist and professor of medicine at Yale University in New Haven who has extensively studied the SGLT2 inhibitors.

The analyses reported by Dr. Raz showed that the protection against fast decline during the 6-month to 4-year period with dapagliflozin treatment was consistent across a range of patient subgroups regardless of age, duration of their type 2 diabetes, their baseline level of hyperglycemia, and their baseline eGFR. Nearly half the patients enrolled in DECLARE-TIMI 58 had an eGFR at baseline of at least 91 mL/min per 1.73 m² and in this subgroup the incidence of fast decliners was 23% with dapagliflozin and 31% on placebo. Among the 45% of patients who began with an eGFR of 60-90 mL/min per 1.73 m² the fast-decliner incidence was 32% and 43% when on or off dapagliflozin. Among the 7% of patients who entered with an eGFR below 60 mL/min per 1.73 m², the fast-decliner incidence was 25% on dapagliflozin and 36% among controls. All the between-group differences were statistically significant.

The incidence of fast decliners was also lower with dapagliflozin treatment when the analysis included the entire first 4 years on treatment, including the first 6 months when SGLT2s usually spikes a loss of renal function. For the entire 4-year period, fast decline occurred among 34% of patients on dapagliflozin and in 37% of control patients, a statistically significant difference.

The mechanisms behind the consistent renal-protective effects of the SGLT2 inhibitors remain unclear right now, but likely seem related to the “perfect” diuretic action the drugs produce, said Dr. Inzucchi. “They’re not as hugely effective as diuretics, but they’re gentler.” While the SGLT2 inhibitors cause a modest amount of fluid loss ”for some reason they don’t activate the compensatory mechanisms that prevent further reductions in plasma volume,” a property that manifests as little or no change in catecholamines or renin-angiotensin activity, which sets this diuretic action apart from what happens with conventional diuretic drugs, he said in an interview.

In DECLARE-TIMI 58 treatment with dapagliflozin met its primary safety outcome of noninferiority to placebo with respect to major adverse cardiovascular events. The results failed to show statistically significant superiority for one of the primary efficacy endpoints, the rate of major adverse coronary events, but they did show significantly better performance for the second primary efficacy outcome of the rate of cardiovascular death or hospitalization for heart failure, which occurred in 4.9% of patients treated with dapagliflozin and in 5.8% of the control patients during a median follow-up of 4.2 years (N Engl J Med. 2019 Jan 24;380[4]:347-57).

DECLARE-TIMI 58 was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Raz has been an advisor to and speaker on behalf of AstraZeneca as well as several other companies. Dr. Gabbay had no relevant disclosures. Dr. Inzucchi has been a consultant to AstraZeneca, and also to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics.

mzoler@mdedge.com

SOURCE: Raz I et al. ADA 2020, Abstract 303-OR.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

mzoler@mdedge.com

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

mzoler@mdedge.com

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

Dapagliflozin treatment of patients with heart failure but without diabetes in the DAPA-HF trial led to a one-third cut in the relative incidence of new-onset diabetes over a median follow-up of 18 months in a prespecified analysis from the multicenter trial that included 2,605 heart failure patients without diabetes at baseline.

The findings represented the first evidence that a drug from dapagliflozin’s class, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, could prevent or slow the onset of type 2 diabetes. It represents “an additional benefit” that dapagliflozin (Farxiga) offers to patients with heart failure with reduced ejection fraction (HFrEF) like those enrolled in the DAPA-HF trial, Silvio E. Inzucchi, MD, said at the virtual annual scientific sessions of the American Diabetes Association. DAPA-HF had previously proved that treatment with this drug significantly reduced the study’s primary endpoint of cardiovascular death or heart failure worsening.

During 18 months of follow-up, 7.1% of patients in the placebo arm developed type 2 diabetes, compared with 4.9% in those who received dapagliflozin, a 2.2% absolute difference and a 32% relative risk reduction that was statistically significant for this prespecified but “exploratory” endpoint, reported Dr. Inzucchi, an endocrinologist and professor of medicine at Yale University, New Haven, Conn.

For this analysis, a hemoglobin A1c level of at least 6.5% measured in two consecutive assessments was the criterion for diagnosing incident diabetes. The 2,605 enrolled patients without diabetes in the DAPA-HF trial represented 55% of the entire trial cohort of 4,744 patients with HFrEF.

The 32% relative risk reduction for incident diabetes was primarily relevant to enrolled patients with prediabetes at entry, who constituted 67% of the enrolled cohort based on the usual definition of prediabetes, an A1c of 5.7%-6.4%.

Among all 157 (6%) of the DAPA-HF patients who developed diabetes during the trial, 150 (96%) occurred in patients with prediabetes by the usual definition; 136 of the incident cases (87%) had prediabetes by a more stringent criterion of an A1c of 6.0%-6.4%.

To put the preventive efficacy of dapagliflozin into more context, Dr. Inzucchi cited the 31% relative protection rate exerted by metformin in the Diabetes Prevention Program study (N Engl J Med. 2002 Feb 7;346[6]:393-403).

The findings showed that “dapagliflozin is the first medication demonstrated to reduce both incident type 2 diabetes and mortality in a single trial,” as well as the first agent from the SGLT2 inhibitor class to show a diabetes prevention effect, Dr. Inzucchi noted. Patients with both heart failure and diabetes are known to have a substantially increased mortality risk, compared with patients with just one of these diseases, and the potent risk posed by the confluence of both was confirmed in the results Dr. Inzucchi reported.

The 157 HFrEF patients in the trial who developed diabetes had a statistically significant 70% increased incidence of all-cause mortality during the trial’s follow-up, compared with similar HFrEF patients who remained free from a diabetes diagnosis, and they also had a significant 77% relative increase in their incidence of cardiovascular death. This analysis failed to show that incident diabetes had a significant impact on hospitalizations for heart failure coupled with cardiovascular death, another endpoint of the trial.

Mitchel L. Zoler/Frontline Medical News

“This is a tremendously important analysis. We recognize that diabetes is an important factor that can forecast heart failure risk, even over relatively short follow-up. A drug that targets both diseases can be quite beneficial,” commented Muthiah Vaduganathan, MD, a cardiologist at Brigham and Women’s Hospital in Boston.

The impact of dapagliflozin on average A1c levels during the DAPA-HF trial was minimal, reducing levels by an average of 0.04% among those who entered with prediabetes and by 0.05% among the other patients. This suggests that the mechanisms by which dapagliflozin reduced incident diabetes was by routes that did not involve simply reducing hyperglycemia, and the observed decrease in incident diabetes was not apparently caused by “masking” of hyperglycemia by dapagliflozin, said Dr. Inzucchi.

One possibility is that dapagliflozin, which also improved quality of life and reduced hospitalizations in the DAPA-HF trial, led to improved function and mobility among patients that had beneficial effects on their insulin sensitivity, Dr. Vaduganathan speculated in an interview.

The new finding of dapagliflozin’s benefit “is great news,” commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of the Metabolic Institute of America in Tarzana, Calif. “It’s an impressive and important result, and another reason to use dapagliflozin in patients with HFrEF, a group of patients whom you want to prevent from having worse outcomes” by developing diabetes.

The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial enrolled HFrEF patients at 410 centers in 20 countries during February 2017–August 2018. The study’s primary endpoint was the composite incidence of cardiovascular death or worsening heart failure, which occurred in 16.3% of patients randomized to receive dapagliflozin and in 21.2% of control patients on standard care but on placebo instead of the study drug, a statistically significant relative risk reduction of 26% (N Engl J Med. 2019 Nov 21;381[21]:1995-2008). In the 2,605-patient subgroup without type 2 diabetes at baseline the primary endpoint fell by a statistically significant 27% with dapagliflozin treatment, the first time an SGLT2 inhibitor drug was shown effective for reducing this endpoint in patients with HFrEF but without diabetes. DAPA-HF did not enroll any patients with type 1 diabetes.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). Dr. Inzucchi has been a consultant to AstraZeneca and to Abbott, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Vaduganathan has been an adviser to AstraZeneca and to Amgen, Baxter, Bayer, Boehringer Ingelheim, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including AstraZeneca.

mzoler@mdedge.com

SOURCE: Inzucchi SE et al. ADA 2020, abstract 271-OR.

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com

Drug adherence, healthcare use, medical costs, and heart failure rates were better among patients with type 2 diabetes who were newly prescribed a sodium-glucose cotransporter 2 (SGLT2) inhibitor than a glucagon-like peptide 1 (GLP-1) receptor agonist in a real-world, observational study.

Composite cardiovascular (CV) outcomes were similar between the two drug classes.

Insiya Poonawalla, PhD, a researcher at Humana Healthcare Research, Flower Mound, Texas, reported the study results in an oral presentation on June 12 at the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

The investigators matched more than 10,000 patients with type 2 diabetes — half initiated on an SGLT2 inhibitor and half initiated on a GLP-1 agonist — from the Humana database of insurance claims data.

“These findings suggest potential benefits” of SGLT2 inhibitors, “particularly where risk related to heart failure is an important consideration,” Poonawalla said, but as always, any benefits need to be weighed against any risks.

And “while this study provides a pretty complete and current picture of claims until 2018,” it has limitations inherent to observational data (such as possible errors or omissions in the claims data), she conceded.

Mitchel L. Zoler/MDedge News

Mikhail Kosiborod, MD, invited to comment on the research, said this preliminary study was likely too short and small to definitively demonstrate differences in composite CV outcomes between the two drug classes, but he noted that the overall findings are not unexpected.

And often, the particular CV risk profile of an individual patient will point to one or the other of these drug classes as a best fit, he noted.

Too soon to alter clinical practice

Kosiborod, from Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, said he nevertheless feels “it would be a bit premature to use these findings as a guide to change clinical practice.”

“The study is relatively small in scope and likely underpowered to examine CV outcomes,” he said in an email interview.

Larger population-based studies and ideally head-to-head randomized controlled trials of various type 2 diabetes agents could compare these two drug classes more definitively, he asserted.

In the meantime, safety profiles of both medication classes “have been well established — in tens of thousands of patients in clinical trials and millions of patients prescribed these therapies in clinical practice,” he noted.

In general, the drugs in both classes are well-tolerated and safe for most patients with type 2 diabetes when used appropriately.

“Certainly, patients with type 2 diabetes and established CV disease (or at high risk for CV complications) are ideal candidates for either an SGLT2 inhibitor or a GLP-1 receptor agonist,” Kosiborod said.

“Given the data we have from outcome trials, an SGLT2 inhibitor would be a better initial strategy in a patient with type 2 diabetes and heart failure (especially heart failure with reduced ejection fraction) and/or diabetic kidney disease,” he continued.

On the other hand, “a GLP-1 receptor agonist may be a better initial strategy in a type 2 diabetes patient with (or at very high risk for) atherosclerotic cardiovascular disease (ASCVD), especially if there is concomitant obesity contributing to the disease process.”

Limited comparisons of these two newer drug classes

“Real-world evidence comparing these two therapeutic classes based on CV outcomes is limited,” Poonawalla said at the start of her presentation, and relative treatment persistence, utilization, and cost data are even less well studied.

To investigate this, the researchers identified patients aged 19 to 89 years who were newly prescribed one of these two types of antidiabetic agents during January 1, 2015 through June 30, 2017.

Poonawalla and senior study author Phil Schwab, PhD, research lead, Humana Healthcare Research, Louisville, Kentucky, clarified the study design and findings in an email to this new organization.

The team matched 5507 patients initiated on a GLP-1 agonist with 5507 patients newly prescribed an SGLT2 inhibitor.

Patients were a mean age of 65 years and 53% were women.

More than a third (37%) had established ASCVD, including myocardial infarction (MI) (7.9%) and stroke (9.8%), and 11.5% had heart failure.

About two thirds were receiving metformin and about a third were receiving insulin.

In the GLP-1 agonist group, more than half of patients were prescribed liraglutide (57%), followed by dulaglutide (33%), exenatide, and lixisenatide (two patients).

In the SGLT2 inhibitor group, close to 70% received canagliflozin, about a quarter received empagliflozin, and the rest received dapagliflozin.

During up to 3.5 years of follow-up, a similar percentage of patients in each group had either an MI, stroke, or died (the primary composite CV outcome) (hazard ratio [HR], 0.98; 95% CI, 0.89 - 1.07).

However, more patients in the GLP-1 agonist group had heart failure or died (the secondary composite CV outcome), driven by a higher rate of heart failure in this group.

But after adjusting for time to events there was no significant between-group difference in the secondary composite CV outcome (HR, 1.09; 95% CI, 0.99 - 1.21).

During the 12-months after the initial prescription, patients who were started on a GLP-1 agonist versus an SGLT2 inhibitor had higher mean monthly medical costs, which included hospitalizations, emergency department (ED) visits, and outpatient visits ($904 vs $834; P < .001).

They also had higher pharmacy costs, which covered all drugs ($891 vs $783; P < .001).

And they were more likely to discontinue treatment (HR, 1.15; 95% CI, 1.10 - 1.21), be hospitalized (14.4% vs 11.9%; P < .001), or visit the ED (27.4% vs 23.5%; P < .001).

“Not too surprising” and “somewhat reassuring”

Overall, Kosiborod did not find the results surprising.

Given the sample size and follow-up time, event rates were probably quite low and insufficient to draw firm conclusions about the composite CV outcomes, he reiterated.

However, given the comparable effects of these two drug types on major adverse cardiac events (MACE) in similar patient populations with type 2 diabetes, it is not too surprising that there were no significant differences in these outcomes.

It was also “somewhat reassuring” to see that heart failure rates were lower with SGLT2 inhibitors, “as one would expect,” he said, because these agents “have been shown to significantly reduce the risk of hospitalization for heart failure in multiple outcome trials, whereas GLP-1 receptor agonists’ beneficial CV effects appear to be more limited to MACE reduction.”

The higher rates of discontinuation with GLP-1 receptor agonists “is also not a surprise, since patients experience more gastrointestinal tolerability issues with these agents (mainly nausea),” which can be mitigated in the majority of patients with appropriate education and close follow up — but is not done consistently.

Similarly, “the cost differences are also expected, since GLP-1 receptor agonists tend to be more expensive.”

On the other hand, the higher rates of hospitalizations with GLP-1 agonists compared to SGLT2 inhibitors “requires further exploration and confirmation,” Kosiborod said.

But he suspects this may be due to residual confounding, “since GLP-1 agonists are typically initiated later in the type 2 diabetes treatment algorithm,” so these patients could have lengthier, more difficult-to-manage type 2 diabetes with more comorbidities despite the propensity matching.

Poonawalla and Schwab are employed by Humana. Kosiborod has disclosed research support from AstraZeneca and Boehringer Ingelheim; honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and consulting fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk, and Sanofi Aventis .



This article first appeared on Medscape.com

Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.

Courtesy Cincinnati Children&#039;s Hospital Medical Center

Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.

The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A_1c.

“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.

Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.

“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.

Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:

• The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
• The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
• The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.

The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA_1c values.

Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m², 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.

SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.

mzoler@mdedge.com

SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.

Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.

Courtesy Cincinnati Children&#039;s Hospital Medical Center

Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.

The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A_1c.

“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.

Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.

“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.

Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:

• The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
• The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
• The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.

The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA_1c values.

Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m², 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.

SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.

mzoler@mdedge.com

SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.

Roughly half of adolescents and young adults with either type 1 or type 2 diabetes for about a decade had diastolic dysfunction, a direct precursor to heart failure, in a multicenter echocardiography survey of 479 American patients.

Courtesy Cincinnati Children&#039;s Hospital Medical Center

Using tissue Doppler echocardiography findings from 258 adolescents and young adults with type 1 diabetes, and 221 with type 2 diabetes, the study found at least one imaging marker of ventricular stiffness – diastolic dysfunction – in 58% of the patients with type 2 diabetes and in 47% of those with type 1 diabetes. The type 1 patients averaged 21 years of age with a median 12 years of diagnosed disease, while the type 2 patients had an average age of 25 years and a median 11 years disease duration.

The analysis also identified several measures that significantly linked with the presence of diastolic dysfunction: older age, female sex, nonwhite race, type 2 diabetes, higher heart rate, higher body mass index, higher systolic blood pressure, and higher hemoglobin A_1c.

“Our data suggest targeting modifiable risk factors” in these patients in an effort to slow the process causing the diastolic dysfunction, Amy S. Shah, MD, said at the virtual annual scientific sessions of the American Diabetes Association. She particularly cited interventions aimed at reducing body mass index, lowering blood pressure, and improving glycemic control, as well as preventing type 2 diabetes in the first place.

Prevention of type 2 diabetes, as well as prevention of diastolic dysfunction development and progression, are key steps because of the substantial clinical consequences of diastolic dysfunction, triggered by stiffening of the left ventricle. Diastolic dysfunction leads to increased left ventricular diastolic pressure, left atrial dysfunction, and ultimately heart failure with preserved ejection fraction, a common diabetes complication that currently has no treatment with proven efficacy, said Dr. Shah, a pediatric endocrinologist and director of the Adolescent Type 2 Diabetes Program at Cincinnati Children’s Hospital Medical Center.

“It’s very concerning that diastolic dysfunction is so prevalent in this age group,” commented Robert A. Gabbay, MD, Chief Science & Medical Officer of the American Diabetes Association. “An important question is whether you can see an improvement by reversing risk factors.” He noted the importance of confirming the finding in additional cohorts as well as running prospective studies looking at the impact of risk factor modification.

Dr. Shah and her associates used data collected at four U.S. centers from patients enrolled in the SEARCH for Diabetes in Youth study who underwent a tissue Doppler examination during 2016-2019, and used three measures derived from the scans to identify diastolic dysfunction:

• The E/A ratio, which compares the early flow wave across the mitral valve (E) with the atrial flow wave (A) that occurs after atrial contraction. Lower values reflect worse pathology.
• The E/e’ ratio, which compares the early flow wave across the mitral valve (E) with the rate of cardiac wall relaxation in early diastole (e’). Higher values reflect worse pathology.
• The e’/a’ ratio, which compares the rate of cardiac wall relaxation in early diastole (e’) with the rate of cardiac wall relaxation in late diastole (a’). Lower values reflect worse pathology.

The most common abnormality involved the e’/a’ measure, which occurred in roughly 38% of the patients with type 2 diabetes and in about 23% of those with type 1 diabetes. Next most common was an abnormally high E/e’ ratio, and fewer than 10% of patients had an abnormally low E/A ratio. Both the E/A and E/e’ values were significantly worse among patients with type 2 diabetes compared with type 1 patients, while no statistically significant difference separated the two subgroups for prevalence of an e’/a’ abnormality after adjustment for body mass index, blood pressure, and HbA_1c values.

Average body mass index among the 221 studied patients with type 2 diabetes was 38 kg/m², 74% were girls or women, and 57% were non-Hispanic black and 24% non-Hispanic white. Mean blood pressure among the patients with type 2 diabetes was 123/80 mm Hg, while it was 110/72 mm Hg among the 258 patients with type 1 diabetes.

SEARCH for Diabetes in Youth receives no commercial funding. Dr. Shah had no disclosures.

mzoler@mdedge.com

SOURCE: Shah AS et al. ADA 2020 abstract 58-OR.

Patients with type 2 diabetes treated with the SGLT2 inhibitor empagliflozin during the landmark EMPA-REG OUTCOME trial had a solidly reduced need to either start insulin treatment or intensify existing insulin treatment, compared with those given placebo, in a post-hoc analysis of the study’s findings.

Mitchel L. Zoler/Frontline Medical News

“Empagliflozin markedly and durably delayed the need for insulin initiation, and reduced the need for large dose increases in patients already using insulin,” Muthiah Vaduganathan, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

The patients in the empagliflozin (Jardiance) arm of EMPA-REG OUTCOME had a 9% rate of initiating insulin treatment after 4 years in the study, compared with a 20% rate among patients who received placebo, a statistically significant 60% relative risk reduction. All patients in the trial continued on their background oral glucose-lowering medications.

Among the 48% of study patients who entered the study already using insulin as part of their usual regimen, 18% of those receiving empagliflozin required a significant increase in their insulin dosage (an increase of at least 20% from baseline) after 4 years. But among the control patients, 35% needed this level of insulin-dosage intensification, again a statistically significant difference that computed to a 58% relative reduction in the need for boosting the insulin dosage.

For both of these endpoints, the divergence between the empagliflozin and control arms became apparent within the first 6 months on treatment, and the between-group differences steadily increased during further follow-up. The analyses pooled the patients who received empagliflozin in the trial, which studied two different dosages of the drug.

Results add to the ‘risk and benefit conversation’

“This is one of the first studies to look at this question in a more granular fashion” in patients with type 2 diabetes receiving a drug from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, said Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston. It provides “compelling” information to include when discussing oral diabetes-drug options with patients, he said in an interview.

Patients newly diagnosed with type 2 diabetes “often think about insulin” and their potential need to eventually start taking it, with the requirements it brings for training, monitoring, and drug delivery, along with the costs for insulin and glucose monitoring. “Patients are very attuned to potentially needing insulin and often ask about it. A reduced need for insulin will be an important part of the risk and benefit conversation” with patients about potential use of an SGLT2 inhibitor, he said.

Dr. Vaduganathan hypothesized that three factors could contribute to the impact of empagliflozin on insulin initiation and dosage level: a direct glycemic-control effect of the drug, the drug’s positive impact on overall well-being and function that could enhance patient movement, and the documented ability of treatment with empagliflozin and other drugs in its class to cut the rate of heart failure hospitalizations. This last feature is potentially relevant because insulin treatment often starts in patients with type 2 diabetes during a hospitalization, he noted.
 

Handelsman: Analysis shows no ‘spectacular effect’

The association of empagliflozin treatment with a reduced need for insulin seen in these data is consistent with expectations for patients with type 2 diabetes who receive an additional oral drug, commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of American in Tarzana, Calif. “In large part it has to do with patients on placebo having to get more insulin” because their additional oral-drug options were limited. Dr. Handelsman pointed out that during the period when the EMPA-REG OUTCOME trial ran, from 2010-2015, fewer oral drugs were available than today, and clinicians in the study were encouraged to treat patients to their goal glycemia level according to local guidelines. In addition to a modest but useful glycemic control effect from SGLT2 inhibitors that, on average, cut hemoglobin A_1c levels by about 0.5%, they may also give a small boost to insulin sensitivity that can also defer the need to add or increase insulin. The level of insulin-treatment deference reported in the new analysis was “not a spectacular effect” he said in an interview.

The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study followed 7,020 patients at 590 sites in 42 countries for a median of 3.1 years. The study’s primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent MI), or nonfatal stroke, and the results showed a statistically significant 14% relative risk reduction with empagliflozin treatment (N Engl J Med. 2015 Nov 26;373[22]:2117-28 ). The results also showed that 12 weeks into the study, before patients could receive any additional drugs, HbA_1c levels averaged 0.54%-0.6% lower among the empagliflozin-treated patients than those in the placebo arm, with smaller between-group differences maintained through the balance of the study. At entry, more than half the enrolled patients were routinely treated with metformin, and close to half were receiving a sulfonyurea agent.

The EMPA-REG OUTCOME results were also notable as showing for the first time that treatment with an SGLT2 inhibitor drug produced a substantial decrease in heart failure hospitalizations, incident heart failure, and progression of renal dysfunction, effects subsequently confirmed and also found for other agents in this drug class.

EMPA-REG OUTCOME was funded in part by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin (Jardiance). Dr. Vaduganathan has been an advisor to Boehringer Ingelheim and to Amgen, AstraZeneca, Baxter, Bayer, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including Boehringer Ingelheim and Eli Lilly.

mzoler@mdedge.com

SOURCE: Vaduganathan M et al. ADA 2020, Abstract 30-OR.

Patients with type 2 diabetes treated with the SGLT2 inhibitor empagliflozin during the landmark EMPA-REG OUTCOME trial had a solidly reduced need to either start insulin treatment or intensify existing insulin treatment, compared with those given placebo, in a post-hoc analysis of the study’s findings.

Mitchel L. Zoler/Frontline Medical News

“Empagliflozin markedly and durably delayed the need for insulin initiation, and reduced the need for large dose increases in patients already using insulin,” Muthiah Vaduganathan, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

The patients in the empagliflozin (Jardiance) arm of EMPA-REG OUTCOME had a 9% rate of initiating insulin treatment after 4 years in the study, compared with a 20% rate among patients who received placebo, a statistically significant 60% relative risk reduction. All patients in the trial continued on their background oral glucose-lowering medications.

Among the 48% of study patients who entered the study already using insulin as part of their usual regimen, 18% of those receiving empagliflozin required a significant increase in their insulin dosage (an increase of at least 20% from baseline) after 4 years. But among the control patients, 35% needed this level of insulin-dosage intensification, again a statistically significant difference that computed to a 58% relative reduction in the need for boosting the insulin dosage.

For both of these endpoints, the divergence between the empagliflozin and control arms became apparent within the first 6 months on treatment, and the between-group differences steadily increased during further follow-up. The analyses pooled the patients who received empagliflozin in the trial, which studied two different dosages of the drug.

Results add to the ‘risk and benefit conversation’

“This is one of the first studies to look at this question in a more granular fashion” in patients with type 2 diabetes receiving a drug from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, said Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston. It provides “compelling” information to include when discussing oral diabetes-drug options with patients, he said in an interview.

Patients newly diagnosed with type 2 diabetes “often think about insulin” and their potential need to eventually start taking it, with the requirements it brings for training, monitoring, and drug delivery, along with the costs for insulin and glucose monitoring. “Patients are very attuned to potentially needing insulin and often ask about it. A reduced need for insulin will be an important part of the risk and benefit conversation” with patients about potential use of an SGLT2 inhibitor, he said.

Dr. Vaduganathan hypothesized that three factors could contribute to the impact of empagliflozin on insulin initiation and dosage level: a direct glycemic-control effect of the drug, the drug’s positive impact on overall well-being and function that could enhance patient movement, and the documented ability of treatment with empagliflozin and other drugs in its class to cut the rate of heart failure hospitalizations. This last feature is potentially relevant because insulin treatment often starts in patients with type 2 diabetes during a hospitalization, he noted.
 

Handelsman: Analysis shows no ‘spectacular effect’

The association of empagliflozin treatment with a reduced need for insulin seen in these data is consistent with expectations for patients with type 2 diabetes who receive an additional oral drug, commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of American in Tarzana, Calif. “In large part it has to do with patients on placebo having to get more insulin” because their additional oral-drug options were limited. Dr. Handelsman pointed out that during the period when the EMPA-REG OUTCOME trial ran, from 2010-2015, fewer oral drugs were available than today, and clinicians in the study were encouraged to treat patients to their goal glycemia level according to local guidelines. In addition to a modest but useful glycemic control effect from SGLT2 inhibitors that, on average, cut hemoglobin A_1c levels by about 0.5%, they may also give a small boost to insulin sensitivity that can also defer the need to add or increase insulin. The level of insulin-treatment deference reported in the new analysis was “not a spectacular effect” he said in an interview.

The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study followed 7,020 patients at 590 sites in 42 countries for a median of 3.1 years. The study’s primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent MI), or nonfatal stroke, and the results showed a statistically significant 14% relative risk reduction with empagliflozin treatment (N Engl J Med. 2015 Nov 26;373[22]:2117-28 ). The results also showed that 12 weeks into the study, before patients could receive any additional drugs, HbA_1c levels averaged 0.54%-0.6% lower among the empagliflozin-treated patients than those in the placebo arm, with smaller between-group differences maintained through the balance of the study. At entry, more than half the enrolled patients were routinely treated with metformin, and close to half were receiving a sulfonyurea agent.

The EMPA-REG OUTCOME results were also notable as showing for the first time that treatment with an SGLT2 inhibitor drug produced a substantial decrease in heart failure hospitalizations, incident heart failure, and progression of renal dysfunction, effects subsequently confirmed and also found for other agents in this drug class.

EMPA-REG OUTCOME was funded in part by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin (Jardiance). Dr. Vaduganathan has been an advisor to Boehringer Ingelheim and to Amgen, AstraZeneca, Baxter, Bayer, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including Boehringer Ingelheim and Eli Lilly.

mzoler@mdedge.com

SOURCE: Vaduganathan M et al. ADA 2020, Abstract 30-OR.

Patients with type 2 diabetes treated with the SGLT2 inhibitor empagliflozin during the landmark EMPA-REG OUTCOME trial had a solidly reduced need to either start insulin treatment or intensify existing insulin treatment, compared with those given placebo, in a post-hoc analysis of the study’s findings.

Mitchel L. Zoler/Frontline Medical News

“Empagliflozin markedly and durably delayed the need for insulin initiation, and reduced the need for large dose increases in patients already using insulin,” Muthiah Vaduganathan, MD, said at the virtual annual scientific sessions of the American Diabetes Association.

The patients in the empagliflozin (Jardiance) arm of EMPA-REG OUTCOME had a 9% rate of initiating insulin treatment after 4 years in the study, compared with a 20% rate among patients who received placebo, a statistically significant 60% relative risk reduction. All patients in the trial continued on their background oral glucose-lowering medications.

Among the 48% of study patients who entered the study already using insulin as part of their usual regimen, 18% of those receiving empagliflozin required a significant increase in their insulin dosage (an increase of at least 20% from baseline) after 4 years. But among the control patients, 35% needed this level of insulin-dosage intensification, again a statistically significant difference that computed to a 58% relative reduction in the need for boosting the insulin dosage.

For both of these endpoints, the divergence between the empagliflozin and control arms became apparent within the first 6 months on treatment, and the between-group differences steadily increased during further follow-up. The analyses pooled the patients who received empagliflozin in the trial, which studied two different dosages of the drug.

Results add to the ‘risk and benefit conversation’

“This is one of the first studies to look at this question in a more granular fashion” in patients with type 2 diabetes receiving a drug from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class, said Dr. Vaduganathan, a cardiologist at Brigham and Women’s Hospital in Boston. It provides “compelling” information to include when discussing oral diabetes-drug options with patients, he said in an interview.

Patients newly diagnosed with type 2 diabetes “often think about insulin” and their potential need to eventually start taking it, with the requirements it brings for training, monitoring, and drug delivery, along with the costs for insulin and glucose monitoring. “Patients are very attuned to potentially needing insulin and often ask about it. A reduced need for insulin will be an important part of the risk and benefit conversation” with patients about potential use of an SGLT2 inhibitor, he said.

Dr. Vaduganathan hypothesized that three factors could contribute to the impact of empagliflozin on insulin initiation and dosage level: a direct glycemic-control effect of the drug, the drug’s positive impact on overall well-being and function that could enhance patient movement, and the documented ability of treatment with empagliflozin and other drugs in its class to cut the rate of heart failure hospitalizations. This last feature is potentially relevant because insulin treatment often starts in patients with type 2 diabetes during a hospitalization, he noted.
 

Handelsman: Analysis shows no ‘spectacular effect’

The association of empagliflozin treatment with a reduced need for insulin seen in these data is consistent with expectations for patients with type 2 diabetes who receive an additional oral drug, commented Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of American in Tarzana, Calif. “In large part it has to do with patients on placebo having to get more insulin” because their additional oral-drug options were limited. Dr. Handelsman pointed out that during the period when the EMPA-REG OUTCOME trial ran, from 2010-2015, fewer oral drugs were available than today, and clinicians in the study were encouraged to treat patients to their goal glycemia level according to local guidelines. In addition to a modest but useful glycemic control effect from SGLT2 inhibitors that, on average, cut hemoglobin A_1c levels by about 0.5%, they may also give a small boost to insulin sensitivity that can also defer the need to add or increase insulin. The level of insulin-treatment deference reported in the new analysis was “not a spectacular effect” he said in an interview.

The EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) study followed 7,020 patients at 590 sites in 42 countries for a median of 3.1 years. The study’s primary endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction (excluding silent MI), or nonfatal stroke, and the results showed a statistically significant 14% relative risk reduction with empagliflozin treatment (N Engl J Med. 2015 Nov 26;373[22]:2117-28 ). The results also showed that 12 weeks into the study, before patients could receive any additional drugs, HbA_1c levels averaged 0.54%-0.6% lower among the empagliflozin-treated patients than those in the placebo arm, with smaller between-group differences maintained through the balance of the study. At entry, more than half the enrolled patients were routinely treated with metformin, and close to half were receiving a sulfonyurea agent.

The EMPA-REG OUTCOME results were also notable as showing for the first time that treatment with an SGLT2 inhibitor drug produced a substantial decrease in heart failure hospitalizations, incident heart failure, and progression of renal dysfunction, effects subsequently confirmed and also found for other agents in this drug class.

EMPA-REG OUTCOME was funded in part by Boehringer Ingelheim and Eli Lilly, the companies that market empagliflozin (Jardiance). Dr. Vaduganathan has been an advisor to Boehringer Ingelheim and to Amgen, AstraZeneca, Baxter, Bayer, Cytokinetics, and Relypsa. Dr. Handelsman has been a consultant to several drug companies including Boehringer Ingelheim and Eli Lilly.

mzoler@mdedge.com

SOURCE: Vaduganathan M et al. ADA 2020, Abstract 30-OR.

Clinically significant sex-based differences in left ventricular ejection fraction related to mortality emerged in a real-world, observational, big data study from Australia, Simon Stewart, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

This analysis from the ongoing National Echocardiography Database of Australia (NEDA) included 499,153 men and women who underwent echocardiography in routine clinical practice for a variety of indications, with more than 3 million person-years of follow-up.

This study broke new ground. There is surprisingly little information from routine clinical practice to describe the spectrum and prognostic importance of left ventricular ejection fraction (LVEF). Indeed, most data have come from clinical trials in patients with heart failure with reduced ejection fraction (HFrEF), in which women are traditionally underrepresented. By comparison, the NEDA analysis included 237,046 women in routine care, noted Dr. Stewart, a National Health and Medical Research Council of Australia Senior Principal Research Fellow at Torrens University in Adelaide.

Among the novel findings in the new NEDA analysis: an LVEF below 50% was more than twice as common in men than women, occurring in 17.6% and 8.3%, respectively. Also, women had a higher average LVEF: 64.2%, compared with 59.5% in men. The overall 1- and 5-year all-cause mortality rates in the half-million participants were 5.8% and 18.4%.

Cardiovascular-related mortality occurred in 7.1% of women in median of 5.6 years of follow-up and in 8.1% of men with 5.5 years of follow-up.

All-cause and cardiovascular mortality rates followed a J-shaped curve, with the clear nadir occurring at an LVEF of 65%-69.9% in both women and men. But for LVEF values outside the nadir, a striking sex-based difference was present. Cardiovascular mortality, when adjusted for body mass index, age, heart rate, valvular heart disease, E-wave velocity, and other potential confounders, wasn’t significantly different between men whose LVEF was 65%-69.9% and those with an LVEF of 45%-64.9%. It started climbing in earnest only at an LVEF below 45%. In contrast, women with an LVEF of 45%-54.9% had a statistically significant twofold increased cardiovascular mortality rate compared to those in the nadir. Moreover, women with an LVEF of 55%-59.9% showed a trend in the same unwanted direction.
 

High LVEF, higher mortality in women

Dr. Stewart drew attention to an inflection point in the mortality curve for women whereby mortality began climbing at LVEF values of 70% or more. Values in that high range were documented in 72,379 women and 51,317 men.

He noted that the NEDA finding of an increasing mortality risk at LVEFs of at least 70%, especially in women, is similar to a recent report from another big data study, this one involving more than 200,000 patients who underwent echocardiography in routine clinical practice in the Geisinger health system in Pennsylvania. The investigators found in this retrospective study that during a median of 4 years of follow-up after echocardiography, the adjusted risk for all-cause mortality followed a U-shaped curve. The nadir of risk occurred in patients with an LVEF of 60%-65%, with a 1.71-fold increased risk at an LVEF at 70% or more and a near-identical 1.73-fold increased risk at an LVEF of 35%-40%. In this study, however, which was less than half the size of the NEDA analysis, the U-shaped LVEF/mortality curve applied to both men and women. Similar findings were seen in a validation cohort of nearly 36,000 patients from New Zealand (Eur Heart J. 2020 Mar 21;41[12]:1249-57).

The investigators predicted that in addition to the existing categories of HFrEF, heart failure with preserved ejection fraction (HFpEF), and the more recently proposed heart failure with midrange ejection fraction (HFmrEF), their results “may herald the recognition of a new phenotype characterized by supranormal LVEF,” with a moniker of HFsnEF.
 

New treatment opportunity for women?

Discussant Lars Lund, MD, PhD, professor of cardiology at the Karolinska Institute, Stockholm, said that it’s not possible to make any statements about what constitutes a “normal” LVEF in men or women based on the NEDA study, since all participants underwent medically indicated echocardiography. He added that what he found most interesting about the NEDA analysis was the observation that women with mid-range or mildly reduced LVEF had increased mortality, while men didn’t. That’s a finding that helps explain the suggestion of possible benefit for sacubitril-valsartan in patients with lower ejection fraction and in women in the PARAGON-HF trial of angiotensin-neprilysin inhibition in patients with heart failure with preserved ejection fraction (N Engl J Med. 2019 Oct 24;381[17]:1609-20).

Dr. Lund expressed the hope that the NEDA investigators will do an analysis of the relationship between echocardiographic left atrial size and mortality. Dr. Stewart replied that, as a matter of fact,such a study is planned. The enormous and continuously growing NEDA database has already been used to provide new insights into aortic stenosis and pulmonary hypertension, he noted.

Session moderator Andrew Coats, MD, incoming president of the ESC Heart Failure Association, said that there are many different methods used for echocardiographic measurement of LVEF. He wondered about the validity of pooling them in a single analysis.

Dr. Stewart replied that NEDA software applies a hierarchical weighting of the various methods used to quantify LVEF. And the submitted data come from the top echocardiography laboratories throughout Australia.

“We’ve done some sensitivity analyses around the different methods of quantifying LVEF and we get the same patterns,” he said. “We’re comfortable with the validity of what we’ve done. The big data allows us to do that.”

Dr. Stewart reported receiving speakers fees and travel support from Novartis, a partial funder of NEDA.

bjancin@mdedge.com

SOURCE: Stewart S. ESC Heart Failure 2020.

Clinically significant sex-based differences in left ventricular ejection fraction related to mortality emerged in a real-world, observational, big data study from Australia, Simon Stewart, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

This analysis from the ongoing National Echocardiography Database of Australia (NEDA) included 499,153 men and women who underwent echocardiography in routine clinical practice for a variety of indications, with more than 3 million person-years of follow-up.

This study broke new ground. There is surprisingly little information from routine clinical practice to describe the spectrum and prognostic importance of left ventricular ejection fraction (LVEF). Indeed, most data have come from clinical trials in patients with heart failure with reduced ejection fraction (HFrEF), in which women are traditionally underrepresented. By comparison, the NEDA analysis included 237,046 women in routine care, noted Dr. Stewart, a National Health and Medical Research Council of Australia Senior Principal Research Fellow at Torrens University in Adelaide.

Among the novel findings in the new NEDA analysis: an LVEF below 50% was more than twice as common in men than women, occurring in 17.6% and 8.3%, respectively. Also, women had a higher average LVEF: 64.2%, compared with 59.5% in men. The overall 1- and 5-year all-cause mortality rates in the half-million participants were 5.8% and 18.4%.

Cardiovascular-related mortality occurred in 7.1% of women in median of 5.6 years of follow-up and in 8.1% of men with 5.5 years of follow-up.

All-cause and cardiovascular mortality rates followed a J-shaped curve, with the clear nadir occurring at an LVEF of 65%-69.9% in both women and men. But for LVEF values outside the nadir, a striking sex-based difference was present. Cardiovascular mortality, when adjusted for body mass index, age, heart rate, valvular heart disease, E-wave velocity, and other potential confounders, wasn’t significantly different between men whose LVEF was 65%-69.9% and those with an LVEF of 45%-64.9%. It started climbing in earnest only at an LVEF below 45%. In contrast, women with an LVEF of 45%-54.9% had a statistically significant twofold increased cardiovascular mortality rate compared to those in the nadir. Moreover, women with an LVEF of 55%-59.9% showed a trend in the same unwanted direction.
 

High LVEF, higher mortality in women

Dr. Stewart drew attention to an inflection point in the mortality curve for women whereby mortality began climbing at LVEF values of 70% or more. Values in that high range were documented in 72,379 women and 51,317 men.

He noted that the NEDA finding of an increasing mortality risk at LVEFs of at least 70%, especially in women, is similar to a recent report from another big data study, this one involving more than 200,000 patients who underwent echocardiography in routine clinical practice in the Geisinger health system in Pennsylvania. The investigators found in this retrospective study that during a median of 4 years of follow-up after echocardiography, the adjusted risk for all-cause mortality followed a U-shaped curve. The nadir of risk occurred in patients with an LVEF of 60%-65%, with a 1.71-fold increased risk at an LVEF at 70% or more and a near-identical 1.73-fold increased risk at an LVEF of 35%-40%. In this study, however, which was less than half the size of the NEDA analysis, the U-shaped LVEF/mortality curve applied to both men and women. Similar findings were seen in a validation cohort of nearly 36,000 patients from New Zealand (Eur Heart J. 2020 Mar 21;41[12]:1249-57).

The investigators predicted that in addition to the existing categories of HFrEF, heart failure with preserved ejection fraction (HFpEF), and the more recently proposed heart failure with midrange ejection fraction (HFmrEF), their results “may herald the recognition of a new phenotype characterized by supranormal LVEF,” with a moniker of HFsnEF.
 

New treatment opportunity for women?

Discussant Lars Lund, MD, PhD, professor of cardiology at the Karolinska Institute, Stockholm, said that it’s not possible to make any statements about what constitutes a “normal” LVEF in men or women based on the NEDA study, since all participants underwent medically indicated echocardiography. He added that what he found most interesting about the NEDA analysis was the observation that women with mid-range or mildly reduced LVEF had increased mortality, while men didn’t. That’s a finding that helps explain the suggestion of possible benefit for sacubitril-valsartan in patients with lower ejection fraction and in women in the PARAGON-HF trial of angiotensin-neprilysin inhibition in patients with heart failure with preserved ejection fraction (N Engl J Med. 2019 Oct 24;381[17]:1609-20).

Dr. Lund expressed the hope that the NEDA investigators will do an analysis of the relationship between echocardiographic left atrial size and mortality. Dr. Stewart replied that, as a matter of fact,such a study is planned. The enormous and continuously growing NEDA database has already been used to provide new insights into aortic stenosis and pulmonary hypertension, he noted.

Session moderator Andrew Coats, MD, incoming president of the ESC Heart Failure Association, said that there are many different methods used for echocardiographic measurement of LVEF. He wondered about the validity of pooling them in a single analysis.

Dr. Stewart replied that NEDA software applies a hierarchical weighting of the various methods used to quantify LVEF. And the submitted data come from the top echocardiography laboratories throughout Australia.

“We’ve done some sensitivity analyses around the different methods of quantifying LVEF and we get the same patterns,” he said. “We’re comfortable with the validity of what we’ve done. The big data allows us to do that.”

Dr. Stewart reported receiving speakers fees and travel support from Novartis, a partial funder of NEDA.

bjancin@mdedge.com

SOURCE: Stewart S. ESC Heart Failure 2020.

Clinically significant sex-based differences in left ventricular ejection fraction related to mortality emerged in a real-world, observational, big data study from Australia, Simon Stewart, PhD, reported at the European Society of Cardiology Heart Failure Discoveries virtual meeting.

This analysis from the ongoing National Echocardiography Database of Australia (NEDA) included 499,153 men and women who underwent echocardiography in routine clinical practice for a variety of indications, with more than 3 million person-years of follow-up.

This study broke new ground. There is surprisingly little information from routine clinical practice to describe the spectrum and prognostic importance of left ventricular ejection fraction (LVEF). Indeed, most data have come from clinical trials in patients with heart failure with reduced ejection fraction (HFrEF), in which women are traditionally underrepresented. By comparison, the NEDA analysis included 237,046 women in routine care, noted Dr. Stewart, a National Health and Medical Research Council of Australia Senior Principal Research Fellow at Torrens University in Adelaide.

Among the novel findings in the new NEDA analysis: an LVEF below 50% was more than twice as common in men than women, occurring in 17.6% and 8.3%, respectively. Also, women had a higher average LVEF: 64.2%, compared with 59.5% in men. The overall 1- and 5-year all-cause mortality rates in the half-million participants were 5.8% and 18.4%.

Cardiovascular-related mortality occurred in 7.1% of women in median of 5.6 years of follow-up and in 8.1% of men with 5.5 years of follow-up.

All-cause and cardiovascular mortality rates followed a J-shaped curve, with the clear nadir occurring at an LVEF of 65%-69.9% in both women and men. But for LVEF values outside the nadir, a striking sex-based difference was present. Cardiovascular mortality, when adjusted for body mass index, age, heart rate, valvular heart disease, E-wave velocity, and other potential confounders, wasn’t significantly different between men whose LVEF was 65%-69.9% and those with an LVEF of 45%-64.9%. It started climbing in earnest only at an LVEF below 45%. In contrast, women with an LVEF of 45%-54.9% had a statistically significant twofold increased cardiovascular mortality rate compared to those in the nadir. Moreover, women with an LVEF of 55%-59.9% showed a trend in the same unwanted direction.
 

High LVEF, higher mortality in women

Dr. Stewart drew attention to an inflection point in the mortality curve for women whereby mortality began climbing at LVEF values of 70% or more. Values in that high range were documented in 72,379 women and 51,317 men.

He noted that the NEDA finding of an increasing mortality risk at LVEFs of at least 70%, especially in women, is similar to a recent report from another big data study, this one involving more than 200,000 patients who underwent echocardiography in routine clinical practice in the Geisinger health system in Pennsylvania. The investigators found in this retrospective study that during a median of 4 years of follow-up after echocardiography, the adjusted risk for all-cause mortality followed a U-shaped curve. The nadir of risk occurred in patients with an LVEF of 60%-65%, with a 1.71-fold increased risk at an LVEF at 70% or more and a near-identical 1.73-fold increased risk at an LVEF of 35%-40%. In this study, however, which was less than half the size of the NEDA analysis, the U-shaped LVEF/mortality curve applied to both men and women. Similar findings were seen in a validation cohort of nearly 36,000 patients from New Zealand (Eur Heart J. 2020 Mar 21;41[12]:1249-57).

The investigators predicted that in addition to the existing categories of HFrEF, heart failure with preserved ejection fraction (HFpEF), and the more recently proposed heart failure with midrange ejection fraction (HFmrEF), their results “may herald the recognition of a new phenotype characterized by supranormal LVEF,” with a moniker of HFsnEF.
 

New treatment opportunity for women?

Discussant Lars Lund, MD, PhD, professor of cardiology at the Karolinska Institute, Stockholm, said that it’s not possible to make any statements about what constitutes a “normal” LVEF in men or women based on the NEDA study, since all participants underwent medically indicated echocardiography. He added that what he found most interesting about the NEDA analysis was the observation that women with mid-range or mildly reduced LVEF had increased mortality, while men didn’t. That’s a finding that helps explain the suggestion of possible benefit for sacubitril-valsartan in patients with lower ejection fraction and in women in the PARAGON-HF trial of angiotensin-neprilysin inhibition in patients with heart failure with preserved ejection fraction (N Engl J Med. 2019 Oct 24;381[17]:1609-20).

Dr. Lund expressed the hope that the NEDA investigators will do an analysis of the relationship between echocardiographic left atrial size and mortality. Dr. Stewart replied that, as a matter of fact,such a study is planned. The enormous and continuously growing NEDA database has already been used to provide new insights into aortic stenosis and pulmonary hypertension, he noted.

Session moderator Andrew Coats, MD, incoming president of the ESC Heart Failure Association, said that there are many different methods used for echocardiographic measurement of LVEF. He wondered about the validity of pooling them in a single analysis.

Dr. Stewart replied that NEDA software applies a hierarchical weighting of the various methods used to quantify LVEF. And the submitted data come from the top echocardiography laboratories throughout Australia.

“We’ve done some sensitivity analyses around the different methods of quantifying LVEF and we get the same patterns,” he said. “We’re comfortable with the validity of what we’ve done. The big data allows us to do that.”

Dr. Stewart reported receiving speakers fees and travel support from Novartis, a partial funder of NEDA.

bjancin@mdedge.com

SOURCE: Stewart S. ESC Heart Failure 2020.

Although clinical outcomes improved for patients with high-risk heart failure (HF) who received vericiguat (Merck/Bayer) on top of standard therapy in a major randomized trial, a subgroup study failed to show any corresponding gains in ventricular function.

The discordant results from the 5,050-patient VICTORIA trial and its echocardiographic substudy highlight something of a mystery as to the mechanism of the investigational oral soluble guanylate cyclase stimulator’s clinical effects. In the overall trial, they included a drop in risk of cardiovascular (CV) death or first HF hospitalization, the primary endpoint.

In the echo substudy, which assessed patients with evaluable echocardiograms at both baseline and 8 months, vericiguat, compared with placebo, had no significant effect on two measures of left ventricular (LV) function. Patients in the prospectively conducted substudy made up less than 10% of the total trial population.

Both LV ejection fraction (LVEF) and LV end-systolic volume index (LVESVI) significantly improved in the vericiguat and control groups, but vericiguat “had no additional significant effect,” said Burkert Pieske, MD, of Charité University Medicine Berlin.

Still, he said, there was “evidence of a lower risk of events, evidence of a clinical benefit,” for those who received vericiguat, although it fell slightly short of significance in the substudy cohort of fewer than 500 patients.

Dr. Pieske reported the VICTORIA echo substudy results June 5 in a Late-Breaking Science Session during HFA Discoveries, the online backup for the Heart Failure Association of the European Society of Cardiology annual scientific meeting.

The traditional live HFA meeting had been scheduled for Barcelona but was canceled this year as a result of the COVID-19 pandemic.

Pointing to the significant echo improvements in both treatment groups, invited discussant Rudolf A. de Boer, MD, PhD, University of Groningen (the Netherlands), said the substudy shows that HF in high-risk patients “is associated with a transient deterioration of LV function and geometry, which can to a certain extent be reversed over time.”

That the effect apparently wasn’t influenced by vericiguat “may be explained by the fact that, in randomized controlled trials, patients – including those on placebo – tend to be treated very well.” In clinical practice, he said, “less complete reverse remodeling may be expected.”

Dr. de Boer also pointed to likely survivor bias in the study, in that only patients who survived to at least 8 months were included. That meant, among other things, that they were likely at lower overall risk than the total VICTORIA population, leaving less room for any treatment effect.

“Further, likely because of the play of chance in this substudy, the LV volumes were smaller in the vericiguat group at baseline, creating less of an opportunity for vericiguat to make a difference,” he said. “It could be speculated that, with larger volumes, the window of opportunity for vericiguat would have been wider.”

But “most strikingly,” the lack of vericiguat effect on echo parameters contrasts with the clinical benefits associated with the drug in the main trial, and possibly in the echo substudy, Dr. de Boer said, “creating a dissociation between the surrogate echo parameters and the clinical hard endpoints. And it could be imagined that the rather crude echo measures presented here, LVEF and LV volume, miss a more subtle effect of vericiguat.”

For example, it’s possible that the drug’s clinical effect in heart failure does not depend on any improvements in ventricular function, Dr. de Boer said, adding that vericiguat “may potentially also have important effects on pulmonary and peripheral vasculature,” so he recommended future studies look for any changes in arterial and right ventricular function from the drug.

VICTORIA enrolled only patients with HF and reduced ejection fraction who had previously experienced a decompensation event, usually only within the last 3 months, as it turned out. Those assigned to vericiguat on top of standard drug and device therapies showed a modest 10% decline in adjusted relative risk (P = .019) for the trial’s primary endpoint, CV death or first HF hospitalization.

But when the results were unveiled at a meeting, trialists and observers were more enthused about the drug’s effect in absolute terms, which by one measure was 4.2 fewer events on vericiguat per 100 patient-years. That translated to a number to treat of 24 to prevent one event, said to be impressive, given that the study’s patients were so high risk.

The echo substudy included 419 prospectively selected patients, 208 on vericiguat and 211 assigned to placebo, who had evaluable echocardiograms at both baseline and 8 months, as assessed at the VICTORIA echo core lab. They averaged 64.5 years in age with a mean baseline LVEF of 29%; about 27% were women.

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

Although clinical outcomes improved for patients with high-risk heart failure (HF) who received vericiguat (Merck/Bayer) on top of standard therapy in a major randomized trial, a subgroup study failed to show any corresponding gains in ventricular function.

The discordant results from the 5,050-patient VICTORIA trial and its echocardiographic substudy highlight something of a mystery as to the mechanism of the investigational oral soluble guanylate cyclase stimulator’s clinical effects. In the overall trial, they included a drop in risk of cardiovascular (CV) death or first HF hospitalization, the primary endpoint.

In the echo substudy, which assessed patients with evaluable echocardiograms at both baseline and 8 months, vericiguat, compared with placebo, had no significant effect on two measures of left ventricular (LV) function. Patients in the prospectively conducted substudy made up less than 10% of the total trial population.

Both LV ejection fraction (LVEF) and LV end-systolic volume index (LVESVI) significantly improved in the vericiguat and control groups, but vericiguat “had no additional significant effect,” said Burkert Pieske, MD, of Charité University Medicine Berlin.

Still, he said, there was “evidence of a lower risk of events, evidence of a clinical benefit,” for those who received vericiguat, although it fell slightly short of significance in the substudy cohort of fewer than 500 patients.

Dr. Pieske reported the VICTORIA echo substudy results June 5 in a Late-Breaking Science Session during HFA Discoveries, the online backup for the Heart Failure Association of the European Society of Cardiology annual scientific meeting.

The traditional live HFA meeting had been scheduled for Barcelona but was canceled this year as a result of the COVID-19 pandemic.

Pointing to the significant echo improvements in both treatment groups, invited discussant Rudolf A. de Boer, MD, PhD, University of Groningen (the Netherlands), said the substudy shows that HF in high-risk patients “is associated with a transient deterioration of LV function and geometry, which can to a certain extent be reversed over time.”

That the effect apparently wasn’t influenced by vericiguat “may be explained by the fact that, in randomized controlled trials, patients – including those on placebo – tend to be treated very well.” In clinical practice, he said, “less complete reverse remodeling may be expected.”

Dr. de Boer also pointed to likely survivor bias in the study, in that only patients who survived to at least 8 months were included. That meant, among other things, that they were likely at lower overall risk than the total VICTORIA population, leaving less room for any treatment effect.

“Further, likely because of the play of chance in this substudy, the LV volumes were smaller in the vericiguat group at baseline, creating less of an opportunity for vericiguat to make a difference,” he said. “It could be speculated that, with larger volumes, the window of opportunity for vericiguat would have been wider.”

But “most strikingly,” the lack of vericiguat effect on echo parameters contrasts with the clinical benefits associated with the drug in the main trial, and possibly in the echo substudy, Dr. de Boer said, “creating a dissociation between the surrogate echo parameters and the clinical hard endpoints. And it could be imagined that the rather crude echo measures presented here, LVEF and LV volume, miss a more subtle effect of vericiguat.”

For example, it’s possible that the drug’s clinical effect in heart failure does not depend on any improvements in ventricular function, Dr. de Boer said, adding that vericiguat “may potentially also have important effects on pulmonary and peripheral vasculature,” so he recommended future studies look for any changes in arterial and right ventricular function from the drug.

VICTORIA enrolled only patients with HF and reduced ejection fraction who had previously experienced a decompensation event, usually only within the last 3 months, as it turned out. Those assigned to vericiguat on top of standard drug and device therapies showed a modest 10% decline in adjusted relative risk (P = .019) for the trial’s primary endpoint, CV death or first HF hospitalization.

But when the results were unveiled at a meeting, trialists and observers were more enthused about the drug’s effect in absolute terms, which by one measure was 4.2 fewer events on vericiguat per 100 patient-years. That translated to a number to treat of 24 to prevent one event, said to be impressive, given that the study’s patients were so high risk.

The echo substudy included 419 prospectively selected patients, 208 on vericiguat and 211 assigned to placebo, who had evaluable echocardiograms at both baseline and 8 months, as assessed at the VICTORIA echo core lab. They averaged 64.5 years in age with a mean baseline LVEF of 29%; about 27% were women.

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

Although clinical outcomes improved for patients with high-risk heart failure (HF) who received vericiguat (Merck/Bayer) on top of standard therapy in a major randomized trial, a subgroup study failed to show any corresponding gains in ventricular function.

The discordant results from the 5,050-patient VICTORIA trial and its echocardiographic substudy highlight something of a mystery as to the mechanism of the investigational oral soluble guanylate cyclase stimulator’s clinical effects. In the overall trial, they included a drop in risk of cardiovascular (CV) death or first HF hospitalization, the primary endpoint.

In the echo substudy, which assessed patients with evaluable echocardiograms at both baseline and 8 months, vericiguat, compared with placebo, had no significant effect on two measures of left ventricular (LV) function. Patients in the prospectively conducted substudy made up less than 10% of the total trial population.

Both LV ejection fraction (LVEF) and LV end-systolic volume index (LVESVI) significantly improved in the vericiguat and control groups, but vericiguat “had no additional significant effect,” said Burkert Pieske, MD, of Charité University Medicine Berlin.

Still, he said, there was “evidence of a lower risk of events, evidence of a clinical benefit,” for those who received vericiguat, although it fell slightly short of significance in the substudy cohort of fewer than 500 patients.

Dr. Pieske reported the VICTORIA echo substudy results June 5 in a Late-Breaking Science Session during HFA Discoveries, the online backup for the Heart Failure Association of the European Society of Cardiology annual scientific meeting.

The traditional live HFA meeting had been scheduled for Barcelona but was canceled this year as a result of the COVID-19 pandemic.

Pointing to the significant echo improvements in both treatment groups, invited discussant Rudolf A. de Boer, MD, PhD, University of Groningen (the Netherlands), said the substudy shows that HF in high-risk patients “is associated with a transient deterioration of LV function and geometry, which can to a certain extent be reversed over time.”

That the effect apparently wasn’t influenced by vericiguat “may be explained by the fact that, in randomized controlled trials, patients – including those on placebo – tend to be treated very well.” In clinical practice, he said, “less complete reverse remodeling may be expected.”

Dr. de Boer also pointed to likely survivor bias in the study, in that only patients who survived to at least 8 months were included. That meant, among other things, that they were likely at lower overall risk than the total VICTORIA population, leaving less room for any treatment effect.

“Further, likely because of the play of chance in this substudy, the LV volumes were smaller in the vericiguat group at baseline, creating less of an opportunity for vericiguat to make a difference,” he said. “It could be speculated that, with larger volumes, the window of opportunity for vericiguat would have been wider.”

But “most strikingly,” the lack of vericiguat effect on echo parameters contrasts with the clinical benefits associated with the drug in the main trial, and possibly in the echo substudy, Dr. de Boer said, “creating a dissociation between the surrogate echo parameters and the clinical hard endpoints. And it could be imagined that the rather crude echo measures presented here, LVEF and LV volume, miss a more subtle effect of vericiguat.”

For example, it’s possible that the drug’s clinical effect in heart failure does not depend on any improvements in ventricular function, Dr. de Boer said, adding that vericiguat “may potentially also have important effects on pulmonary and peripheral vasculature,” so he recommended future studies look for any changes in arterial and right ventricular function from the drug.

VICTORIA enrolled only patients with HF and reduced ejection fraction who had previously experienced a decompensation event, usually only within the last 3 months, as it turned out. Those assigned to vericiguat on top of standard drug and device therapies showed a modest 10% decline in adjusted relative risk (P = .019) for the trial’s primary endpoint, CV death or first HF hospitalization.

But when the results were unveiled at a meeting, trialists and observers were more enthused about the drug’s effect in absolute terms, which by one measure was 4.2 fewer events on vericiguat per 100 patient-years. That translated to a number to treat of 24 to prevent one event, said to be impressive, given that the study’s patients were so high risk.

The echo substudy included 419 prospectively selected patients, 208 on vericiguat and 211 assigned to placebo, who had evaluable echocardiograms at both baseline and 8 months, as assessed at the VICTORIA echo core lab. They averaged 64.5 years in age with a mean baseline LVEF of 29%; about 27% were women.

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