Meeting NewsPerspective

REWIND: Dulaglutide reduces CV, renal risk in broad type 2 diabetes population

SAN FRANCISCO — In a large cohort of adults with type 2 diabetes with and without established cardiovascular disease, the once-weekly GLP-1 receptor agonist dulaglutide reduced the risk for nonfatal myocardial infarction, nonfatal stroke and CV death by 12% compared with placebo, according to data from the REWIND study presented at the American Diabetes Association Scientific Sessions.

Hertzel C. Gerstein

“We’ve shown in the REWIND trial that in middle-aged and older men and women who are similar to people with type 2 diabetes in the general population and had a broad range of glucose control ... adding dulaglutide (Trulicity, Eli Lilly) safely reduces CV outcomes for more than 5 years,” Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences in Ontario, Canada, said during a presentation. “Similar benefits were seen in men and women, in people with higher BMI and lower BMI, in people with prior CVD and no prior CVD and in people with higher and lower HbA1c levels.”

The findings from REWIND — the first major CV outcomes trial for an antidiabetes therapy to include a large primary prevention population — also demonstrated renal benefits in participants assigned the drug, with the greatest benefit observed in development of new macroalbuminuria.

“REWIND adds to and extends the growing body of evidence that intermediate- or long-acting GLP-1 receptor agonists — in this case, dulaglutide — is superior to standard care for three-point [major adverse cardiac events], including people with CV risk factors,” Sophia Zoungas, MBBS, PhD, FRACP, head of the diabetes and vascular medicine research program at Monash University in Melbourne, Australia, said during an independent commentary after the findings were presented. “There are going to be numerous potential mechanisms of action, beyond glucose, blood pressure and weight effects, and we look forward to those mechanistic studies where we will understand better the role of inflammation, endothelial function and other CV protective effects.”

Largest primary prevention cohort

Gerstein and colleagues analyzed data from 9,901 adults aged at least 50 years with type 2 diabetes (HbA1c 9.5%) and a history of a previous CV event or CV risk factors, recruited from 374 sites in 24 countries from August 2011 to August 2013 (mean age, 66 years; 46.3% women; median diabetes duration, 9.5 years; median HbA1c, 7.2%). Participants were taking stable doses of up to two oral glucose-lowering drugs, with or without basal insulin therapy.

Within the cohort, only 31.5% of participants had prior CVD, making the trial the largest primary prevention CV outcomes study with a GLP-1 receptor agonist, Gerstein said.

“When we look at subgroups of people without prior CVD, REWIND has a lot to add ... 6,221 people in REWIND did not have prior CVD,” Gerstein said during a presentation of the summary findings. “REWIND is the first, and hopefully not the last trial to look at this subgroup of people without prior CVD.”

Researchers randomly assigned patients to receive once-weekly dulaglutide (n = 4,949) or placebo (n = 4,952). Primary endpoint was first occurrence of any component of the composite CV outcome of nonfatal MI, nonfatal stroke and CV death. Secondary outcomes were a composite clinical microvascular outcome including diabetic retinopathy, renal disease, hospitalization for unstable angina and heart failure requiring hospitalization. Follow-up occurred at 2 weeks, 3 and 6 months, and then every 6 months until 1,200 confirmed primary events occurred. Researchers also measured urinary albumin to creatinine ratio and estimated glomerular filtration rate (eGFR) every 12 months.

The data were simultaneously published in the Lancet.

CV findings

During a median 5.4 years, the primary composite outcome occurred in 12% of patients in the dulaglutide arm (incidence rate, 2.4 per 100 person-years) vs. 13.4% of patients in the placebo arm (incidence rate, 2.7 per 100 person-years), for an HR of 0.88 (95% CI, 0.79-0.99).

“As you can see, dulaglutide reduced the occurrence of this primary composite outcome,” Gerstein said to applause as he presented the CV findings. “You can see the effect of the intervention begins before the first year, and continues in a progressive, proportional fashion throughout the full follow-up period, which exceeds 5 years.”

In assessing the individual components of the composite outcome, Gerstein noted that there was no discernable effect on nonfatal MI with dulaglutide (HR = 0.96; 95% CI, 0.79-1.16) and a neutral effect observed for CV death (HR = 0.91; 95% CI, 0.78-1.06), however, researchers observed a 24% reduction in stroke in the dulaglutide arm (HR = 0.76; 95% CI, 0.61-0.95). There were no between-group differences in all-cause mortality.

In subgroup analyses, the CV results were similar when comparing participants with and without previous CVD (P for interaction = .97) and in comparing patients with an HbA1c above and below 7.2% (P for interaction = .75). Results persisted in analyses further stratified by age, sex, diabetes duration and BMI.

Renal findings

In an exploratory analysis assessing the prospectively defined renal effects of dulaglutide, the drug reduced the HR for the composite renal outcome compared with placebo, with the largest effect noted for the development of albuminuria.

During follow-up, the renal outcome developed in 17.1% of participants assigned to dulaglutide (incidence rate, 3.5 per 100 person-years) vs. 19.6% of the placebo arm (incidence rate, 4.1 per 100 person-years), for an HR of 0.85 (95% CI, 0.77-0.93). The greatest observed effect with dulaglutide was observed for new macroalbuminuria, with an HR of 0.77 (95% CI, 0.68-0.87), although researchers also observed reductions in the rates of sustained decline in eGFR of 30% or more (HR = 0.89; 95% CI, 0.78-1.01) and for chronic renal replacement therapy (HR = 0.75; 95% CI, 0.39-1.44).

“Our sensitivity analyses suggested a reduced incidence of a 40% and 50% decline in eGFR with dulaglutide, supporting the possibility that dulaglutide might preserve renal function; this association merits further scrutiny,” the researchers wrote in the Lancet.

Embrace therapy early

In commentary accompanying the two studies, Subodh Verma, MD, PhD, FRCSC, from the division of cardiac surgery at St. Michael’s Hospital, University of Toronto, and colleagues noted that the magnitude of benefit on the composite CV outcome was “modest” and numerically lower compared with CV benefits observed in the LEADER (liraglutide; Victoza, Novo Nordisk) and SUSTAIN-6 (semaglutide; Ozempic, Novo Nordisk) trials; however, the findings were consistent with the overall effect size of the class observed in a meta-analysis of all previous GLP-1 receptor agonist trials.

“Although SGLT2 inhibitors and GLP-1 receptor agonists are recommended in patients with established atherosclerotic vascular disease, we now have evidence from the DECLARE-TIMI 58 and REWIND trials that SGLT2 inhibitors and GLP-1 receptor agonists afford cardiovascular superiority even in primary prevention; with SGLT2 inhibitors preventing heart failure and GLP-1 receptor agonists preventing atherosclerotic events, and both potentially affording renal protection,” Verma and colleagues wrote. “If we are to reduce the burgeoning pump, pipes and filter complications of diabetes, we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably in combination. The REWIND trial makes a strong case in this regard.” – by Regina Schaffer

References:

Gerstein HC, at al. Once-weekly dulaglutide and major cardiovascular events — results of the REWIND trial. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco.

Gerstein HC, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31149-3.

Gerstein HC, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31150-X.

Verma S, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31267-X.

Disclosures: Eli Lilly funded the REWIND study. Gerstein reports he has received consultant fees, grants and honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Cirius, Eli Lilly, Janssen, Kowa, Merck, Novo Nordisk and Sanofi. Verma reports he has received grants and honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier and Valeant. Please see the two studies and commentary for all other authors’ relevant financial disclosures.

SAN FRANCISCO — In a large cohort of adults with type 2 diabetes with and without established cardiovascular disease, the once-weekly GLP-1 receptor agonist dulaglutide reduced the risk for nonfatal myocardial infarction, nonfatal stroke and CV death by 12% compared with placebo, according to data from the REWIND study presented at the American Diabetes Association Scientific Sessions.

Hertzel C. Gerstein

“We’ve shown in the REWIND trial that in middle-aged and older men and women who are similar to people with type 2 diabetes in the general population and had a broad range of glucose control ... adding dulaglutide (Trulicity, Eli Lilly) safely reduces CV outcomes for more than 5 years,” Hertzel C. Gerstein, MD, MSc, FRCPC, professor and population health institute chair in diabetes research at McMaster University and Hamilton Health Sciences in Ontario, Canada, said during a presentation. “Similar benefits were seen in men and women, in people with higher BMI and lower BMI, in people with prior CVD and no prior CVD and in people with higher and lower HbA1c levels.”

The findings from REWIND — the first major CV outcomes trial for an antidiabetes therapy to include a large primary prevention population — also demonstrated renal benefits in participants assigned the drug, with the greatest benefit observed in development of new macroalbuminuria.

“REWIND adds to and extends the growing body of evidence that intermediate- or long-acting GLP-1 receptor agonists — in this case, dulaglutide — is superior to standard care for three-point [major adverse cardiac events], including people with CV risk factors,” Sophia Zoungas, MBBS, PhD, FRACP, head of the diabetes and vascular medicine research program at Monash University in Melbourne, Australia, said during an independent commentary after the findings were presented. “There are going to be numerous potential mechanisms of action, beyond glucose, blood pressure and weight effects, and we look forward to those mechanistic studies where we will understand better the role of inflammation, endothelial function and other CV protective effects.”

Largest primary prevention cohort

Gerstein and colleagues analyzed data from 9,901 adults aged at least 50 years with type 2 diabetes (HbA1c 9.5%) and a history of a previous CV event or CV risk factors, recruited from 374 sites in 24 countries from August 2011 to August 2013 (mean age, 66 years; 46.3% women; median diabetes duration, 9.5 years; median HbA1c, 7.2%). Participants were taking stable doses of up to two oral glucose-lowering drugs, with or without basal insulin therapy.

Within the cohort, only 31.5% of participants had prior CVD, making the trial the largest primary prevention CV outcomes study with a GLP-1 receptor agonist, Gerstein said.

“When we look at subgroups of people without prior CVD, REWIND has a lot to add ... 6,221 people in REWIND did not have prior CVD,” Gerstein said during a presentation of the summary findings. “REWIND is the first, and hopefully not the last trial to look at this subgroup of people without prior CVD.”

Researchers randomly assigned patients to receive once-weekly dulaglutide (n = 4,949) or placebo (n = 4,952). Primary endpoint was first occurrence of any component of the composite CV outcome of nonfatal MI, nonfatal stroke and CV death. Secondary outcomes were a composite clinical microvascular outcome including diabetic retinopathy, renal disease, hospitalization for unstable angina and heart failure requiring hospitalization. Follow-up occurred at 2 weeks, 3 and 6 months, and then every 6 months until 1,200 confirmed primary events occurred. Researchers also measured urinary albumin to creatinine ratio and estimated glomerular filtration rate (eGFR) every 12 months.

The data were simultaneously published in the Lancet.

CV findings

During a median 5.4 years, the primary composite outcome occurred in 12% of patients in the dulaglutide arm (incidence rate, 2.4 per 100 person-years) vs. 13.4% of patients in the placebo arm (incidence rate, 2.7 per 100 person-years), for an HR of 0.88 (95% CI, 0.79-0.99).

“As you can see, dulaglutide reduced the occurrence of this primary composite outcome,” Gerstein said to applause as he presented the CV findings. “You can see the effect of the intervention begins before the first year, and continues in a progressive, proportional fashion throughout the full follow-up period, which exceeds 5 years.”

In assessing the individual components of the composite outcome, Gerstein noted that there was no discernable effect on nonfatal MI with dulaglutide (HR = 0.96; 95% CI, 0.79-1.16) and a neutral effect observed for CV death (HR = 0.91; 95% CI, 0.78-1.06), however, researchers observed a 24% reduction in stroke in the dulaglutide arm (HR = 0.76; 95% CI, 0.61-0.95). There were no between-group differences in all-cause mortality.

In subgroup analyses, the CV results were similar when comparing participants with and without previous CVD (P for interaction = .97) and in comparing patients with an HbA1c above and below 7.2% (P for interaction = .75). Results persisted in analyses further stratified by age, sex, diabetes duration and BMI.

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Renal findings

In an exploratory analysis assessing the prospectively defined renal effects of dulaglutide, the drug reduced the HR for the composite renal outcome compared with placebo, with the largest effect noted for the development of albuminuria.

During follow-up, the renal outcome developed in 17.1% of participants assigned to dulaglutide (incidence rate, 3.5 per 100 person-years) vs. 19.6% of the placebo arm (incidence rate, 4.1 per 100 person-years), for an HR of 0.85 (95% CI, 0.77-0.93). The greatest observed effect with dulaglutide was observed for new macroalbuminuria, with an HR of 0.77 (95% CI, 0.68-0.87), although researchers also observed reductions in the rates of sustained decline in eGFR of 30% or more (HR = 0.89; 95% CI, 0.78-1.01) and for chronic renal replacement therapy (HR = 0.75; 95% CI, 0.39-1.44).

“Our sensitivity analyses suggested a reduced incidence of a 40% and 50% decline in eGFR with dulaglutide, supporting the possibility that dulaglutide might preserve renal function; this association merits further scrutiny,” the researchers wrote in the Lancet.

Embrace therapy early

In commentary accompanying the two studies, Subodh Verma, MD, PhD, FRCSC, from the division of cardiac surgery at St. Michael’s Hospital, University of Toronto, and colleagues noted that the magnitude of benefit on the composite CV outcome was “modest” and numerically lower compared with CV benefits observed in the LEADER (liraglutide; Victoza, Novo Nordisk) and SUSTAIN-6 (semaglutide; Ozempic, Novo Nordisk) trials; however, the findings were consistent with the overall effect size of the class observed in a meta-analysis of all previous GLP-1 receptor agonist trials.

“Although SGLT2 inhibitors and GLP-1 receptor agonists are recommended in patients with established atherosclerotic vascular disease, we now have evidence from the DECLARE-TIMI 58 and REWIND trials that SGLT2 inhibitors and GLP-1 receptor agonists afford cardiovascular superiority even in primary prevention; with SGLT2 inhibitors preventing heart failure and GLP-1 receptor agonists preventing atherosclerotic events, and both potentially affording renal protection,” Verma and colleagues wrote. “If we are to reduce the burgeoning pump, pipes and filter complications of diabetes, we will need to overcome clinical inertia, and embrace these disease-modifying therapies early, and preferably in combination. The REWIND trial makes a strong case in this regard.” – by Regina Schaffer

References:

Gerstein HC, at al. Once-weekly dulaglutide and major cardiovascular events — results of the REWIND trial. Presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco.

Gerstein HC, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31149-3.

Gerstein HC, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31150-X.

Verma S, et al. Lancet. 2019; doi:10.1016/S0140-6736(19)31267-X.

Disclosures: Eli Lilly funded the REWIND study. Gerstein reports he has received consultant fees, grants and honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, Cirius, Eli Lilly, Janssen, Kowa, Merck, Novo Nordisk and Sanofi. Verma reports he has received grants and honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier and Valeant. Please see the two studies and commentary for all other authors’ relevant financial disclosures.

    Perspective
    Daniel Einhorn

    Daniel Einhorn

    The main take home message, which we hoped to and expected to finally find, is that earliest intervention yields the best benefits. What a revelation to have hard data confirm what we were so sure for so long was true. Now we have to get the FDA and health plans to recognize and pay for this major advance in public health. Is it even moral to deny therapy to people whose lives will be transformed by therapy? We will have to grapple with this issue, especially when the absolute benefits are much smaller than the relative ones and the cost is not insubstantial.

    • Daniel Einhorn, MD, FACP, FACE
    • Medical Director, Scripps Whittier Diabetes Institute
      Clinical Professor of Medicine
      University of California, San Diego
      President, Diabetes and Endocrine Associates

    Disclosures: Einhorn reports he has served as a consultant for Sanofi.

    Perspective
    Kevin M. Pantalone

    Kevin M. Pantalone

    While there are important differences between the GLP-1 receptor agonist molecules and their pharmacology, and the study populations and designs of their respective CV outcomes trials, as a whole, the evidence is very clear that long-acting GLP-1 receptor agonists confer a benefit on the risk for adverse CV outcomes, particularly in those with established CVD. It was novel and reassuring to observe a reduction of major adverse CV events in REWIND, which was comprised of a large lower-risk population (lower baseline A1C and lower prevalence of established CVD) when compared with the CV outcomes trials for other long-acting GLP-1 receptor agonists. Given the CV outcomes trials for other long-acting GLP-1 receptor agonists either did not contain primary prevention subjects (HARMONY; albiglutide), or contained a much smaller number of primary prevention subjects (LEADER; liraglutide; EXSCEL; exenatide; and SUSTAIN-6; semaglutide) vs. REWIND, primary prevention, as a class-effect, remains less clear. Regardless, one must remember that the primary indication for GLP-1 receptor agonists therapy in patients with type 2 diabetes is to improve glycemic control. Additional reasons to use these therapies, in patients with or without established CVD, are the potential for weight loss and avoidance of hypoglycemia. The CV (and potential renal) benefits observed in REWIND, and observed in the CV outcomes trials with other long-acting GLP-1 receptor agonists, provide yet additional reasons to use GLP-1 receptor agonist therapy across the entire spectrum of patients with type 2 diabetes.

    • Kevin M. Pantalone, DO, ECNU, FACE
    • Staff Endocrinologist
      Director of Clinical Research
      Department of Endocrinology
      Cleveland Clinic

    Disclosures: Pantalone reports he has received research support from Merck and Novo Nordisk, speaker honoraria from AstraZeneca, Merck and Novo Nordisk, and consulting honoraria from Merck, Novo Nordisk, Sanofi and Eli Lilly.

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