CommentaryPerspective

REWIND: Assessing the role of dulaglutide for primary prevention of CVD

by Bolanle Akinyele, MD; Roger S. Blumenthal, MD; and Sudipa Sarkar, MD, MSCI

Bolanle Akinyele

Within the past decade, there has been a rapid development of novel antihyperglycemic agents that not only improve glycemic control but also reduce CV events in patients with known atherosclerotic CVD. Two major drug classes have been associated with a reduction in major adverse cardiac events: the SGLT2 inhibitors and the GLP-1 receptor agonists. GLP-1 receptor agonists are a class of antihyperglycemic agents that mimic the actions of glucagon-like peptide, one of several endogenous incretin compounds secreted by the intestinal enteroendocrine L-cells. GLP-1 receptor agonists increase the glucose-dependent secretion of insulin from beta cells, promote beta-cell proliferation, decrease glucagon release after meals, decrease hepatic glucose production, delay gastric emptying and suppress appetite. One member of this class is dulaglutide (Trulicity, Eli Lilly), a long-acting GLP-1 receptor agonist and the study drug in the recent REWIND trial, which was presented at the American Diabetes Association Scientific Sessions in June and simultaneously published in The Lancet.

Deep dive on REWIND

REWIND was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 371 sites in 24 countries. The study enrolled 9,901 eligible participants aged 50 years and older with type 2 diabetes (HbA1c 9.5%) who were on two or fewer oral glucose-lowering drugs with or without basal insulin therapy. Additional inclusion criteria were BMI of 23 kg/m2 or greater and an estimated glomerular filtration rate greater than 15 mL/min/1.73 m2.

Study participants were randomly assigned to either weekly subcutaneous dulaglutide 1.5 mg or placebo and were followed for a median of 5.4 years. The aim of the REWIND trial was to assess whether adding dulaglutide to the treatment of patients with type 2 diabetes with either CV risk factors or established CVD reduced the occurrence of CV events.

The REWIND trial investigators reported a 12% reduction in the primary composite outcome of nonfatal MI, nonfatal stroke and death from CVD or unknown etiology in those participants treated with dulaglutide compared with placebo (HR = 0.88; 95% CI, 0.79-0.99). This finding was driven by a 24% decrease in nonfatal stroke and was significant in non-U.S. cohorts. Reductions in the individual outcomes of nonfatal MI and CV death were not significant.

Compared with other GLP-1 receptor agonist trials, which included a large proportion of patients with established ASCVD, the REWIND trial enrolled a relatively low proportion (31.5%) of adults with established ASCVD, perhaps closer to the prevalence of ASCVD that might be seen in a typical primary care practice. Reductions in major adverse CV events were similar in patients with and without established CVD, raising a potential role for dulaglutide in primary prevention of CVD. The REWIND trial also notably had the longest follow-up of the GLP-1 receptor agonist CV outcome trials to date.

Roger S. Blumenthal

Although the benefit of dulaglutide for primary prevention in the REWIND trial was mostly in the reduction of nonfatal stroke, the investigators also observed a significant benefit in reducing ASCVD risk factors including HbA1c, weight and systolic BP. This was seen despite a relatively heterogeneous population, with women representing 46% of study participants. Although the effect of dulaglutide on major CV events was slightly lower than that observed with the GLP-1 receptor agonists liraglutide (Victoza, Novo Nordisk), semaglutide (Ozempic, Novo Nordisk) and albiglutide (Tanzeum, GlaxoSmithKline), and the SGLT2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) and canagliflozin (Invokana, Janssen), its benefits in conjunction with its minimal side-effect profile make it a suitable second choice for patients already on a baseline antihyperglycemic regimen.

The median monthly average wholesale price of dulaglutide without insurance is about $750 vs. approximately $490 for SGLT2 inhibitors. The number needed to treat (NNT) for study participants without established CVD in the REWIND trial was 60 vs. an NNT of 18 for those with established CVD. For context, the NNT with a moderate-intensity statin is approximately 40 in a population of patients who have an ASCVD risk of 7.5%. It is likely that the NNT would have been less in participants with higher baseline HbA1c values or in those whose risk factors were not as well managed.

Sudipa Sarkar

Should cardiologists be prescribing dulaglutide?

The question remains: Should cardiologists prescribe dulaglutide or other GLP-1 receptor agonists, given that endocrine and diabetes specialists are in very short supply?

Given the evidence-based reduction in major adverse CV events associated with GLP-1 receptor agonists, the ability of these treatments to help achieve better glycemic control and their weight-loss benefits, we would strongly advocate that cardiologists include this class of drugs in their prescription armamentarium for primary and secondary prevention of CVD.

The adverse effects of GLP-1 receptor agonists, including gastrointestinal symptoms, should be kept in mind when prescribing these medications. It is also useful to know that GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid cancer/ multiple endocrine neoplasia type 2 (MEN2) syndrome.

With the help of ancillary staff to help teach the administration of GLP-1 receptor agonists, cardiologists should feel comfortable prescribing GLP-1 receptor agonists with greater frequency. For those patients on insulin and/or sulfonylurea, it is reasonable to prescribe a GLP-1 receptor agonist either in coordination with the patient’s primary care provider or endocrinologist to help with medication titration to avoid hypoglycemia and/or with close follow-up of the patient’s blood glucose logs.

In summary, the results of the REWIND trial indicate that dulaglutide could be a suitable addition to the antihyperglycemic regimen for a patient with type 2 diabetes who is unable to tolerate a SGLT2 inhibitor or in whom greater weight loss is desired for the benefit of primary prevention of CVD.

References:

Cefalu WT, et al. Diabetes Care. 2018;doi:10.2337/dci17-0057.

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

GoodRx. Estimated retail price of one month’s treatment based on information obtained at www.goodrx.com. Accessed June 2019.

Tran KL, et al. Am Health Drug Benefits. 2017;10:178-188.

Trujillo JM, et al. Ther Adv Endocrinol Metab. 2015;doi:10.1177/2042018814559725.

Xu G, et al. Diabetes. 1999;doi:10.2337/diabetes.48.12.2270.

For more information:

Bolanle Akinyele, MD, is a general cardiology fellow at Johns Hopkins Hospital.

Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board.

Sudipa Sarkar, MD, MSCI, is assistant professor of medicine in the division of endocrinology, diabetes and metabolism at Johns Hopkins University School of Medicine. The authors can be reached at Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 5501 Hopkins Bayview Circle, Baltimore, MD 21224; email: ssarka19@jhmi.edu.

Disclosures: The authors report no relevant financial disclosures.

by Bolanle Akinyele, MD; Roger S. Blumenthal, MD; and Sudipa Sarkar, MD, MSCI

Bolanle Akinyele

Within the past decade, there has been a rapid development of novel antihyperglycemic agents that not only improve glycemic control but also reduce CV events in patients with known atherosclerotic CVD. Two major drug classes have been associated with a reduction in major adverse cardiac events: the SGLT2 inhibitors and the GLP-1 receptor agonists. GLP-1 receptor agonists are a class of antihyperglycemic agents that mimic the actions of glucagon-like peptide, one of several endogenous incretin compounds secreted by the intestinal enteroendocrine L-cells. GLP-1 receptor agonists increase the glucose-dependent secretion of insulin from beta cells, promote beta-cell proliferation, decrease glucagon release after meals, decrease hepatic glucose production, delay gastric emptying and suppress appetite. One member of this class is dulaglutide (Trulicity, Eli Lilly), a long-acting GLP-1 receptor agonist and the study drug in the recent REWIND trial, which was presented at the American Diabetes Association Scientific Sessions in June and simultaneously published in The Lancet.

Deep dive on REWIND

REWIND was a multicenter, randomized, double-blind, placebo-controlled trial conducted at 371 sites in 24 countries. The study enrolled 9,901 eligible participants aged 50 years and older with type 2 diabetes (HbA1c 9.5%) who were on two or fewer oral glucose-lowering drugs with or without basal insulin therapy. Additional inclusion criteria were BMI of 23 kg/m2 or greater and an estimated glomerular filtration rate greater than 15 mL/min/1.73 m2.

Study participants were randomly assigned to either weekly subcutaneous dulaglutide 1.5 mg or placebo and were followed for a median of 5.4 years. The aim of the REWIND trial was to assess whether adding dulaglutide to the treatment of patients with type 2 diabetes with either CV risk factors or established CVD reduced the occurrence of CV events.

The REWIND trial investigators reported a 12% reduction in the primary composite outcome of nonfatal MI, nonfatal stroke and death from CVD or unknown etiology in those participants treated with dulaglutide compared with placebo (HR = 0.88; 95% CI, 0.79-0.99). This finding was driven by a 24% decrease in nonfatal stroke and was significant in non-U.S. cohorts. Reductions in the individual outcomes of nonfatal MI and CV death were not significant.

Compared with other GLP-1 receptor agonist trials, which included a large proportion of patients with established ASCVD, the REWIND trial enrolled a relatively low proportion (31.5%) of adults with established ASCVD, perhaps closer to the prevalence of ASCVD that might be seen in a typical primary care practice. Reductions in major adverse CV events were similar in patients with and without established CVD, raising a potential role for dulaglutide in primary prevention of CVD. The REWIND trial also notably had the longest follow-up of the GLP-1 receptor agonist CV outcome trials to date.

Roger S. Blumenthal

Although the benefit of dulaglutide for primary prevention in the REWIND trial was mostly in the reduction of nonfatal stroke, the investigators also observed a significant benefit in reducing ASCVD risk factors including HbA1c, weight and systolic BP. This was seen despite a relatively heterogeneous population, with women representing 46% of study participants. Although the effect of dulaglutide on major CV events was slightly lower than that observed with the GLP-1 receptor agonists liraglutide (Victoza, Novo Nordisk), semaglutide (Ozempic, Novo Nordisk) and albiglutide (Tanzeum, GlaxoSmithKline), and the SGLT2 inhibitors empagliflozin (Jardiance, Boehringer Ingelheim) and canagliflozin (Invokana, Janssen), its benefits in conjunction with its minimal side-effect profile make it a suitable second choice for patients already on a baseline antihyperglycemic regimen.

The median monthly average wholesale price of dulaglutide without insurance is about $750 vs. approximately $490 for SGLT2 inhibitors. The number needed to treat (NNT) for study participants without established CVD in the REWIND trial was 60 vs. an NNT of 18 for those with established CVD. For context, the NNT with a moderate-intensity statin is approximately 40 in a population of patients who have an ASCVD risk of 7.5%. It is likely that the NNT would have been less in participants with higher baseline HbA1c values or in those whose risk factors were not as well managed.

Sudipa Sarkar

Should cardiologists be prescribing dulaglutide?

The question remains: Should cardiologists prescribe dulaglutide or other GLP-1 receptor agonists, given that endocrine and diabetes specialists are in very short supply?

Given the evidence-based reduction in major adverse CV events associated with GLP-1 receptor agonists, the ability of these treatments to help achieve better glycemic control and their weight-loss benefits, we would strongly advocate that cardiologists include this class of drugs in their prescription armamentarium for primary and secondary prevention of CVD.

The adverse effects of GLP-1 receptor agonists, including gastrointestinal symptoms, should be kept in mind when prescribing these medications. It is also useful to know that GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid cancer/ multiple endocrine neoplasia type 2 (MEN2) syndrome.

With the help of ancillary staff to help teach the administration of GLP-1 receptor agonists, cardiologists should feel comfortable prescribing GLP-1 receptor agonists with greater frequency. For those patients on insulin and/or sulfonylurea, it is reasonable to prescribe a GLP-1 receptor agonist either in coordination with the patient’s primary care provider or endocrinologist to help with medication titration to avoid hypoglycemia and/or with close follow-up of the patient’s blood glucose logs.

In summary, the results of the REWIND trial indicate that dulaglutide could be a suitable addition to the antihyperglycemic regimen for a patient with type 2 diabetes who is unable to tolerate a SGLT2 inhibitor or in whom greater weight loss is desired for the benefit of primary prevention of CVD.

References:

Cefalu WT, et al. Diabetes Care. 2018;doi:10.2337/dci17-0057.

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

GoodRx. Estimated retail price of one month’s treatment based on information obtained at www.goodrx.com. Accessed June 2019.

Tran KL, et al. Am Health Drug Benefits. 2017;10:178-188.

Trujillo JM, et al. Ther Adv Endocrinol Metab. 2015;doi:10.1177/2042018814559725.

Xu G, et al. Diabetes. 1999;doi:10.2337/diabetes.48.12.2270.

For more information:

Bolanle Akinyele, MD, is a general cardiology fellow at Johns Hopkins Hospital.

Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board.

Sudipa Sarkar, MD, MSCI, is assistant professor of medicine in the division of endocrinology, diabetes and metabolism at Johns Hopkins University School of Medicine. The authors can be reached at Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes and Metabolism, 5501 Hopkins Bayview Circle, Baltimore, MD 21224; email: ssarka19@jhmi.edu.

Disclosures: The authors report no relevant financial disclosures.

    Perspective
    George L. Bakris

    George L. Bakris

    The REWIND trial adds further information on the spectrum of GLP-1 agonists and their effects on CV risk reduction. The aim of the REWIND trial was to assess whether adding dulaglutide to the treatment of patients with type 2 diabetes with either CV risk factors or established CVD reduced the occurrence of CV events. The trial showed a significant 12% reduction in major adverse CV events with dulaglutide vs. placebo, a finding driven by a 24% decrease in nonfatal stroke in non-U.S. cohorts. Reductions in the individual outcomes of nonfatal MI and CV death were not significant. The important point of REWIND was the cohort was relatively low with established ASCVD, perhaps closer to the prevalence of ASCVD that might be seen in a typical primary care practice.

    This was considered a primary trial; however, the outcomes were driven by reduction of nonfatal stroke. This trial, taken together with the other GLP-1 agents tested, shows benefit of primary prevention in a relatively lower-risk group than previous trials; however, it was driven by stroke events.

    Cardiologists should be aware of this class of agents as beneficial, but given their gastrointestinal side effects, cost and being injectable rather than oral should leave the prescribing to diabetologists rather than moving forward themselves. Clearly, further research is needed in this class, as the mechanism for benefit is not clear, although they are excellent weight-reducing agents, and this could be part of their benefit, ie, reducing inflammation.

    • George L. Bakris, MD
    • Cardiology Today Editorial Board Member
      The University of Chicago Medicine

    Disclosures: Bakris reports he received research funding that was paid to his institution from Bayer and Vascular Dynamics; consults for AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Pfizer, Relypsa, Sanofi and Vascular Dynamics; is an editor for American Journal of Nephrology; the Nephrology and Hypertension Section Editor for UpToDate, and is an associate editor for Diabetes Care and Hypertension Research.