The recent REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial provides ample opportunity to pause and reflect on the recent data on novel glucose-lowering medications and their associated cardiovascular outcomes—a topic of intense interest. Both sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists have demonstrated benefit in reducing major adverse cardiovascular events (MACE), particularly among patients with known atherosclerotic cardiovascular disease (ASCVD). In fact, these agents not only lower A1c but improve cardiovascular outcomes, begging the questions: are these drugs diabetes medicines that help the heart or heart disease prevention medicines that lower blood glucose?

This article reviews how the recently published REWIND trial adds to the growing number of trials on GLP-1 receptor agonists and SGLT-2 inhibitors with demonstrable benefits in reducing MACE. We also discuss how this new data might affect future American College of Cardiology/American Heart Association (ACC/AHA) prevention guidelines, in particular, whether the evidence supports a possible upgrade in the level of recommendation from "Weak/Modest" (IIb)¹ to "Moderate" (IIa) on the use of GLP-1 receptors agonists, which would more strongly favor the use of GLP-1 receptor agonist therapy in primary prevention of ASCVD.

Background
SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) randomized approximately 3,300 adults with type 2 diabetes mellitus (T2DM) and elevated cardiovascular (CV) risk to standard of care and either the GLP-1 receptor agonist, semaglutide or placebo.² Over a median 2 years of follow-up, the study authors found a 26% reduction in CV death, nonfatal myocardial infarction (MI) and nonfatal stroke in the semaglutide arm compared to the placebo arm (HR 0.74, 95% CI 0.58 to 0.95, p < 0.001 for noninferiority, p = 0.02 for superiority). No significant difference in CV mortality was noted between the two groups.²

The LEADER (Liraglutide Effect and Action in Diabetes) trial, which focused on liraglutide, has been the largest study to date on the effect of GLP-1 receptor agonists on CV events with over 9,300 patients with T2DM (81% with established CV disease) followed for a median of 3.8 years.³ Liraglutide was associated with a 13% reduction (608 of 4,668 participants in the liraglutide arm vs. 964 out of 4,672 participants in the placebo arm) in the primary outcome of CV death, nonfatal MI and nonfatal stroke (HR 0.87, 95% CI 0.78 to 0.97; p < 0.001 for noninferiority, p = 0.01 for superiority). A 15% reduction in all-cause mortality (HR 0.85, 95% CI 0.74 to 0.97, p = 0.02) in the liraglutide arm compared to the placebo arm was also observed.³

Unlike the SUSTAIN-6 trial, the LEADER trial demonstrated significant differences in the primary composite outcome for those with established ASCVD compared to those with CV disease risk factors (p for interaction = 0.04), with a greater benefit seen with liraglutide in those with a history of ASCVD.³

The Harmony Outcomes trial also showed a reduction in MACE with the GLP-1 receptor agonist albiglutide.⁴ Other trials, namely the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial (for patients after acute coronary syndrome) and the EXSCEL (Exenatide Study of Cardiovascular Event Lowering) trial,^5,4 showed no cardiovascular benefits of lixisenatide or exenatide, respectively, over placebo, although these studies had shorter (<3.5 year) follow-up times.

Combining data from published GLP-1 receptor agonist CV outcomes trials to date, a recent meta-analysis showed a 12% reduction in MACE (HR 0.88; 95% CI, 0.84-0.94; P < 0.001) among those with cardiovascular disease and no benefit for those without ASCVD (P for interaction = 0.028).⁶

The REWIND Trial
The REWIND trial sought to determine if the GLP-1 receptor agonist dulaglutide demonstrated a CV benefit over a longer period of time in a study population that included patients with T2DM and CV risk factors.⁷ Individuals with type 2 diabetes (A1c < 9.5%) and age ≥50 years with either known ASCVD or CV risk factors, as pre-specified based on age cut-offs, participated in the study. This allowed for a lower annual risk of CV event at 2.7% than in the LEADER study. REWIND was a pharmaceutical-sponsored trial, with an independent steering committee, though scientists employed by the pharmaceutical company were included.

With 9,901 participants, REWIND was a large trial and had a median follow-up time of 5.4 years, compared to 3.8 years in the LEADER study. The average age of REWIND participants was 66.2 years, 46.3% were women, and they had a mean A1c of 7.3%, reflective of a general population of patients with well-controlled diabetes in a primary care clinic.

However, in contrast to the other CV outcomes trials of GLP-1 receptor agonists, the REWIND trial included a substantial proportion of patients without established CV disease (68.5%), which provided more information as to whether GLP-1 receptor agonists may be beneficial in a primary prevention setting.

Results
The results demonstrated an association between dulaglutide and a 12% reduction in the primary outcome of nonfatal MI, nonfatal stroke, CV death or death of unknown etiology (HR 0.88, 95% CI 0.79 to 0.99, p = 0.026; 2.4 events per 100 person-years in the dulaglutide arm compared to 2.7 events per 100 person-years in the placebo arm).⁷ No statistically significant effect on all-cause mortality was observed. This equates to a number needed to treat (NNT) of about 72 over 5.4 years to prevent one major adverse cardiac event.

The primary outcome was driven largely by a reduction in nonfatal stroke (HR 0.76, 95% CI 0.61-0.95), and the benefits were mostly seen in the non-US cohorts. The NNT for those without established CV disease was 60, whereas the NNT for those with established CV disease was 18. For those with hemoglobin A1c ≥7.2%, the NNT was 59 compared to those with a hemoglobin A1c of <7.2% where the NNT was 91.

Discussion
Given the lower prevalence of ASCVD in the REWIND trial, it is no surprise that the level of impact in the study was less than other CV outcomes trials (the NNT in EMPA-REG was 63 over 3.1 years,⁸ 53 over 3.8 years in LEADER,³ 50 over 1.6 years in Harmony Outcomes,⁴ and 44 over 2 years in SUSTAIN-6²). These study populations had much higher prevalences of documented cardiovascular disease than REWIND.

Indeed, among patients with a previous cardiovascular event, the NNT was 18 in REWIND. For secondary prevention of CV disease, GLP-1 agonists seem unobjectionably beneficial. The patients in the REWIND trial also had significantly better controlled diabetes than those in other CV outcomes trials of GLP-1 receptor agonists and SGLT2 inhibitors, which may also account for the relatively lower cardiovascular benefit.

For primary prevention, the NNT of 72 seen in REWIND is slightly higher than the NNT values of other well-established primary prevention interventions. The 5 year NNT for statin therapy in patients with hyperlipidemia was found to be under 50 in all subgroups of the JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) trial and in AFCAPS-TexCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study).^9,10

The REWIND trial showed no significant differences in adverse effects between dulaglutide and placebo except for some non-severe gastrointestinal events. This is consistent with known adverse effects of the medication. The study was a large, well-designed, double-blind randomized control trial that appropriately targeted a population that with good generalizability for many patients with type 2 diabetes.

Ultimately, the REWIND trial confirms findings from multiple trials supporting the benefit of GLP-1 receptor agonists for MACE reduction. No significant adverse side effects were noted with dulaglutide, and the effect size for primary prevention was relatively small. With a NNT of 72 that was driven mostly by stroke reduction and seen in non-US populations, the evidence does not appear robust enough to change current guidelines regarding the use of dulaglutide. Certainly, shared decision-making can assist in developing an optimal regimen and GLP-1 receptor agonists have a significant role in diabetes treatment and cardiovascular risk reduction, particularly in secondary prevention.

References

1. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019. [Epub ahead of print]
2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834-44.
3. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-22.
4. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind randomised placebo-controlled trial. Lancet 2018;392:1519-29.
5. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015;373:2247-57.
6. Zelniker TA, Wiviott SD, Raz I, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019;139:2022-31.
7. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019. [Epub ahead of print]
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
9. Ridker PM, MacFadyen JG, Fonseca FA, et al. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes 2009;2:616-23.
10. Grundy S. Primary prevention of cardiovascular disease with statins: assessing the evidence base behind clinical guidance. Clin Pharm. 2016.

Keywords: Dyslipidemias, Incretins, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diabetes Mellitus, Type 2, Blood Glucose, Risk Factors, American Heart Association, Secondary Prevention, Cardiovascular Diseases, Coronary Artery Disease, Acute Coronary Syndrome, Glucose, Factor VII, Follow-Up Studies, Standard of Care, Glucagon-Like Peptides, Peptides, Immunoglobulin Fc Fragments, Recombinant Fusion Proteins, Hyperlipidemias, Myocardial Infarction, Primary Prevention, Stroke, Primary Health Care

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