Patients with type 2 diabetes mellitus (T2DM) have two to four times increased cardiovascular disease (CVD) risk as compared to the general population – with CVD accounting for two out of every three deaths in patients with diabetes.¹ Despite significant progress in treatment during last four decades, patients with diabetes remain at high risk of cardiovascular morbidity and mortality.

The worldwide prevalence of diabetes is increasing in the majority of countries.² The number of people living with diabetes is growing with aging of population, and we are not able to provide them an optimal care in real-world settings. The most recent EUROASPIRE V Survey on Cardiovascular Disease Prevention and Diabetes (EUROASPIRE)³ revealed an unacceptably poor glycemic control even in very high-risk patients with confirmed coronary heart disease (CHD): after myocardial infarction, unstable angina, bypass surgery and revascularization procedures, there was no significant improvement of glycemic control as compared to the previous EUROASPIRE surveys.

Recently we started to receive good news regarding T2DM. Perhaps the most inspiring is the decrease in diabetes incidence and a stabilization of disease prevalence in the US between 2009 and 2017.⁴ Very important are also the results of the Prediabetes and Risk for Cardiac Death Among Patients with Coronary Artery Disease: The ARTEMIS Study⁵ showing than prediabetes does not increase the cardiovascular events risk in CHD patients. But the real revolution started earlier, in 2008, when the US Food and Drug Administration stated in the guidance to industry⁶ that cardiovascular risk should be evaluated for any new antidiabetic therapy. This led to a multitude of large CVD outcome trials aimed to assess cardiovascular risk from antidiabetic medications. Due to these trials, in recent years two relatively new classes of drugs for T2DM have been recognized as agents that could assist in the prevention of CVD, namely sodium-glucose cotransporter-2 (SGLT‐2) inhibitors and glucagon‐like peptide-1 (GLP‐1) receptor agonists. The SGLT-2 inhibitor empagliflozin was the first one to arrive at this scene,⁷ but it was quickly followed by canagliflozin, that belongs to the same drug class, and by the GLP-1 receptor agonists.

Until recently, we had three GLP-1 receptor agonists with established cardiovascular benefit in terms of a lower risk of major atherothrombotic events in T2DM. These included liraglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER®) trial; n=9340), semaglutide (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN™ 6) trial; n=3297) and albiglutide (Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial; n=9463).^8-10 The first two agents, liraglutide and semaglutide, are already recommended by the most recent American Diabetes Association (ADA) Guidelines for Diabetes Care.¹¹

Now, with the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial published¹² we have one more GLP-1 receptor agonist, namely dulaglutide, added to this armamentarium. As in other GLP-1 receptor agonists trials, the primary outcome was the first occurrence of any component of the 3-point composite, which included non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular causes and unknown causes. This randomized long-duration (median follow-up 5.4 years) controlled trial of people with T2DM showed that a weekly injection of 1.5 mg dulaglutide reduced by 12% the risk of cardiovascular outcomes as compared to placebo, with the Kaplan Meier curves starting to diverge within the first year of treatment: hazard ratio (HR) 0.88, 95% confidence interval 0.79–0.99; p=0.026. Among the three components of the composite primary outcome, the greatest benefit was found for nonfatal strokes. It is important to note that dilaglutide reduced HbA1c by a mean absolute amount of 0·6% more than placebo without increasing hypoglycaemia, and also modestly reduced weight, LDL cholesterol, and systolic blood pressure. The reduction of glycaemia, weight, cholesterol and blood pressure in the dulaglutide group during long observation may explain the positive effects of the medication on the cardiovascular outcomes.

What does the REWIND trial add to the existing evidence, except for giving additional support to the hypothesis of cardioprotection being a class effect of GLP-1 receptor agonists?

Most notably, the REWIND trial tells us that cardiovascular benefits of the GLP-1 receptor agonists, in particular, dulaglutide, apply to a much broader population than ever before. The cardiovascular effects of other GLP-1 receptor agonists have been tested predominantly in middle-aged people with high HbA1c concentrations and a very high annual CVD events risk, mostly with a history of previous CVD. On the opposite side, the REWIND trial had no lower limit for baseline HbA1c and its flexible eligibility criteria allowed for the inclusion of multiple age groups and of patients without baseline CVD. As a result, only one third of participants had a positive history of CVD, and only about 20% of patients had a previous myocardial infarction or stroke. Specially, it should be emphasized there were a high proportion (more than 46%) of women. Despite the study population being so broad, the prespecified subgroup analysis did not find any differences of dulaglutide effect with respect to age, sex, body mass index, diabetes duration, baseline HbA1c and CVD history.

The REWIND trial has a number of other strengths, which include having a superiority design, whereas other trials of the GLP-1 agonists were primarily designed to test non-inferiority. The fact that dulaglutide proved to be superior despite a quite low events rate in the placebo group adds to the overall robustness of the results. Moreover, the trial had a very long follow-up period of more than 5 years, showing that the cardiovascular benefits of GLP-1 receptor agonists may extend much longer than previously considered.

Should we today prescribe dulaglutide or other GLP-1 agonists to all patients with T2DM? The ADA Guidelines still recommend metformin as the best choice for both, initial therapy and the antidiabetic drugs combinations, and one of the main reasons is the affordability of the drug. But it seems that, even taking into consideration the economic issues and inconvenience of self-injections, we should embrace any possibility for achievement of a better cardiovascular health in people living with diabetes, and the GLP-1 receptor agonists, particularly dulaglutide, do offer such benefits.

References

1. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–22.
2. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 2018;138:271-81.
3. Kotseva K, De Backer G, De Bacquer D, et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry. Eur J Prev Cardiol 2019;26:824-35.
4. Benoit SR, Hora I, Albright AL, Gregg EW. New directions in incidence and prevalence of diagnosed diabetes in the USA. BMJ Open Diabetes Res Care 2019;7:e000657.
5. Kiviniemi AM, Lepojärvi ES, Tulppo MP, et al. Prediabetes and risk for cardiac death among patients with coronary artery disease: the ARTEMIS study. Diabetes Care 2019;42:1312-25.
6. US Department of Health and Human Services Food and Drug Administration. Guidance for Industry. Diabetes Mellitus ‐ Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. 2008. Available at www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf (accessed October 8, 2018).
7. 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.
8. 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.
9. 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.
10. 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.
11. American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019;42 (Suppl 1):S90-S102.
12. 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;394:121-30.

Keywords: Diabetes Mellitus, Metabolic Syndrome, Incretins, Hypoglycemic Agents, Diabetes Mellitus, Type 2, Hemoglobin A, Cholesterol, LDL, Metformin, Prediabetic State, Coronary Artery Disease, Cardiovascular Diseases, Blood Pressure, Body Mass Index, Pharmaceutical Preparations, United States Food and Drug Administration, Double-Blind Method, Follow-Up Studies, Risk Factors, Glucagon-Like Peptides, Immunoglobulin Fc Fragments, Glucosides, Benzhydryl Compounds, Recombinant Fusion Proteins, Angina, Unstable, Hypoglycemia, Myocardial Infarction, Stroke, Aging, Sodium-Glucose Transport Proteins

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