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  • Evidence of Cardioprotection With Type 2 Diabetes Drugs

    Most adults with type 2 diabetes (T2D) have cardiometabolic syndrome: 75% to 85% have hypertension, 70% to 80% have elevated low density lipoprotein cholesterol, and 60% to 70% are obese.1 Adults with T2D are up to 4 times more likely to develop cardiovascular (CV) complications compared with adults without diabetes, and life expectancy is reduced, on average, by approximately 8 years. As demonstrated in several landmark trials, early control of hyperglycemia (A1C < 7%) is associated with long-term reduction in CV disease. Thus, contemporary management of T2D should take into account the important implications of these findings and address CV risks in addition to glycemic control. In response to this initiative, the FDA now mandates that reduction in CV events and improved survival are among the key outcomes for new diabetes drugs under investigation.2,3

    Recent randomized, controlled trials of the 2 newest T2D drug classes, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated reductions in CV-related events in patients with high CV risk. Within the GLP-1 agonist class, the LEADER trial demonstrated that liraglutide was associated with a lower rate of the primary composite of major CV outcome (CV death, nonfatal myocardial infarction, or stroke) compared with placebo (13.0% vs 14.9%, respectively; P = .01 for superiority).4 Semaglutide (SUSTAIN-6 trial) also demonstrated CV protection: Composite CV outcome occurred in 6.6% in the semaglutide group compared with 8.9% in the placebo group (P < .001 for noninferiority).5 Among SGLT2 inhibitors, the EMPA-REG trial determined that empagliflozin protected against CV events, with 10.5% occurrence in the empagliflozin group and 12.1% occurrence in the placebo group (P = .04 for superiority).6 Similarly, the CANVAS trial found that canagliflozin was associated with a lower rate of CV events compared with placebo (26.9 vs. 31.5 participants/1000 patient-years; P = .02 for superiority); canagliflozin also reduced the rate of hospitalization due to heart failure (HHF) by 33%.7 Based on compelling cardioprotection evidence, liraglutide, empagliflozin, and canagliflozin have FDA-approved indications to reduce major CV events in adults with T2D and established CV disease.

    Although CV benefits of SGLT2 inhibitors and GLP-1 agonists have been established in patients with high CV risk, less is known about the CV impact of these drugs on populations without established CV disease or with otherwise lower CV risk. Real-world, long-term analyses from large patient databases are starting to shed some light on whether cardioprotective effects of these drug classes extend to a heterogeneous population. The CVD-REAL study provided evidence of the effectiveness of SGLT2 inhibitors, as a class, in reducing CV events.8 Data from the United States and 5 European countries, amounting to 309,056 patients newly initiated on either SGLT2 inhibitors or other glucose-lowering drugs, primarily without (87%) established CV disease, were evaluated for risk of HHF and/or death. Use of SGLT2 inhibitors was associated with lower rates of HHF (HR: 0.61; 95% CI: 0.51-0.73; P < .001) or death (HR: 0.49; 95% CI: 0.41-0.57; P < .001) compared with therapy with other T2D drugs. This evidence suggests that SGLT2 inhibitors may provide CV benefit to patients with moderate or low CV risk. As more CV outcomes data emerge on this and other T2D drug classes, clinicians should consider the latest evidence when individualizing T2D therapy for their patients with varying levels of CV risk (NCT03648424, NCT03363464, NCT03549754).

    1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38-e360. 2. Mannucci E, Mosenzon O, Avogaro A. Analyses of results from cardiovascular safety trials with DPP-4 inhibitors: cardiovascular outcomes, predefined safety outcomes, and pooled analysis and meta-analysis. Diabetes Care. 2016;39:S196-S204. 3. Smith R, Goldfine A, Hiatt W. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39:738-742. 4. Marso S, Daniels H, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med. 2016;375:311-322. 5. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844. 6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. 7. Neal B, Perkovic V, Kenneth W, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657. 8. Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259.