Cardiovascular Protection with Anti-hyperglycemic Agents

Diabetes mellitus is a major risk factor for cardiovascular (CV) disease. Conversely, CV disease is responsible for a majority of the deaths in patients with diabetes. Many drug trials have concentrated on blood glucose (hemoglobin A_1c) reduction. This strategy, while reducing microvascular outcomes like nephropathy and neuropathy, has little or no effect on reducing macrovascular events like heart attack, stroke, and heart failure. It has been postulated that hypoglycemia may counterbalance some of the beneficial effects of anti-hyperglycemic agents, but this is not proven. Further, trial evidence for thiazolidinediones (rosiglitazone and pioglitazone) showed increased risk of heart failure and raised concerns about increased myocardial infarction. This heightened awareness of potentially harmful CV effects of otherwise effective hypoglycemic drugs resulted in regulatory mandates for CV outcome trials to ascertain the safety of newer anti-hypoglycemic agents appearing on the market. Three new classes of anti-hyperglycemic agents have been introduced in recent years. While dipeptidyl peptidase-4 (DPP-4) inhibitors exhibited increased heart failure hospitalization in the SAVOR-TIMI 53 trial evaluating saxagliptin and in the secondary analysis of the EXAMINE trial for alogliptin, the effects of glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose co-transporter-2 (SGLT2) inhibitors on CV outcomes in diabetes have largely been positive. The LEADER and SUSTAIN-6 trials evaluating the safety and efficacy of the GLP-1 analogs liraglutide and semaglutide, respectively, showed a statistically significant reduction in the primary outcome (major adverse cardiac events [MACE]: CV death, myocardial infarction, and stroke) and the secondary combined outcome when compared to placebo. Results of the TECOS trial for sitagliptin were, however, neutral (no net CV benefit or harm), questioning the class effect of GLP-1 analogs. Results of the SGLT2 inhibitor trials were more uniform. While EMPA-REG (evaluating empagliflozin) and CANVAS (evaluating canagliflozin) showed a reduction in the MACE end point, dapagliflozin had a net neutral effect on MACE in DECLARE-TIMI 58. All three SGLT2 inhibitors, however, showed a significant reduction in heart failure hospitalizations. Although initially designed to keep potentially harmful anti-hyperglycemic agents off the market, the CV outcome trials have provided clinicians with a new set of anti-hyperglycemic drugs with proven CV benefit in patients with diabetes and CV disease, thus expanding the field of CV secondary prevention. There is a need to inculcate GLP-1 analogs and SGLT2 inhibitors that reduce major CV events and heart failure hospitalizations (alongside lifestyle management and metformin) in the treatment of patients with diabetes and CV disease.