Cardiovascular Protection With Anti-Hyperglycemic Agents

Prakash Deedwania; Tushar Acharya


Am J Cardiovasc Drugs. 2019;19(3):249-257. 

In This Article

Abstract and Introduction


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 A1c) 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.


Diabetes mellitus (DM) is considered predominantly a metabolic condition due to glycemic control perturbations. However, it is now well-recognized that cardiovascular disease (CVD) accounts for 60–75% of deaths in persons with DM and is also the leading cause of disability.[1] Diabetes increases the risk of CVD by two- to fourfold, and its presence in those with CVD is one of the most powerful predictors of adverse clinical outcome.[2] Much of the morbidity and mortality is from coronary artery disease, cerebrovascular disease leading to stroke, congestive heart failure, peripheral arterial disease, and sudden cardiac death.

It is therefore essential that clinicians familiarize themselves with the implications of diabetes and provide comprehensive therapeutic strategies to reduce the risk of cardiovascular (CV) events in their diabetic patients. Comprehensive CV risk reduction in DM should focus on aggressive management of glycemic status, blood pressure, and lipids, the use of antithrombotic agents, as well as therapeutic lifestyle modification including regular physical activities and prudent diet.[3]

Anti-diabetic drugs form a cornerstone of diabetes management. The primary focus of this article is to elaborate on the results and clinical implications of the recent CV outcome trials (CVOTs) with newer anti-diabetic drugs. We will present data regarding the safety profiles of these new medications and highlight some of their encouraging cardioprotective effects in diabetic patients with pre-existing CVD as well as those at high risk of future CV events.