The Changing Landscape of Diabetes Therapy for Cardiovascular Risk Reduction: JACC State-of-the-Art Review

Abstract

Type 2 diabetes mellitus (T2D) is a major risk factor for cardiovascular disease (CVD), the most common cause of death in T2D. Despite improved risk factor control, however, adults with T2D continue to experience substantial excess CVD risk. Until recently, however, improved glycemic control has not been associated with robust macrovascular benefit. The advent of 2 new classes of antihyperglycemic agents, the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, and their respective large cardiovascular outcome trials, has led to a paradigm shift in how cardiologists and heath care practitioners conceptualize T2D treatment. Herein, the authors review the recent trial evidence, the potential mechanisms of action of the sodium-glucose cotransporter-2 inhibitors and the glucagon-like peptide-1 receptor agonists, safety concerns, and their use for the primary prevention of CVD as well as in diabetic patients with impaired renal function and heart failure.

Keywords: antidiabetic therapy; cardiovascular disease; primary prevention; secondary prevention; type 2 diabetes.

Figure 1:. Summary of Reductions in Major Adverse Cardiac Events in recent SGLT2-i Trials.

MACE, major adverse cardiac event; MI, myocardial infarction; SGLT2-i, sodium-glucose cotransporter 2 inhibitor. Both empagliflozin and canagliflozin significantly reduced MACE-3 and heart failure hospitalization in EMPA-REG and CANVAS Program, respectively. A reduction in cardiovascular death and all-cause mortality was observed with use of empagliflozin.

Figure 2:. Summary of Reductions in Major Adverse Cardiac Events in recent GLP-1 RA trials.

CV, cardiovascular; GLP-1 RA, glucagon-like peptide receptor agonist; MACE, major adverse cardiac events; MI, myocardial infarction. Liraglutide and semaglutide significantly reduced MACE-3 in LEADER and SUSTAIN-6, respectively. Liraglutide significantly reduced CV death, heart-failure hospitalization, and all-cause mortality. Semaglutide significantly reduced non-fatal stroke.

Figure 3:. Summary of Side Effects in Major Recent Trials of SGLT2-i and GLP-1 RA.

GI, gastrointestinal; GLP-1RA, glucagon-like peptide receptor agonist; SGLT2-i, sodium-glucose cotransporter 2 inhibitor. Panel A. Side effects of SGLT2-i. Genital infections were significantly increased with SGLT-2i use in EMPA-REG OUTCOME and the CANVAS Program. Amputation risk was significantly increased with canagliflozin use. Panel B. Side effects of GLP-1 RA. Liraglutide and semaglutide were significantly associated with higher drug discontinuation rates due to adverse GI symptoms. Acute gallstone disease was significantly increased with liraglutide use and retinopathy complication was significantly increased with semaglutide use.

Figure 4:. Summary of Renal Benefits in Major Recent Trials of SGTL2-i and GLP-1 RA.

Renal outcomes were all favorably reduced by therapy in EMPA-REG, CANVAS Program, LEADER, and SUSTAIN-6. All trials used a roughly similar composite for adverse renal outcomes including progression of albuminuria.

Figure 5:. A New Algorithm for CVD Risk Reduction in T2D.

ASCVD, atherosclerotic cardiovascular disease; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2-i, sodium-glucose cotransporter 2 inhibitor. Proposed algorithm to reduce cardiovascular risk with glucose lowering agents in type 2 diabetics. After the addition of metformin and a moderate to high-intensity statin, clinicians can consider adding an SGLT2-i or GLP-1 RA if the hemoglobin A1c remains above goal of 7.0%. The preference for adding an SGLT2-i or GLP-1 RA can be individualized based on a history of heart failure, ASCVD, or renal disease. In renal disease, SGLT2-i may be favored over GLP-1 RA given the more comprehensive renal benefits associated with SGLT2-i. There is less robust evidence to support the use of these agents for primary prevention.

eFigure 1. Baseline Cardiovascular Risk Factor Control in Recent Trials of New Antidiabetic Agents

LDL-C, low-density lipoprotein cholesterol Baseline systolic blood pressure, body mass index, and LDL cholesterol.

eFigure 2a. Baseline Medication Use Reported in Recent trials of New Antidiabetic Agents

RAS, renin-angiotensin system Baseline anti-glycemic agent, statin, and RAS inhibitor use.

eFigure 2b. Post Randomization Insulin Use in EMPA-REG, LEADER and SUSTAIN-6

Post-randomization use of insulin in the SGLT2-i or GLP-1 RA group compared to the placebo group.