Glucagon-Like Peptide 1 (GLP-1) Agonists

GLP-1 agonists have a generally beneficial impact on the myocardium by stimulating glucose-dependent insulin release and enhancing myocardial glucose uptake.1 This is especially relevant because in HF, the myocardium becomes insulin resistant.1 These agents have cardioprotective effects in patients recovering from MI and patients with cardiomyopathy, and direct beneficial impact on the heart, vessels, and kidneys.1

A trial of exenatide found decreases in pulmonary capillary wedge pressure, pulmonary artery pressure, and right arterial pressure; increased cardiac output; and decreased circulating atrial natriuretic peptide levels in patients with DM and HF treated with an infusion of exenatide.14,15 And a study of liraglutide randomized 90 patients with type 2 DM and non-ST elevation MI to receive either varying doses of liraglutide or placebo for one week.16 At three months, the placebo-corrected change in LVEF between the two groups was +4.7% (P=0.009). Inflammation and oxidative stress improved significantly with liraglutide. A more recent study, the Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) study, randomized 300 patients with HF, reduced EF, and recent HF hospitalization (despite optimal medical therapy) to receive either liraglutide or placebo for six months.17 Preliminary data show that liraglutide did not improve post-hospitalization clinical stability and that the placebo group was superior in composite of death or HF hospitalization and renal function metrics, although the finding was not statistically significant. And in a large trial of lixisenatide in patients with DM and acute coronary syndromes, the agent did not significantly alter the rate of major cardiovascular events, including HF hospitalization.18 Other trials of GLP-1 agonists are ongoing.

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Sodium-Glucose Cotransporter 2 (SGLT-2) Inhibitors

SGLT-2 mediates over 90% of glucose reabsorption in the kidney; SGLT-2 inhibitors block “proteins that use the sodium gradient generated by the Na/K pump to move glucose against its concentration gradient in the proximal tubules.”1 Inhibiting SGLT-2 therefore prevents most glucose reabsorption. In HF, SGLT-2 inhibitors increase hematocrit by 3%, suggesting volume contraction.1

SGLT-2 inhibitors have shown promising results with regard to HF.1 A trial of 7020 patients with type 2 DM were randomized to receive either empagliflozin or placebo once daily.19 After a median follow-up of 3.1 years, the risk of cardiovascular death, non-fatal MI, or non-fatal stroke was reduced by 24% in the empagliflozin group, and all-cause mortality was reduced by 32% (P<0.001). Empagliflozin reduced HF hospitalizations by 35% (P=0.0002). Studies underway are investigating whether these findings can be generalized to other SGLT-2 inhibitors; the REFORM study will evaluate the safety and efficacy of dapagliflozin in patients with diabetes and heart failure.