Heart failure prevention with sodium‐glucose cotransporter 2 inhibitors

Abstract

The prevalence of type 2 diabetes (T2D) has increased by 60% over the past three decades. Current projections estimate that by 2030 T2D will be the seventh leading cause of death worldwide. Despite recent advances in medical care, cardiovascular disease continues to be the leading cause of morbidity and mortality in this cohort. Multiple studies have shown that T2D not only increases the risk of stroke and myocardial infarction, but also increases the risk of heart failure (HF). Heart failure is a common complication of T2D, with especially poor outcomes and 5-year survival rates of less than 25%. Even asymptomatic diabetic patients with minimal cardiovascular risk factors may develop impaired diastolic function early in the course. Middle-aged diabetic patients may have HF in the absence of a vascular event. Most current preventive therapeutic interventions for this cohort primarily aim to reduce the risk of ischemic cardiovascular events and do not target the pathophysiological mechanisms responsible for the development of diabetic cardiomyopathy and subsequent HF, highlighting the need for novel treatments. In 2008, the US Food and Drug Administration (FDA) released an industry guidance statement (https://www.fda. gov/downloads/Drugs/Guidances/ucm071627.pdf. Accessed February November 20, 2018) requiring all glucoselowering drug trials to report major adverse cardiovascular events in patients with T2D. Several trials assessing the cardiovascular effects of novel drug classes, such as glucagonlikepeptide-1(GLP-1) receptor agonists, dipeptidyl peptidase (DPP)-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, were completed and published. These studies were designed to demonstrate that the cardiovascular safety of the respective drugs was not inferior to placebo. A network meta-analysis of these trials showed that a 99.6% probability existed of SGLT2 inhibitors being the optimal treatment for reducing the risk of HF hospitalization in T2D, followed by GLP-1 agonists (0.27%) and DPP-4 inhibitors (0.1%). These findings suggest that among the novel antihyperglycemic medications, SGLT2 inhibitors are the most beneficial in reducing the risk of HF. The impetus of these results is largely driven by two large scale trials, namely the Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) and Empagliflozin Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG) trials. Both CANVAS and EMPA-REG trials showed reductions of more than 30% in HF hospitalization among T2D patients, with hazard ratios (HR) of 0.67 (95% confidence interval [CI] 0.52-0.8) and 0.65 (95% CI 0.50-0.85), respectively. Recent analyses outlining the comparative effects of SGLT2 inhibitors among patients with and without HF at baseline has broadened our understanding regarding SGLT2 inhibitors for the primary and secondary prevention of HF. Subgroup analysis of the CANVAS and the EMPA-REG OUTCOME trials showed that both canagliflozin and empagliflozin reduce HF admissions in patients with (HR 0.51 [95% CI 0.33-0.79] and 0.75 [95% CI 0.48-1.17], respectively) or without (HR 0.79 [95% CI 0.57-1.09] and 0.59 [95% CI 0.43-0.81], respectively) HF at baseline. Consistent with the findings in CANVAS and EMPA-REG OUTCOME, the effect of SGLT2 inhibition on the prevention of HF hospitalization has also been observed in real-world studies, such as CVD-REAL(Comparative Effectiveness of DOI: 10.1111/1753-0407.12932