Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes

Published - Written by Amanda Fernandes, MD

Mrs. Jones is a 54-year-old female who you are seeing in clinic for diabetes follow up. She has a long-standing history of diabetes that has been well controlled with diet and metformin. She had a myocardial infarction (MI) more than a year ago and subsequently developed ischemic cardiomyopathy that resulted in numerous hospital admissions for heart failure exacerbations. She embarrassingly admits that diabetes has no longer been a priority for her. Her HbA1C today is 8.8%. What would you recommend given her worsening glycemic control?

In the last decade, an explosion of diabetes medications has become available. In 2008, the FDA mandated that all new diabetes drugs be evaluated for cardiovascular risk.  As a result, we now have drugs that lower both HbA1c and improve cardiovascular outcomes.

Sodium glucose transporter 2 (SGLT-2) inhibitors is one such category of drugs. They work by inhibiting the reabsorption of glucose in the glomeruli, which reduces serum blood glucose. SGLT-2 inhibitors, such as empagliflozin and canagliflozin, have been shown to reduce cardiovascular mortality in individuals at high risk for cardiovascular events.

Given Mrs. Jones’ recent MI and ischemic cardiomyopathy, starting an SGLT-2 inhibitor could both lower her HbA1C and reduce her cardiovascular risk and hospitalizations for heart failure.  One question that remains is whether the benefits of empagliflozin and canagliflozin apply to other SGLT-2 inhibitors.

In a randomized, placebo-controlled trial published in the NEJM, the DECLARE-TIMI trial evaluated the cardiovascular profile of another SGLT-2 inhibitor, dapagliflozin. The results suggested that dapagliflozin was noninferior to placebo for the composite of cardiovascular death, MI, or stroke but did lower the risk for the combination of cardiovascular death or hospitalization for heart failure.

The following NEJM Journal Watch summary explains the study.


Dapagliflozin Appears to Be a Safe Option in Patients with Diabetes

Harlan M. Krumholz, MD, SM reviewing Wiviott SD et al. N Engl J Med 2018 Nov 10

Dapagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, blocks glucose resorption in the kidney's proximal tubule and reduces not only glucose levels but also risk for heart failure. The DECLARE–TIMI 58 trial (NCT01730534) tested the effect of dapagliflozin in people with diabetes who had, or were at high risk for, cardiovascular disease. The primary outcome was the combination of cardiovascular death, myocardial infarction, or ischemic stroke.

A total of 17,160 people were randomized to receive dapagliflozin (10 mg/day) or placebo. Median follow-up was 4.2 years; mean HbA1c was 8.3%. In a safety analysis, dapagliflozin met the prespecified criterion for noninferiority. An efficacy analysis found no significant difference in risk for the primary outcome (8.8% with dapagliflozin and 9.4% with placebo), but dapagliflozin was associated with a significantly lower risk for the combination of cardiovascular death or heart failure hospitalization (4.9% vs. 5.8%; hazard ratio, 0.83), owing to differences in the latter. The dapagliflozin group also had a significantly lower risk for renal events (4.3 vs. 5.6%; HR, 0.76). The overall risk for safety events was similar in the two groups.

Comment: These findings indicate that dapagliflozin does not raise concerns for cardiovascular safety. In the efficacy analysis, there was evidence of benefit with regard to heart failure risk, consistent with prior studies. The EMPA-REG OUTCOME trial (NEJM JW Gen Med Oct 15 2015 and N Engl J Med 2015; 373:2117) found that empagliflozin, another SGLT2 inhibitor, had a mortality benefit — which was not seen here with dapagliflozin, for reasons that are not clear — but it's possible that there are differences within the class.


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 Amanda Fernandes is a 2018-2019 NEJM editorial fellow.