Cardiovascular Safety of Empagliflozin in Patients with Type 2 Diabetes

Published - Written by James Yeh, M.D. M.P.H.

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 DiabetesYou are a primary care provider and you’ve heard about a new class of anti-diabetic drugs called the “flozins,” including empagliflozin. You wonder what this drug class is and what we know about its safety and its effect on cardiovascular events.

What is empagliflozin?

Empagliflozin is a sodium-glucose transporter-2 (SGLT-2) inhibitor. Since glucose is freely filtered in the glomeruli and SGLT-2 reabsorbs 90% of the filtered glucose in the renal tubule, the inhibition of SGLT-2 can reduce blood glucose levels and, ultimately, lower HbA1c. There are a number of SGLT-2 inhibitors currently on the market.

What is this study about?

In the late 2000s, the FDA began to require drug companies to conduct studies to assess the cardiovascular (CV) risks of new anti-diabetic drugs.

In this week’s issue of NEJM, Zinman and colleagues present their findings from a double-blind randomized controlled trial evaluating the long-term cardiovascular safety of empagliflozin versus placebo.

The trial was conducted at nearly 600 sites in over 40 countries. Over 7000 patients with diabetes who were at high-risk for CV events and were either drug-naïve or on background glucose-lowering therapy were randomized to receive either empagliflozin (10 mg or 25 mg) or placebo on top of standard of care. The primary outcome was the first occurrence of a 3-point major cardiovascular event– CV death, non-fatal MI, or non-fatal stroke. The patients were followed for a median time of 3.1 years.

Who is in the study?

At baseline, about 30% of the participants were on monotherapy with either metformin or insulin and 45%, on dual therapy with either metformin with sulfonylurea or metformin and insulin. 85% of the patients were on aspirin and over 75%, on a statin therapy. Study participants had baseline HbA1c of slightly over 8%.

What were the results?

At the end of 12 weeks, patients taking empagliflozin had a reduction in their HbA1c of about 0.5% and at the end of 207 weeks a reduction of about 0.25%. Patients taking empagliflozin had lower rates of the primary outcome (composite events of CV death, non-fatal MI, or non-fatal stroke) than those on placebo (10.5% versus 12.1%, HR 0.86, P=0.04). The primary outcome was driven by CV deaths (12.4% versus 20.2%, HR 0.68).

Treatment with empagliflozin reduced hospitalization for heart failure (HR 0.65, P=0.002) and all-cause mortality (5.7 versus 8.3%, HR=0.68, P<0.001). Outcomes for fatal and non-fatal strokes and MIs were not statistically different. Overall, adverse events were similar between the empagliflozin and placebo groups. However, genital infections were more common in those taking empagliflozin (6.4% versus 1.8%).

What is known about CV events in previous trials?

The evidence for macrovascular benefit is mixed. The DCCT/EDIC study showed that intensive glucose control reduced CV risks in individuals with type 1 diabetes while the VADT and the UKPDS studies demonstrated reduced CV risks in type 2 diabetes. On the other hand, the ACCORD and ADVANCE studies showed no clear macrovascular benefit in type 2 diabetes.

Does this study result apply to my patients and are there any other drug safety concerns?

A NEJM editorial by Ingelfinger and Rosen cautions that the results of this study may not be generalizable to everyone, since the study population had very high cardiovascular risks at baseline: “nearly half had prior myocardial infarctions, and about three quarters had evidence of coronary artery disease, 25% had previous strokes, and 20%, peripheral vascular disease.”

Additionally, the FDA had recently issued a number of safety warnings on the SGLT-2 class of drugs including the risk of increased ketoacidosis and increased bone fractures.

What is my take-away?

The addition of empagliflozin to background therapy in patients with type 2 diabetes resulted in fewer CV events. However, the long-term effects on CV events as well as drug safety concerns about this drug and this drug class will have to be assessed.

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