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Diabetes Drug Decreases Mortality

Darrell Hulisz, RPh, PharmD
Patrick Helman,

April 4, 2016

Recently, the New England Journal of Medicine published the results of a study investigating the effects of empagliflozin on cardiovascular outcomes and mortality in type 2 diabetics. Empagliflozin (Jardiance) is a member of the SGLT2 inhibitor class indicated for use in glycemic control for patients with type 2 diabetes mellitus. The medication works by decreasing renal glucose absorption, thus increasing the body's excretion of glucose through urination. Empagliflozin decreases hemoglobin A1c levels, reduces blood pressure, and does not cause weight gain and may even produce modest weight loss in patients with diabetes.

The EMPA-REG trial evaluated a total of 7,020 patients at 590 treatment sites in 42 countries. The study primarily compared the combined reduction in death from cardiovascular causes, nonfatal myocardial infarcts and nonfatal strokes in patients taking empagliflozin (at 10mg and 25mg), versus placebo. At the conclusion of the 2.5-year trial, 10.5% of patients taking empagliflozin had experienced one of the aforementioned events, compared to a 12.1% rate in the placebo group (p=0.04). Additionally, empagliflozin touted several statistically significant differences in other measurable outcomes, such as death from cardiovascular causes alone, death from any cause and hospitalization rates for heart failure.

While these results appear promising for empagliflozin use in diabetic patients, critics and researchers have reservations about this industry-sponsored study and its potential impact on prescribing practices going forward. Many have pointed out that among the three criteria listed in the primary outcome, only death from cardiovascular events was significantly improved in the empagliflozin group. Development of myocardial infarction and stroke was not significantly impacted, leaving researchers to question the true cardiovascular benefit of the drug. The authors of the study have responded saying that the benefit likely comes from osmotic diuresis, possibly explaining the reduction in patients being hospitalized for heart failure complications.

Another question is whether this cardiovascular benefit can be seen class-wide among the SGLT2 inhibitors. There are studies currently being conducted to see whether canagliflozin (CANVAS study) or dapagliflozin (DECLARE-TIMI 58) provide the same benefits to diabetic patients. The results of these trials will be published in 2017 and will help further determine empagliflozin's place in therapy.

Finally, researchers hope to determine the optimal dosing for empagliflozin. There was no attempt by the authors of the study to prove a dose-dependent relationship in the outcomes between the 10mg and 25mg doses. While there was no difference in the cardiovascular safety outcomes between doses, there were secondary benefits of decreased A1c values, lower blood pressure values and increased weight loss. Further studies will likely be conducted to answer the growing number of questions resulting from this trial.

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

2. Sarafidis PS, Tsapas A, Fishereder M, et al. Letters to the Editor on Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2016;374(11):1092-1094

3. Nainggolan, L. "After EMPA-REG: Docs dissect diabetes study, discuss implications." Medscape Medical News. Medscape. 24 September 2015. Web. 25 March 2016.

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