he Food and Drug Administration (FDA) approved canagliflozin (or INVOKANA) as the first sodium glucose co-transporter-2 (SGLT-2) inhibitor. Two other inhibitors have been approved: empagliflozin and dapagliflozin. In previous blogs, I have described these medications, but wanted to mention new evidence particularly with empagliflozin and cardiovascular risk.
For any new anti-hyperglycemic medication approved by the FDA, the manufacturer must conduct post-marketing studies evaluating the medication on cardiovascular outcomes. There are several ongoing clinical trials, which can be searched and found through ClinicalTrials.gov
. In a recent article published in the New England Journal of Medicine
, the EMPA-REG OUTCOME trial evaluated empagliflozin and its risk on cardiovascular outcomes.
This trial was a multi-centered, randomized, double-blind, placebo-controlled trial. It randomized adult patients who had type 2 diabetes, a BMI less than 45, and a GFR above 30 to either empagliflozin 10 mg per day, empagliflozin 25 mg per day or a placebo. The primary outcome was a composite and point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes were composite of the primary outcome with hospitalization for unstable angina. Under an intent-to-treat analysis, the rates of the primary and secondary outcomes were evaluated over four years.
Empagliflozin lowered the risk of death from any cause by 32% and death from cardiovascular cause by 38%.
Based on the results, empagliflozin can lower the risk of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by 14% (HR 0.86, 95% CI 0.74 to 0.9, p-value <0.001 for noninferiority and 0.04 for superiority). More specifically, empagliflozin lowered the risk of death from any cause by 32% (p-value <0.001) and death from cardiovascular cause by 38% (p-value <0.001). Empagliflozin also improved glycemic control but there was no difference in the 10 mg or 25 mg daily dose.
While these outcomes are good, it is important to note adverse events. Placebo-treated participants had significantly higher rates of any adverse event, severe adverse event, death from adverse event, and discontinuation of the drug due to adverse events compared to empagliflozin. One could evaluate these safety endpoints and determine clinical significance, as the percent difference was small between the two groups. It is important to note that empagliflozin did have a higher rate of genital infections among both male and female patients than placebo.
There have been several studies evaluating cardiovascular outcomes with newer therapeutic classes of anti-hyperglycemic medications. Dipeptidyl peptidase-IV inhibitors have had recent published evidence on cardiovascular outcomes. As mentioned earlier, ongoing studies are being conducted over the next five years with glucagon-like peptide-1 agonists and SGLT-2 inhibitors. Based on the EMPA-REG OUTCOME trial, empagliflozin is safe to prescribe long-term (i.e. four years) among patients that are or will be at risk of cardiovascular disease with a diagnosis of type 2 diabetes.
About the Author
Jennifer Clements received her Doctorate of Pharmacy from Campbell University in 2006 and completed a primary care residency at a Veterans Affairs Medical Center in 2007. She is also a certified diabetes educator and board certified in pharmacotherapy. Currently, she is the Interim Chair and Associate Professor in the Department of Pharmacy Practice at Presbyterian College School of Pharmacy.