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Cardiac and Renal Effects of Sodium-Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-of-the-Art Review

https://doi.org/10.1016/j.jacc.2018.06.040Get rights and content
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Abstract

Patients with type 2 diabetes mellitus have an increased risk for the development of cardiac and other vascular events, heart failure (HF), and decline in renal function. After several large cardiovascular outcome trials with mostly neutral results, 2 studies of the sodium–glucose co-transporter 2 inhibitors (SGLT2is), empagliflozin and canagliflozin, reported favorable effects on the primary endpoint, a composite of myocardial infarction, stroke, and cardiovascular death. In addition, reductions of hospitalizations for HF were observed; in the case of empagliflozin, reductions in both cardiovascular mortality and total mortality occurred. These findings prompted several analyses to elucidate the mechanisms of action of SGLT2is and have initiated several large clinical trials in patients with HF without type 2 diabetes mellitus. This review summarizes known and possible mechanisms that contribute to these salutary effects of SGLT2is. Also discussed is the interplay between cardiac and renal function, as well as safety issues associated with this class of drugs.

Key Words

diabetes
heart failure
renal function
SGLT2 inhibitor

Abbreviations and Acronyms

Ca2+
calcium
CI
confidence interval
FDA
U.S. Food and Drug Administration
GFR
glomerular filtration rate
GLP
glucagon-like peptide
HF
heart failure
HR
hazard ratio
Na+
sodium
NHE
sodium/hydrogen exchanger
RAAS
renin-angiotensin-aldosterone system
SGLT
sodium-glucose co-transporter
SGLT2i
sodium-glucose co-transporter 2 inhibitor
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus

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Dr. Zelniker has been funded by the Deutsche Forschungsgemeinschaft (ZE 1109/1-1). Dr. Braunwald has received grant support to his institution from Daiichi-Sankyo, AstraZeneca, GlaxoSmithKline, Merck, and Novartis; has provided uncompensated consultancies and lectures for Merck and Novartis; has received consulting fees from Theravance; and has received personal fees for lectures from Medscape.

Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.