Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes: Cardiovascular and Kidney Effects, Potential Mechanisms and Clinical Applications
Sodium glucose co-transporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin and canagliflozin, are now widely approved anti-hyperglycemic therapies. Due to their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more importantly are osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures (BP) by 4-6/1-2 mmHg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition is also associated with an acute, dose-dependent reduction in eGFR by ~5 ml/min/1.73m2 and ~30-40% reduction in albuminuria. These effects mirror pre-clinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (CKD, eGFR <60 ml/min/1.73m2). In contrast, BP lowering, eGFR and albuminuric effects are preserved, and perhaps exaggerated in CKD. With regards to long term clinical outcomes, the EMPA-REG OUTCOME trial in patients with type 2 diabetes (T2D) and established cardiovascular disease randomized to empagliflozin versus placebo reported a 14% reduction in the primary composite outcome of CV death, nonfatal myocardial infarction, nonfatal stroke, and >30% reductions in cardiovascular mortality, overall mortality and heart failure hospitalizations associated with empagliflozin - even though by design, the HbA1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with T2D who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis - such as the impact on BP, heart failure, kidney protection and mortality - will be a major management focus.
- Received May 11, 2016.
- Accepted July 21, 2016.