SGLT-2 Inhibitors: What the Nephrologist Needs to Know

Be on the lookout for increased use of SGLT-2 inhibitors in 2016 after a recent study published in the New England Journal of Medicine demonstrated a lower composite rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in high risk type 2 diabetics (n = 7020) treated with empagliflozin compared to placebo.

Reduction in death in the treated group was mostly due to a reduction in cardiovascular deaths (18% risk reduction). Active treatment also reduced renal events by 21% primarily related to a reduction in the development of microalbuminuria.

Empagliflozin is one of several SGLT-2 inhibitors now on the market. This class of drugs represents selective inhibitors of sodium glucose cotransporter 2 in the proximal tubule that lead to substantial glycosuria and hence, a reduction in blood glucose. Patients treated with these agents can have small decreases in weight (typically 2–4 kg) and systolic blood pressure (BP) (4–6 mm Hg), likely related to the osmotic diuresis that accompanies the glycosuria. The major side effect appears to be an increase in urinary tract and genital infections, some leading to septicemia and hospitalization. Ketoacidosis is another unusual complication typically seen within the first year and associated with another risk factor, e.g., fasting, alcohol, or reduction/discontinuation of insulin.

The hypoglycemic effects of SGLT-2 inhibitors diminish with worsening kidney function. SGLT-2 inhibitors are currently not indicated in patients with GFR <30 mL/min. A study using canagliflozin demonstrated hypoglycemic efficacy in CKD stage 3 with small reductions in GFR seen within 3 weeks of initiation of drug and a reduction in urinary albumin excretion (20–30% vs. 7.5% in controls). Others have found similar effects on GFR, BP, microalbuminuria, and progression of albuminuria. A small study of patients with type 1 diabetes demonstrated a reduction in glomerular hyperfiltration by empagliflozin under both euglycemic and hyperglycemic clamped conditions. The authors postulated that the SGLT-2 inhibitor restores tubular-glomerular feedback, leading to an increase in afferent arteriolar tone.

Taken together, these findings raise the intriguing possibility that early use of SGLT-2 inhibitors might have significant renal protective effects. Does one believe a reduction in proteinuria signals renal protection? Only time and well conducted clinical trials will answer this question as it relates to SGLT-2 inhibitors. However, kidney care givers should prepare to answer questions about the safety and efficacy of SGLT-2 inhibitors, their effects on the kidney, and how they perform in patients with various degrees of renal dysfunction.