Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon


Curr Opin Nephrol Hypertens. 2016;25(1):50-58. 

In This Article

Sodium Glucose Cotransporter 2 Inhibition Reduces Hypertension, Body Weight, and Cardiovascular Mortality in Type 2 Diabetes Mellitus

Hypertension and obesity are important cardiovascular risk factors. Consistent with preclinical data, a meta-analysis of T2DM patients treated with SGLT2 inhibitors showed a consistent small decrease in SBP of between 3–6 mmHg.[23] This effect is likely because of a direct natriuretic and osmotic effect and body weight reduction by SGLT2 inhibition (Fig. 1). Recent studies provided evidence that SGLT2 and NHE3 may be functionally linked such that SGLT2 inhibition may also inhibit the Na/H exchanger NHE3 in the proximal tubule[33,34] (Fig. 2). Although such an interaction could be relevant for the effects of SGLT2 inhibition on GFR and blood pressure, more studies are required to further establish this interaction and its cardiovascular relevance. SGLT2 inhibition may also induce beneficial cardiovascular effects by lowering plasma uric acid levels. Although the involved transport mechanism and relevance remains to be determined, there is evidence that glycosuria rather than hyperglycemia increases uricosuria in T1DM patients.[35]

In both animal studies and human trials in T2DM, the glucosuric effect of SGLT2 inhibition was consistently associated with lower body weight. In obese rats and mice, the reduction in body weight in response to SGLT2 inhibition was associated with lower body fat and increased lipolysis and fatty acid oxidation.[36,37] Lesser visceral and subcutaneous fat has been reported in T2DM patients treated with SGLT2 inhibitors[38,39] (Fig. 1). In contrast to T2DM, lipolysis is increased and body fat and body weight are often reduced in poorly controlled T1DM. Notably, SGLT2 inhibition improved blood glucose in T1DM Akita mice, and this was associated with increased body weight and epididymal fat adipocyte size,[14] indicating that the effect of SGLT2 inhibition on body fat may be affected by the underlining pathophysiology.

The EMPA-REG OUTCOME trial compared the treatment of the SGLT2 inhibitor empagliflozin versus placebo for 3 years in addition to standard care in 7020 patients with T2DM and high cardiovascular risk.[32] Empagliflozin was associated with small improvements in blood glucose control and small reductions in weight, waist circumference, uric acid level, and SBP and DBP, with no increase in heart rate, and small increases in both low-density lipoprotein and high-density lipoprotein cholesterol. Importantly, empagliflozin treatment reduced the risk of death from cardiovascular disease, hospitalization for heart failure, and death from any cause (relative risk reductions of 38, 35, and 32%, respectively).[32]