Renal, metabolic and cardiovascular considerations of SGLT2 inhibition

Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.

Arterial distensibility measures, generally from pulse-wave velocity (PWV), are widely used with little knowledge of relationships to patient outcome. We tested whether aortic PWV predicts cardiovascular and all-cause mortality in type 2 diabetes and glucose-tolerance-tested (GTT) multiethnic population samples. Participants were randomly sampled from (1) a type 2 diabetes outpatient clinic and (2) primary care population registers, from which nondiabetic control subjects were given a GTT. Brachial blood pressures and Doppler-derived aortic PWV were measured. Mortality data over 10 years' follow-up were obtained. At any level of systolic blood pressure (SBP), aortic PWV was greater in subjects with diabetes than in controls. Mortality risk doubled in subjects with diabetes (hazard ratio 2.34, 95% CI 1.5 to 3.74) and in those with glucose intolerance (2.12, 95% CI 1.11 to 4.0) compared with controls. For all groups combined, age, sex, and SBP predicted mortality; the addition of PWV independently predicted all-cause and cardiovascular mortality (hazard ratio 1.08, 95% CI 1.03 to 1.14 for each 1 m/s increase) but displaced SBP. Glucose tolerance status and smoking were other independent contributors, with African-Caribbeans experiencing reduced mortality risk (hazard ratio 0.41, 95% CI 0.25 to 0.69). Aortic PWV is a powerful independent predictor of mortality in both diabetes and GTT population samples. In displacing SBP as a prognostic factor, aortic PWV is probably further along the causal pathway for arterial disease and may represent a useful integrated index of vascular status and hence cardiovascular risk.

Type 2 diabetes mellitus causes excessive morbidity and premature cardiovascular (CV) mortality. Although tight glycemic control improves microvascular complications, its effects on macrovascular complications are unclear. The recent publication of the EMPA-REG OUTCOME study documenting impressive benefits with empagliflozin (a sodium-glucose cotransporter 2 [SGLT2] inhibitor) on CV and all-cause mortality and hospitalization for heart failure without any effects on classic atherothrombotic events is puzzling. More puzzling is that the curves for heart failure hospitalization, renal outcomes, and CV mortality begin to separate widely within 3 months and are maintained for >3 years. Modest improvements in glycemic, lipid, or blood pressure control unlikely contributed significantly to the beneficial cardiorenal outcomes within 3 months. Other known effects of SGLT2 inhibitors on visceral adiposity, vascular endothelium, natriuresis, and neurohormonal mechanisms are also unlikely major contributors to the CV/renal benefits. We postulate that the cardiorenal benefits of empagliflozin are due to a shift in myocardial and renal fuel metabolism away from fat and glucose oxidation, which are energy inefficient in the setting of the type 2 diabetic heart and kidney, toward an energy-efficient super fuel like ketone bodies, which improve myocardial/renal work efficiency and function. Even small beneficial changes in energetics minute to minute translate into large differences in efficiency, and improved cardiorenal outcomes over weeks to months continue to be sustained. Well-planned physiologic and imaging studies need to be done to characterize fuel energetics-based mechanisms for the CV/renal benefits.