The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

Abstract

Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA 1c , systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA 1c , SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 3 0 -3 0 0 m g / g ; n = 6 3 6 ) o r m a c r o a l b u m i n u r i a (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA 1c , SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (−32% vs placebo; p < 0.001) or macroalbuminuria (−41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA 1c , SBP or weight. Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes

“…We also identified 2 high-quality meta-analyses and multiple publications as well as unpublished data from 9 RCTs that directly compared empagliflozin with other antidiabetic drugs in people with type 2 diabetes (5)(6)(7)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

“…Moderate-quality evidence suggests that empagliflozin reduces all-cause mortality (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61) and increases the rates of diabetes control without increasing the risk of serious adverse effects and hypoglycemia when compared with placebo in adults with type 2 diabetes ( Table 1) (50,51,70). The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1).…”

“…The increase in rates of glycemic improvement starts at the dose of 10 mg/day (150 attributable events per 1,000 treated, Figure 1) and increases to 210 attributable events per 1,000 treated after the larger dose of empagliflozin (25 mg/day, Figure 1). Low-quality evidence suggests that empagliflozin reduces cardiovascular mortality, the risk of hospitalization for any cause (73), and hospitalizations for heart failure (59), as well as the risk of developing heart failure (73), developing or worsening of nephropathy (58), and the risk of treatment discontinuation due to lack of efficacy, at the expense of higher risk of adverse effects (Table 1) (7,11,40,44,46,47,(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)70,(75)(76)(77). The observed improvement in patient outcomes is attributable to the largest RCT, EMPA-REG OUTCOME, which enrolled patients with established orally, once daily; comparator: placebo.…”

Metformina en enfermedad renal diabética: estado actual

“…Sin embargo, solo se han obtenido resultados esperanzadores y consistentes con el efecto sobre el control metabólico con los nuevos fármacos, como glifozinas o incretinas (específicamente, los agonistas del receptor del péptido-1, similar al glucagón [GLP-1], ya que, para los inhibidores de la dipeptidil peptidasa [DPP-4], no hay información pertinente) y los inhibidores del cotransportador-2 de sodio-glucosa (SGLT2 por sus siglas en inglés) o glifozinas se han obtenido resultados esperanzadores y consistentes con el efecto sobre el control metabólico 20,21 .…”

“…• En la publicación del Registro sueco de diabetes, la metformina fue bien tolerada en pacientes con ERC-3 y su uso estuvo asociado con una reducción del 13 % en la mortalidad total 21 . Más aún, en comparación con las sulfonilureas, el uso de metformina está asociado con una menor probabilidad de deterioro de la función renal 33 .…”