Empagliflozin for T2D easy on kidneys

Use of the sodium–glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin in the treatment of type 2 diabetes (T2D) is effective even in patients with lower renal function and regardless of albuminuria status, with benefits including estimated glomerular filtration rate (eGFR) preservation, reduced body mass index (BMI), and lower risk of major adverse kidney events (MAKE) compared with other glucose-lowering drugs, as shown in a real-world study.

“Until recently, SGLT2i use has been limited to people with eGFR >45 mL/min/1.73 m². Except for the CREDENCE trial, which enrolled people with albuminuria and eGFR 30 to <90 mL/min/ 1.73 m², all of the other randomized controlled trials (RCTs) of SGLT2i and kidney outcomes included a minority of patients with reduced kidney function or albuminuria,” according to researchers.

“Our data capture the recent increase in empagliflozin use in people with low eGFR and provide evidence of effectiveness that empagliflozin use was associated with a reduced risk of MAKE in [those] with eGFR 45 to <60 and ≥30 to <45 mL/min/1.73 m²—extending evidence of efficacy of canagliflozin in eGFR 45 to <60 and ≥30 to <45 mL/min/1.73 m² from the CREDENCE trial and also providing plausibility to the notion of a salutary class effect of SGLT2i on kidney outcomes,” they added.

The current study involved a real-world cohort of 379,033 patients with T2D and eGFR ≥30 mL/min/1.73 m², corresponding to 644,311.59 person-years of follow-up. The researchers conducted a variable ratio matching analysis, which included 52,535 empagliflozin users and 52,850 users of non-SGLT2i antihyperglycaemics (control) to estimate the risk of MAKE (a composite of eGFR decline >50 percent, end-stage kidney disease, or all-cause mortality).

Participants in the weighted cohort were aged 65.63 years on average, and most of them (95.58 percent) were men. Over 3 years of follow-up, MAKE occurred less frequently in the empagliflozin group than in in the control group (4.39 percent vs 6.89 percent; incidence rate, 34.80 vs 51.18 per 1,000 person-years). Although empagliflozin users exhibited a rapid drop of eGFR in the first 90 days of treatment, the control group showed a greater overall eGFR decline (–5.30 vs –8.27 mL/min/1.73 m²). [Diabetes Care 2020;doi:10.2337/dc20-1231]

Compared with other glucose-lowering drugs, empagliflozin was associated with less annual reduction in eGFR (difference, 0.99 mL/min/1.73 m²), with a net of 2.97 mL/min/1.73 m² preserved over 3 years (p<0.001). Body mass index (BMI) decreased generally, but the SGLT2i produced a greater annual reduction (difference, –0.25 kg/m² at year 1 and –0.74 kg/m² at year 3; p<0.001).

Empagliflozin also reduced the risk of MAKE by about 30 percent (hazard ratio [HR], 0.68, 95 percent confidence interval [CI], 0.64–0.73). This benefit was observed across eGFR categories (≥90 mL/min/1.73 m²: HR, 0.70; ≥60 to <90 mL/min/1.73 m²: HR, 0.66; ≥45 to <60 mL/min/1.73 m²: HR, 0.78; ≥30 to <45 mL/min/1.73 m²: HR, 0.71), regardless of the presence of albuminuria (without albuminuria: HR, 0.65; with microalbuminuria: HR, 0.72; with macroalbuminuria: HR, 0.74), and in patients with and without cardiovascular disease (HRs, 0.67 and 0.76, respectively).

Furthermore, the association persisted in per-protocol analyses, which required continuation of the assigned antihyperglycaemic medication (empagliflozin or other agents) during follow-up (HR, 0.64, 95 percent CI, 0.60–0.70), and in analyses requiring concurrent metformin use in at least the first 90 days of follow-up (HR, 0.63, 95 percent CI, 0.57–0.69).

“Taken together, the results from this analysis complement observations from prior RCTs, [including DECLARE-TIMI 58, CANVAS Program, BI 10773 EMPA-REG OUTCOME, and CREDENCE], by providing real-world evidence of effectiveness in several eGFR groups (including lower eGFR categories) and regardless of albuminuria status,” the researchers said. [Lancet Diabetes Endocrinol 2019;7:606-617; N Engl J Med 2016;375:323-334; N Engl J Med 2017;377:644-657; N Engl J Med 2019;380:2295-2306; Lancet Diabetes Endocrinol 2019;7:845-854]