SGLT2 inhibitor lowers risk of microvascular events and renal impairment in high risk T2DM patients

Wanner C, Inzucchi SE, Lachin JM et al., for the EMPA-REG OUTCOME Investigators
NEJM June 14, 2016DOI: 10.1056/NEJMoa1515920

Background

Approximately 35% of patients with type 2 diabetes (T2DM) develop kidney disease [1], which is associated with increased mortality [2]. Surrogate markers of renal complications have been shown to be reduced in response to intensive glucose-lowering strategies in T2DM patients, but evidence for improvement in advanced renal complications is limited [3-6].
Empagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces renal reabsorption of glucose, thereby increasing urinary glucose excretion. This reduces hyperglycemia in patients with T2DM. Treatment with empagliflozin has been associated with lower glycated haemoglobin levels in T2DM, including in patients with stage 2 or 3a chronic kidney disease [7-14]. In patients with type 1 diabetes, empagliflozin has been shown to reduce intraglomerular pressure and improve hyperfiltration [15,16]. While these effects may translate to improved renal outcomes, concern has also been expressed that SGLT2-inhibitors may be associated with long-term adverse renal effects.
The EMPA-REG OUTCOME trial [17] assessed CV outcomes, and found a significantly lower risk of 3-point MACE in those treated with empagliflozin as compared with placebo. The difference was driven by a lower rate of CV death [17].
This paper reports on a prespecified secondary objective of the trial, to examine the effects of empagliflozin on microvascular outcomes and progression of kidney disease in patients with T2DM at high CV risk. Included patients had eGFR of at least 30 ml/min/1.73m² of body surface area according to the MDRD formula. This report focusses on renal microvascular outcomes, among which incident or worsening nephropathy, defined as progression to macroalbuminuria (urinary albumin to-creatinine ratio, >300 mg of albumin per gram of creatinine); a doubling of the serum creatinine level, accompanied by an eGFR of ≤45 ml/minute/per 1.73 m2; the initiation of renal-replacement therapy; or death from renal disease.

Main results

• The composite microvascular outcome (including retinal and renal outcomes) occurred in 577 of 4132 (14.0%) in the empagliflozin group and in 424 of 2068 patients (20.5%) in the placebo group, implying a relative risk reduction of 38% (HR: 0.62, 95%CI: 0.54-0.70, P<0.001). This effect was driven by the renal component.
• Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 patients (18.8%) in the placebo group, yielding a significant relative risk reduction of 39% (HR: 0.61, 95%CI: 0.53-0.70, P<0.001).
• Progression to macroalbuminuria occurred in 459 of 4091 patients on empagliflozin and in 330 of 2033 (16.2%) on placebo, meaning a relative risk reduction of 38% (HR: 0.62, 95%CI: 0.54-0.72, P<0.001).
• Doubling of serum creatinine level occurred less often with empagliflozin than in the placebo group (1.5% vs. 2.6%, HR: 0.56, 95%CI: 0.39-0.79, 0.001), as did initiation of renal-replacement therapy (0.3% vs. 0.6%, HR: 0.45, 95%CI: 0.21-0.97, P=0.04).
• A post hoc sensitivity analysis and a subgroup analysis in patients with prevalent kidney disease at baseline confirmed the results for the composite renal outcomes.
• Similar patterns of renal function (eGFR) over time were seen in patients with eGFR >60 ml/min/1.73m² and in patients with eGFR <59 ml/min/1.73m² at baseline.
• The empagliflozin group showed a short-term decrease in eGFR from baseline to week 4, which was reversed after cessation of the study drug. At the follow-up visit, adjusted mean difference from placebo in the change in eGFR from baseline was 4.7 ml/min/1.73m² (95%CI: 4.0-5.5, P<0.001 for comparisons of both doses with placebo).
• Adverse events, serious adverse events or adverse events leading to study-drug continuations were similar in the treatment arms, and in the eGFR groups. Genital infections were reported more often by patients in the empagliflozin group than in the placebo group.

Download Wanner NEJM 2016_EMPA-REG OUTCOME renal_PACE.pptx

Conclusion

Patients with T2DM at high risk for CV events who were treated with empagliflozin in addition to standard care, had a significantly lower risk of microvascular outcome events than did patients receiving placebo. The difference could be attributed to a lower risk of progression of kidney disease (incident or worsening nephropathy). Patients receiving empagliflozin also less often progressed to macroalbuminuria or clinically relevant outcomes.

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