In patients with type 2 diabetes and CVD, empagliflozin reduced incident or worsening nephropathy at 3.1 y

Question In patients with type 2 diabetes and cardiovascular disease (CVD), how does adding empagliflozin to standard care affect renal outcomes? Methods Design Secondary analysis of a randomized placebo-controlled trial (EMPA-REG OUTCOME trial). ClinicalTrials.gov NCT01131676. Allocation {Concealed}*. Blinding Blinded {patients, clinicians, data collectors, outcome adjudicators, data analysts, and manuscript writers}. Follow-up period Median 3.1 years. Setting 590 centers in 42 countries. Patients {7028}* patients (mean age 63 y, 71% men) who had type 2 diabetes, established CVD, and an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2. Intervention Empagliflozin, 10 mg/d {n =2345 treated}*; empagliflozin, 25 mg/d {n =2342 treated}*; or placebo {n =2333 treated}*. All patients received standard care. Outcomes Main outcome was a component of a prespecified composite secondary outcome: incident or worsening nephropathy (progression to macroalbuminuria, serum creatinine level doubling and eGFR 45 mL/min/1.73 m2, renal replacement therapy initiation, or death due to renal disease). Other outcomes included components of incident or worsening nephropathy and incident albuminuria (urinary albumincreatinine ratio 30) in patients with normal baseline albumin levels. Patient follow-up {97% completed the study}*; 99.9% were included in the modified intention-to-treat analysis. Main results Empagliflozin, 10 mg or 25 mg daily, reduced incident or worsening nephropathy compared with placebo (Table). Results were similar for each dose of empagliflozin vs placebo (10 mg, hazard ratio [HR] 0.61, 95% CI 0.53 to 0.72; 25 mg, HR 0.61, CI 0.52 to 0.71). Groups did not differ for incident albuminuria (Table). Conclusion In patients with type 2 diabetes and cardiovascular disease, adding empagliflozin to standard care reduced incident or worsening nephropathy at a median 3.1 years. Empagliflozin, 10 mg or 25 mg daily, vs placebo in patients with type 2 diabetes and cardiovascular disease Outcomes Event rates/1000 patient-y At a median 3.1 y of follow-up Empagliflozin Placebo RRR (95% CI) NNT (CI) Incident or worsening nephropathy 48 76 37% (28 to 44) 15 (12 to 20) Macroalbuminuria 42 65 36% (26 to 44) 18 (15 to 24) Doubling of serum creatinine level and eGFR 45 mL/min/1.73 m2 5.5 9.7 44% (21 to 61) 89 (64 to 186) Renal replacement therapy initiation 1.0 2.1 55% (3 to 79) 304 (212 to 5572) Incident albuminuria after normal baseline albumin levels 253 266 3.5% (3 to 9) Not significant eGFR = estimated glomerular filtration rate; other abbreviations defined in Glossary. RRR, NNT, and CI calculated from placebo event rates and hazard ratios in article. Analysis for incident albuminuria is based on 59% of patients with normal baseline albumin levels; 87% to 99.9% of randomized patients were included in other analyses. Composite of macroalbuminuria, doubling of serum creatinine level with eGFR 45 mL/min/1.73 m2, renal replacement therapy initiation, or death due to renal disease (0.1% vs 0%). Commentary The prespecified secondary analysis of the EMPA-REG OUTCOME trial reports interesting findings about empagliflozin. This is in a new class of antidiabetes drugs that inhibit sodiumglucose co-transporter 2 (SGLT2), which is responsible for glucose reabsorption in proximal renal tubules. It is important to consider several points before changing our practice. First, no doseresponse relation was found: 10 mg and 25 mg of empagliflozin did not differ for clinical outcomes. Second, the US Food and Drug Administration issued a warning about potential SGLT2 inhibitorassociated ketoacidosis (1). However, the trial reported no significant treatment difference for these events, probably due to low power. Third, the cost of the drug may be prohibitive. Finally, the highly selective patient cohort in the EMPA-REG OUTCOME trial limits external validity. Given these limitations, what should be the next steps? Comparative effectiveness analysis of various treatment strategies may help shed light on risks and benefits. In addition, longer, larger trials and patient-level meta-analysis would give a better idea about the population that may benefit from this class of drug. Cost-effectiveness analyses are also needed to assess the benefitcost ratio of the drug, especially for entities that approve drugs for reimbursement in their patient populations. Until then, we should continue to pursue multifactorial interventions to reduce complications (2). Given the growing burden of type 2 diabetes (3), cost-effective interventions are urgently needed to avoid end-stage renal disease, which is equivalent to death in most developing countries.