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Even More Protection for the Kidneys With An SGLT-2 Inhibitor (And a comment from George Bakris, MD)

New data from the EMPA-REG-OUTCOME study provide more evidence of the renoprotective effects of empagliflozin in patients with type 2 and cardiovascular disease.

With analysis in the June issue of Lancet Diabetes and Endocrinology showing the long- and short-term effects of empagliflozin on urinary albumin excretion, irrespective of patients’ albuminuria status at baseline is very likely to encourage physicians to use empagliflozin more often in albuminuric patients, even when taking into account the adverse effects, costs, and cautions associated with SGLT2 inhibitors as amputation, which was not shown for empagliflozin.

In this randomized, double-blind, placebo-controlled trial at 590 sites in 42 countries, researchers randomly assigned patients age 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. They did the randomization with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA1c, BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. For this study, they report urinary albumin-to-creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; and macroalbuminuria: UACR >300 mg/g).

The placebo-controlled EMPA-REG-OUTCOME trial, which involved 7,020 patients with type 2 diabetes and cardiovascular disease, showed that treatment with empagliflozin reduced the risk of major cardiovascular events and death, as well as hospital admissions for heart failure, and new or worsening nephropathy.

Dr. David Cherney from Toronto General Hospital in Ontario, Canada and colleagues added that the current analysis is the first to assess the effects of empagliflozin on urinary albumin-to-creatinine ratio (UACR).

At baseline, they had UACR data for 6,953 patients, of whom 59% had normoalbuminuria, 29% had microalbuminuria, and 11% had macroalbuminuria. On average, patients were treated with empagliflozin or placebo for 2.6 years and observed for 3.1 years. Blood pressure and lipids were well-managed, and about 80% of all subjects used a RAAS inhibitor.

At week 12, compared with placebo, empagliflozin slowed UACR progression in normoalbuminuric patients by 7% and reduced UACR by 25% in microalbuminuric patients and by 32% in macroalbuminuric patients, the authors report.

The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks.  About 35 days after treatment ended after 12 weeks, UACR remained lower in empagliflozin-treated patients with baseline microalbuminuria or macroalbuminuria but not for those with baseline normoalbuminuria.

With empagliflozin, patients were more likely to see sustained improvement from microalbuminuria to normoalbuminuria (P<0.0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (P<0.0001), and less likely to experience sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (P=0.0077), the authors say.

The authors concluded that, “The effect of empagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control. These results suggest a persistent renal hemodynamic effect of empagliflozin, which may confer short-term and long-term renal effects on UACR when used in addition to current standard of care,” they conclude.

The authors note that because the greatest renal benefits were seen in patients with macroalbuminuria, patients with advanced chronic kidney disease might benefit most from SGLT2 inhibition, “a hypothesis that requires further study. It also lends support to the belief that albuminuria is a reasonable surrogate of eGFR decline in type 2 diabetes, and UACR lowering (on top of RAAS inhibition) is a viable target for therapy that might translate into reduced rates of renal (and possibly cardiovascular) events in patients with diabetic kidney disease,” they write.

From the results, it was concluded that the results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients’ albuminuria status at baseline.

Practice Pearls:

  • Urinary albumin-to-creatinine ratio progression slowed by 7%, 25%, and 32% at week 12 among normoalbuminuric, microalbuminuric and macroalbuminuric type 2 diabetes patients with cardiovascular disease, respectively, after treatment with the SGLT2 inhibitor empagliflozin,
  • Patients were more likely to see sustained improvement from microalbuminuria to normoalbuminuria and from macroalbuminuria to microalbuminuria.
  • These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients’ albuminuria status at baseline.

george_bakrisDr. Bakris comments: The paper by Cherney et.al., while interesting, doesn’t make as definitive a statement as implied. First microalbuminuria is a CV risk marker and not indicative of kidney disease (Bakris and Molitch Diabetes Care, 2014). Almost every study done with glucose-lowering agents has shown reductions in microalbuminuria. This is no way implies renal benefit. However, reduction of macroalbuminuria, which is established kidney disease, is important and suggests some potential long-term benefit on kidney function as has been documented in all renal outcome trials powered for events. No other class of glucose-lowering therapy has shown this effect in people with low eGFRs and >300 mg/day of albuminuria. Hence, the benefit of this SGLT2 on CV events and potential benefit on renal outcomes can be anticipated by changes seen in this marker. We await the results of CREDENCE for the definitive answer.

George Bakris, MD
Professor of Medicine
Director, ASH Comprehensive Hypertension Center
University of Chicago Medicine

Lancet Diabetes Endocrinol 2017