EMPA-REG OUTCOME trial was the first positive FDA-mandated cardiovascular (CV) outcome study for anti-hyperglycemia medicine reported last fall.1 Yet, concerns remain as per whether empagliflozin, as one of the sodium-glucose transporter 2 inhibitors (SGLT2i) that primarily exert glucose-lowering effect on kidney, may be associated with long-term adverse renal effects.
“Long-term renal effect of empagliflozin is a pre-specified component of the EMPA-REG OUTCOME trial”, mentioned Christoph Wanner, MD, Professor and Head of Nephrology, University Hospital of Würzburg, Germany, who presented the detailed renal findings at the Scientific Sessions 2016 of American Diabetes Association on June 14,2 and wrote the trial article simultaneously published in the New England Journal of Medicine.3
“Kidney disease develops in approximately 35% of patients with type 2 diabetes and is associated with increased mortality”, Professor Wanner pointed out2,3 and thus, it is necessary to assess the renal outcomes for antidiabetic medicine, not just for safety but efficacy.
In the randomized EMPA-REG OUTCOME trial, 7,020 patients with established CV disease and an estimated glomerular filtration rate (eGFR) of ≥30ml/min/1.73m2 were given empagliflozin 10 mg or 25 mg or placebo once daily in addition to standard care. In this new analysis of secondary composite microvascular endpoint, renal outcomes – worsening nephropathy defined as the progression to macroalbuminuria [urinary albumin-to-creatinine ratio (uACR) >300mg/g], a doubling of serum creatinine (Scr) level, the initiation of renal replacement therapy (RRT) or renal death were assessed.
At baseline, 17.8% and 7.7% of patients had CKD3a (eGFR: 45- 59ml/min/1.73m2) and CKD3b (eGFR: 30-44); 28.7% and 11.0% of patients had microalbuminuria and macroalbuminuria respectively. 80.7% of patients were taking ACEi or ARB.
Slowing kidney disease progression with benefits primarily driven by reduction of new onset albuminuria2,3
With a median follow-up of 3.1 years, an overall of 39% risk reduction for both composite of worsening nephropathy or CV death (16.2% vs 23.6%, HR=0.61, 95%CI:0.55-0.69, p<0.001) and composite worsening nephropathy (12.7% vs 18.8%, HR=0.61, 95%CI:0.53- 0.70, p<0.001) were observed in patients with empagliflozin versus on placebo. Favourable outcomes were seen for all component renal events – 38% reduction for progression to macroalbuminuria (11.2% vs 16.2%, p<0.001), 44% reduction for doubling Scr (5.5% vs 9.7%, p>0.001), 55% reduction in initiating RRT (1.0% vs 2.1%, p=0.04) except renal death (3 cases vs 0 case). Though renal benefit was primarily driven by the reduction of albuminuria, the observed renal benefits remained significant in the post-hoc sensitivity analysis that removed incidence for progression to macroalbuminuria, (HR=0.54, 95%CI:0.40-0.75, p<0.001).
In the subgroup analysis, patients with prevalent kidney disease had 42% lowered risk when assigned empagliflozin compared with placebo (HR=0.58, 95%CI: 0.47-0.71; p<0.001) for incident or worsening nephropathy.
Furthermore, empagliflozin was non-inferior to placebo with respect to incident or worsening nephropathy (51.5% vs 51.2%; HR=0.95, 95%CI:0.87-1.04, p=0.25) regardless of eGFR, uACR, sex, age older or younger than 65 years, race, diabetes duration, HbA1c level, BMI, BP control, and use of other diabetes and antihypertensive medications.
Overall stable renal function after an initial decline on empagliflozin2,3
Empagliflozin, like other SGLT2is, produced a short-term decrease in eGFR (weekly change of -0.62±0.04 and -0.82±0.04ml/ min/1.73m2 for dosing at 10 mg and 25 mg respectively) for the first 4 weeks, followed by eGFR stabilization (annual change of -0.19±0.11ml/min/1.73m2) over 4 years. “This contrasted to the overall decline of eGFR (annual change of -1.67±0.13ml/min/1.73m2) which reflected the natural progression of kidney disease as you would expect in type 2 diabetes”, Professor Wanner noted.
The mechanism for favourable renal outcome remains to be ascertained but the hemodynamic effect of empagliflozin and other SGLT2is have been reported. A lowering of glomerular hypertension may play an important role.
The study uncovered no new safety signals related to hypoglycemia, diabetic ketoacidosis, thromboembolic events, bone fractures, or volume depletion. Rates of overall adverse events, serious adverse events, and adverse events leading to treatment discontinuation were similar across groups. Rates of complicated UTIs did not significantly vary regardless of having impaired kidney function (CKD3 or not) at baseline. Although empagliflozin was associated with higher rate of urosepsis, these events were rare, affecting only 0.3% and 0.7% of patients with baseline CKD and 0.1% and 0.2% of patients without baseline CKD.
“The magnitude of the renal effect associated with empagliflozin was consistent with respect to the competing risk of death from cardiovascular causes and across pre-specified subgroups, including patients with prevalent kidney disease”, summarized Professor Wanner. “These results were particularly noteworthy, especially that patients involved were well-managed with extensive use of renoprotective RAAS blockers.”3
One key message from this new analysis is that “empagliflozin slows kidney disease progression in lower range of renal function (eGFR 30-60ml/min/1.73m2) despite being metabolized by the kidney”, highlighted Professor Wanner.2 However, the study authors recognized that these renal benefits cannot necessarily be generalized to T2D patients at lower CV risk.3
When discussing these findings, “the absolute differences are relatively small and the number needed to treat with empagliflozin to achieve renal benefits was 200”, pointed out William Herman, MD, professor of epidemiology and of internal medicine at University of Michigan, “cost may be a huge issue too.” However, he agreed that empagliflozin in combination with metformin “is a reasonable option for initial dual therapy in patients with type 2 diabetes and CVD, though we still don’t know its exact role”. “But I think it is clear that empagliflozin may be a preferred treatment for older adults with type 2 diabetes and CVD”, he concluded.4
Similarly to LEADER results, these findings “are encouraging, yet not a ‘home run’ with regard to the management of diabetes” wrote Drs Julie R Ingelfinger and Clifford J Rosen, MD from Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, in the accompanying editorial published in the New England Journal of Medicine. More controlled and comparative effectiveness trials that combine newer agents with older agents may help to delineate more effective treatment plan for people with type 2 diabetes.5