Sweetening the Deal: Effects of SGLT-2 Inhibitors on Kidney Disease Progression

Approximately one in three patients with diabetes in the United States have chronic kidney disease (CKD).¹ As CKD is progressive and irreversible, the goal is to slow its progression.  In addition to controlling blood pressure and blood glucose, clinical practice guidelines recommend the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs).² However, these agents are contraindicated in patients who develop intolerance or persistent hyperkalemia.

Sodium-Glucose Cotransporter-2 inhibitors (SGLT-2i) are a newer class of anti-diabetic agents.  Currently approved agents in the U.S. include canagliflozin, dapagliflozin, and empagliflozin. This class exerts anti-hyperglycemic effects through blockade of SGLT-2 in the renal proximal tubules, causing reduced tubular reabsorption of glucose, increased urinary excretion of glucose, and decreased plasma glucose concentrations.³ The Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, first published in Fall 2015, demonstrated a reduction in cardiovascular and all-cause mortality in patients treated with empagliflozin.⁴ [See The Heart of the Matter — Is EMPA-REG a Game Changer for Diabetes Mnagement?]  More recent data from the EMPA-REG OUTCOME trial suggests that empagliflozin may also confer significant renal protection.⁵

EMPA-REG OUTCOME was a randomized, double-blind, placebo controlled, multicenter trial with the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke as the primary outcome. The renal outcomes data from the EMPA-REG OUTCOME study are from a pre-specified, secondary analysis of microvascular endpoints.⁵ Power calculations were not performed for this pre-specified analysis, risking type II error. The microvascular composite outcome consisted of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy. Incident or worsening nephropathy was defined as progression to macroalbuminuria (urinary albumin to creatinine ratio, >300 mg of albumin per gram of creatinine); a doubling of the serum creatinine accompanied by an estimate glomerular filtration rate (eGFR) of ≤45 mL/min/1.73 m² (using the MDRD formula); the initiation of renal replacement therapy; or death from renal disease. Other renal outcomes reported included the separate components of nephropathy as well as incident albuminuria. Patients enrolled in the EMPA-REG study had type 2 diabetes, a BMI≤45 kg/m², and eGFR ≥30ml/min/1.73m². Patients were also required to have pre-existing cardiovascular disease but were excluded if they had a history of stroke, transient ischemic attack, or acute coronary syndrome in the two months preceding study enrollment. Treatment naïve patients with an initial A1c of 7-9% and patients on stable therapy with an A1c of 7-10% were enrolled.⁴

In total, 7,020 patients from 590 sites around the globe received at least one dose of placebo (n=2,068) or empagliflozin (n=4,132). Baseline eGFR was greater than 60 mL/min/1.73 m² in the majority of patients but 17.8% had an eGFR between 45-59 mL/min/1.73 m² and another 7.7% had an eGFR between 30-44 mL/min/1.73 m² calculated using CKD-EPI. Of those receiving empagliflozin, 28.7% had microalbuminuria and 11.0% had macroalbuminuria at baseline. Over 80% of patients were treated with ACEi or ARBs. Median treatment duration was 2.6 years and median follow up was 3.1 years.⁵

The composite microvascular endpoint occurred in 14% of patients in the empagliflozin group compared to 20.5% in the placebo group, representing an absolute risk reduction (ARR) of 6.5% and a number needed to treat (NNT) = 16 (p<0.001). Incident or worsening nephropathy occurred in 12.7% and 18.8% of patients in the empagliflozin and placebo groups, respectively. Other significant renal outcomes include incident/worsening nephropathy or cardiovascular death (ARR = 7.4%, NNT = 14), progression to macroalbuminuria (ARR = 5%, NNT = 20), doubling of serum creatinine and eGFR <45mL/min/1.73m² (ARR = 4.2%, NNT = 24, p<0.001 for all). The rate of initiation of renal replacement therapy was also reduced (ARR = 0.3%, NNT = 334, p<0.04). Annual rates of eGFR decline were also lower in the empagliflozin groups compared to placebo (0.19 +/- 0.11 vs 1.67 +/- 0.13ml/min/1.73m² ; p<0.001). However, the study found no difference in the number of patients with incident albuminuria.⁵ This result may have been due to a type II error.

Adverse outcomes included a treatment-associated decrease in eGFR (mean reduction ~5 mL/min/1.73m²) that improved after discontinuation of study drug. Genital infections occurred more frequently in those treated with empagliflozin (1.8% placebo vs 6.4% empagliflozin p<0.001). The rate of acute kidney injury (AKI) was significantly lower in the empagliflozin group (1.6% vs 1.0%; p<0.05).  This findings contrasts with recent FDA warnings for AKI with other SGLT-2 inhibitors.⁶

These data have strong implications regarding the treatment of the progression of CKD in patients with type 2 diabetes. Use of empagliflozin in this study at either the 10 mg or 25 mg once daily dose conferred kidney protection, decreased annual eGFR loss, reduced the incidence and worsening of nephropathy, and reduced the rates of progression to macroalbuminuria and the need for renal replacement therapy. The renal outcomes seen here are strengthened by the fact that approximately 80% of patients were on an ACE inhibitor or ARB at baseline. Also, approximately three quarters of the patients included in the study were treated with metformin at baseline, demonstrating an added benefit of empagliflozin to guideline-recommended therapy.

Strengths of this study are the randomized, double-blind, multi-center trial design, large sample size, and the concomitant use of guideline recommended therapies. Limitations include generalizability to patients at lower cardiovascular risk, non-whites, and women. The study population consisted of patients with established cardiovascular disease and was largely comprised of white men. Also, the effects of long-term use beyond 3 years are unknown.

The findings of this trial indicate that empagliflozin is an effective therapeutic strategy in patients with diabetes and established cardiovascular disease to prevent cardiovascular and renal morbidity. With a wholesale acquisition cost (WAC) of $13 per tablet, empagliflozin is comparable to other brand name oral antidiabetes agents. These data should not be extrapolated to other SGLT-2 inhibitors. However, large cardiovascular outcomes trials are ongoing for canagliflozin and dapagliflozin.⁷

Application of these findings requires individualized patient considerations. Those with a high risk for genital or urinary tract infections may not be appropriate candidates. Patients should be adequately educated on other risks, especially how to recognize and what to do in the case of euglycemic diabetic ketoacidosis induced by empagliflozin. Empagliflozin does not carry the warning for AKI like other SGLT2i and EMPA-REG data showed a reduction in AKI when compared to placebo. However, it is plausible that empagliflozin may lead to AKI through decreased glomerular capillary pressure and depleted intravascular volume.⁵ Accordingly, patients should be monitored for changes in serum creatinine and fluid status at baseline and after initiation – as was done in the EMPA-REG study. With proper patient selection and monitoring, empagliflozin use sweetens the deal.  Should empagliflozin become the preferred add-on therapy with metformin?  What do you think?