Review: Dapagliflozin increases, and empagliflozin reduces, adverse renal events in type 2 diabetes

A meta-analysis compared renal events in randomized controlled trials (RCTs) of sodium–glucose co-transporter-2 (SGLT2) inhibitors for patients with type 2 diabetes. It included 23 RCTs with dapagliflozin, 19 with empagliflozin, 15 with canagliflozin, and one with luseogliflozin. Compared to placebo, dapagliflozin was found to increase risk for adverse renal events, while empagliflozin reduced renal events compared with placebo, canagliflozin, and dapagliflozin.

The study was published by Diabetes, Obesity and Metabolism online March 31 and in the August issue. The following commentary by John T. Nguyen, MD, and Donald A. Molony, MD, ACP Member, was published in the ACP Journal Club section of the July 18 Annals of Internal Medicine.

Renal disease is one of the most common adverse consequences of uncontrolled type 2 diabetes, especially when complicated by proteinuria and morbid obesity. One of the central tenets of management of patients with type 2 diabetes and chronic kidney disease (CKD) is to use “renal protective” agents that treat diabetes and potentially reduce renal failure. SGLT2 inhibitors reduce renal glucose reabsorption and improve glycemic control in patients with type 2 diabetes.

In their network and cumulative meta-analysis, Tang and colleagues address the fundamental question of whether SGLT2 inhibitors worsen or improve renal outcomes. Their finding of opposite renal effects with different SGLT2 inhibitors cannot be explained by a class effect where renal failure may be induced by glycosuria, hypovolemia, and renal ischemia, nor by differential hepatic versus renal metabolism. Given that sensitivity analyses found similar results in subgroups without CKD and in white patients only, it seems that the findings cannot be explained by patient heterogeneity.

The two most plausible explanations for the observed differences in renal outcomes with empagliflozin compared with dapagliflozin and canagliflozin are that either empagliflozin has direct renal protective properties or the trial's data do not accurately reflect the true occurrence of adverse renal outcomes. In the latter case, an apparent renal protection may result from ascertainment bias. The observed renal protective effect of empagliflozin in the meta-analysis is largely driven by the results of the EMPA-REG OUTCOME study. In this RCT, a doubling of creatinine levels, an estimated glomerular filtration rate <45 mL/min/1.73 m², or need for renal replacement therapy were classified as renal events. Clinically significant but less severe renal failure was not identified as an adverse event. Further, the rate of renal failure might have been skewed by the 23% of study patients who prematurely discontinued their medication.

Despite a rigorous systematic review and meta-analysis, the findings by Tang and colleagues that empagliflozin might confer renal protection need to be confirmed with RCTs designed specifically to evaluate the effect of SGLT2 inhibitors on renal prognosis in patients with and without CKD. The current review does not provide sufficiently compelling evidence to support the use of empagliflozin as the preferred SGLT2 inhibitor in patients with type 2 diabetes who have, or are at risk for, CKD.