Pooled analysis shows no new safety concerns of SGLT2i in T2DM patients with CKD
Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials
Introduction and methods
Several clinical guidelines recommend the use of an SGLT2i in patients with T2DM and CKD [1,2]. However , recommendation for eGFR levels at which SGLT2i can be initiated or should be discontinued vary between agents, and labeling for agents may vary between countries and regions. Knowing that approximately 40% of T2DM patients will eventually develop CKD [3,4], it is interesting that the SGLT2i empagliflozin has been shown to reduce the onset and progression of CKD in T2DM . But what are the safety risks of empagliflozin use if T2DM patients already have CKD?
Aim of the study
The study aim was to assess the safety of empagliflozin in T2DM patients with moderate to severe CKD (category G3-4) who were enrolled in earlier RCTs on the effect of empagliflozin versus placebo.
The authors pooled data from 19 randomized, placebo-controlled, phase 1–4 clinical trials and 1 randomized, placebo-controlled extension study in which T2DM patients received 10 or 25 mg empagliflozin or placebo daily. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (2009).
The outcome was the time to the first occurrence of investigator-reported adverse events (AEs).
T2DM patients with CKD
- Of the 15,081 patients who received at least one study drug dose, 1522 were classified at baseline as having CKD category G3A (eGFR: 45–59 mL/min per 1.73 m2), 722 as category G3B (eGFR: 30–44 mL/min per 1.73 m2), and 123 as category G4 (eGFR: <30 mL/min per 1.73 m2).
- Incidence rates of serious AEs and AEs leading to discontinuation were similar between the empagliflozin and placebo groups, both overall and across CKD subgroups.
- Although in the category G4 group, the rate of serious AEs was numerically higher for empagliflozin (41.31 per 100 patient-years; 95% CI: 27.46–59.69) than for placebo (29.93 per 100 patient-years; 95% CI: 15.94–51.17), 95% CIs were wide and patient numbers in this group were low (52 and 71 patients, respectively).
- The rate of events of special interest (including lower limb amputations and acute renal failure) was also similar between the two treatment groups overall and across CKD subgroups. An exception was a higher overall incidence of genital infections in the empagliflozin group (3.54 per 100 patient-years; 95% CI: 3.25–3.84) than in the placebo group (0.85 per 100 patient-years; 95% CI: 0.75–1.20), which was to be expected as genital infections are a well-recognized side effect of SGLT2is [6-8].
- Of note, incidence rates of genital infections were progressively lower across CKD categories G3A, G3B, and G4 in both treatment groups, whereas most other AEs were more frequent among patients with higher CKD categories.
- Risk of hyperkalemia was lower for empagliflozin versus placebo in the G3A group (hazard ratio (HR): 0.48; 95% CI: 0.26–0.91; P = 0.0243) and in the combined G3B–G4 group (HR: 0.59; 95% CI: 0.37–0.96; P = 0.0323), based on adjusted Cox regression analysis.
- Edema risk was also lower for empagliflozin versus placebo treatment in patients with CKD (HR for G3A group: 0.44; 95% CI: 0.28–0.68; P = 0.0002; HR for G3B–G4 group: 0.47; 95% CI: 0.33–0.68; P < 0.0001) , while risks of volume depletion and acute renal failure were similar between empagliflozin and placebo in both the G3A and G3B–G4 groups.
In a comprehensive safety analysis, treatment with empagliflozin did not result in an overall increased risk of serious AEs, AEs leading to discontinuation, or events of special interest compared with placebo in T2DM patients with moderate to severe CKD, irrespective of baseline eGFR. In addition, empagliflozin may have beneficial effects on the development of hyperkalemia and edema in these patients.