SGLT-2 Inhibitors and Chronic Kidney Disease
The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was the first trial focusing primarily on the renal outcomes with SGLT-2 inhibitors. It evaluated whether canagliflozin confers a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with T2DM, established CKD and macroalbuminuria, who are receiving the standard of care including a maximum ACEi or ARB (Perkovic 2019). In this trial, the risk of the primary outcome (composite of end-stage kidney disease—ESKD, doubling of serum creatinine, or renal or cardiovascular death) was 30% lower in patients treated with canagliflozin compared to placebo (Figure 21, Perkovic 2019).
In addition, canagliflozin was associated with a lower risk of cardiovascular death, myocardial infarction, or stroke, and hospitalization for heart failure compared to placebo; while being relatively safe (no differences in amputation rates or fractures) over a median follow-up period of 2.6 years (Figs 22 & 23, Perkovic 2019). ). Based on CREDENCE results, recently the FDA expanded the indication of canagliflozin to reduce the risk of end-stage kidney disease (ESKD), worsening of kidney function, CV death, and hospitalization for HF in adults with T2DM and DKD, making it the first T2DM therapy with an indication to treat both DKD and reduce HF hospitalization risk in this patient population (Cherney 2019).
A recent meta analysis of the major trials with SGLT-2 inhibitors, encompassing the EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and CREDENCE, showed that benefits of SGLT-2 inhibition on renal outcomes are consistent regardless of baseline eGFR (Figure 24, Dekkers 2020).
Several large phase III trials with SGLT-2 inhibitors in patients with chronic kidney disease are ongoing. These include the DAPA-CKD and EMPA-KIDNEY trials, which have enrolled patients with and without diabetes (Figure 25). These trials are due to report soon; in fact, the DAPA-CKD trial was stopped early in March 2020 due to overwhelming efficacy, and in July 2020 it was announced that the primary and secondary endpoints of the trial were met, with full results still need to be presented.
