SGLT2 inhibitors for non-diabetic kidney disease: drugs to treat CKD that also improve glycaemia

Abstract

Sodium-glucose co-transporter-2 (SGLT2) inhibitors decreased cardiovascular (CV) events and improved renal outcomes in CV safety studies in type 2 diabetes melitus (T2DM) patients at high CV risk. Canagliflozin also improved kidney outcomes in diabetic kidney disease in the Canagliflozin and Renal Events in Diabetes and Nephropathy Clinical Evaluationtrial. More recently, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial showed that dapagliflozin improved CV outcomes in patients with HF with or without diabetes. Protection from HF in non-diabetics was confirmed for empagliflozin in the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trial. A meta-analysis of DAPA-HF and EMPEROR-Reduced confirmed reductions in all-cause and CV death and the combined risk of CV death or worsening HF, as well as in the composite renal endpoint {hazard ratio [HR] 0.62 [95% confidence interval (CI) 0.43-0.90]} without differences based on the presence of diabetes or baseline estimated glomerular filtration rate (eGFR). Moreover, the Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (DAPA-CKD) showed that dapagliflozin as an add-on over renin-angiotensin system blockade in patients with chronic kidney disease (CKD; with or without T2DM) reduced the HR for the primary endpoint (time to the first occurrence of ≥50% eGFR decline, end-stage kidney disease or renal or CV death) to 0.61 (95% CI 0.51-0.72) and for the secondary endpoints of worsening renal function or death from kidney failure [HR 0.56 (95% CI 0.45-0.68)], hospitalization for HF or CV death [HR 0.71 (95% CI 0.55-0.92)] and all-cause mortality [HR 0.69 (95% CI 0.53-0.88)]. These beneficial effects were consistent in patients with and without T2DM. In conclusion, SGLT2 inhibitors offer CV and kidney protection in both diabetic and non-diabetic CKD and, additionally, improve glycaemic control in T2DM, making them first-line therapy for CKD independent from diabetic status.

Keywords: SGLT2 inhibitor; chronic kidney disease; clinical trials; mortality; outcomes.

FIGURE 1

Baseline kidney characteristics for RCTs assessing RAS blockade in CKD as well as RCTs assessing different aspects of SGLT2 inhibitors: CV safety in T2DM, kidney protection in T2DM, HF outcomes in HF patients with and without T2DM and kidney protection in CKD patients with and without T2DM. RCTs assessing patients with and without T2DM are labeled in red. The following SGLT2 inhibitors were tested: canagliflozin (CANVAS and CREDENCE), dapagliflozin (DECLARE, DAPA-HF and DAPA-CKD) and empagliflozin (EMPA-REG and EMPEROR-reduced). No baseline albuminuria data were available for DAPA-HF and EMPEROR-reduced.

FIGURE 2

Key outcomes of RCTs assessing SGLT2 inhibitors in patients with HF or CKD. Results are presented for the full population, which in some RCTs (DAPA-HF, DAPA-CKD and EMPEROR-reduced) was comprised of patients with T2DM and non-diabetic individuals and separately for diabetics and non-diabetics. The primary combined kidney endpoint in CREDENCE and DAPA-CKD consisted of CKD progression, as assessed by a doubling of serum creatinine (CREDENCE) or ≥50% eGFR decline (DAPA-CKD), end-stage kidney disease, renal death or CV death. The endpoint of CV death or hospitalization for HF was the primary endpoint in HF trials (DAPA-HF and EMPEROR-reduced). The following SGLT2 inhibitors were tested: canagliflozin (CREDENCE), dapagliflozin (DAPA-HF and DAPA-CKD) and empagliflozin (EMPEROR-reduced).

FIGURE 3

Current status and key future developments in the study of SGLT2 inhibitors and CV and kidney benefit. Coloured parts indicate populations in whom cardio- and nephroprotection have been demonstrated for SGLT2 inhibitors: dark red for high CV risk, light brown for CKD and light red for HF. Thus colours highlight high CV risk, HF and CKD patients and their overlaps within the T2DM and the non-diabetic populations. Additionally, non-albuminuric CKD is indicated in green when CV and kidney benefit has been demonstrated in large clinical trials, as for non-albuminuric CKD in T2DM patients within HF and high CV risk trials or non-diabetic patients with HF. However, no data are available regarding CV or kidney benefit in non-diabetic patients with CKD and an absence of HF, thus a white (non-coloured) spot is placed over patients with non-albuminuric CKD who are not diabetic and do not have HF. Additionally, there is no information on potential CV or renal benefits in T1DM patients. EMPA-REG will expand data from currently available trial results by exploring T1DM and non-albuminuric CKD in persons without diabetes. Of note, CV and kidney benefit has been observed up to now for populations with an eGFR ≥20 mL/min/1.73 m² in the context of HF and EMPA-REG will also enroll CKD patients with an eGFR ≥20 mL/min/1.73 m².