Cardiorenal outcomes with sodium/glucose cotransporter-2 inhibitors in patients with type 2 diabetes and low kidney risk: real world evidence

Abstract

Background Randomized controlled trials showed that sodium/glucose cotransporter-2 inhibitors (SGLT2i) protect the heart and kidney in an array of populations with type 2 diabetes (T2D) and increased cardiorenal risk. However, the extent of these benefits also in lower kidney-risk T2D populations needs further investigation. Methods Members of Maccabi Healthcare Systems listed in their T2D registry who initiated new glucose lowering agents (GLA), were divided into SGLT2i initiators and other GLAs (oGLAs). Groups were propensity score-matched by baseline demographic and medical characteristics. Two composite cardiovascular outcomes were defined: all-cause mortality (ACM) or hospitalization for heart failure (hHF); and ACM, myocardial infraction (MI) or stroke. The cardiorenal outcome was: ACM, new end-stage kidney disease (ESKD) or ≥ 40% reduction from baseline estimated glomerular filtration rate (eGFR). Renal-specific outcome was new ESKD or ≥ 40% eGFR reduction. Single components of cardiovascular and kidney outcomes were also assessed. Three subgroup definitions of low baseline kidney-risk were used: eGFR > 90 ml/min/1.73 m2; urinary albumin below detectable levels; and low risk according to Kidney Disease: Improving Global Outcomes (KDIGO) classification. Analyses were performed utilizing an unadjusted model, and a model adjusted to baseline eGFR and urinary albumin-to-creatinine ratio. Results Between April 1, 2015 and June 30, 2018; 68,187 patients initiated new GLAs — 11,321 SGLT2i initiators and 42,077 oGLAs initiators were eligible. Propensity score-matching yielded two comparable cohorts; each included 9219 participants. Median follow-up was 1.7 years. Compared to oGLAs, SGLT2i initiators had lower incidence of ACM or hHF [HR95%CI = 0.62(0.51–0.75)]; ACM, MI or stroke [0.67(0.57–0.80)]; the cardiorenal outcome [0.65(0.56–0.76)]; and the renal-specific outcome [0.70(0.57–0.85)]. SGLT2i initiators also had lower risk for ACM, hHF and ≥ 30%, ≥ 40%, ≥ 50%, ≥ 57% eGFR reduction. No difference between groups was observed for MI or stroke. In the low baseline kidney-risk subgroups, SGLT2i initiation was generally associated with lower risk of the cardiovascular and cardiorenal outcomes, driven mainly by lower ACM incidence. Conclusions Our findings in the general population of patients with T2D demonstrates lower risk of cardiorenal outcomes associated with initiation of SGLT2i compared with oGLAs, including specifically in patients with low baseline kidney-risk.

Preventing all‐cause hospitalizations in type 2 diabetes with sodium‐glucose cotransporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: A narrative review and proposed clinical approach

“…12 Position statements recommend DMD treatment independently of glucose control or background metformin use in patients with T2D and increased cardiorenal risk, [73][74][75] yet their use amongst appropriate patients remains low. 68,76,77 Cumulating post hoc analyses of RCTs and RWE suggest that DMDs can also improve prognosis in those with T2D and lower cardiorenal risks 17,24,25,40,[78][79][80][81][82][83] (Figures 1 and 2).…”

Challenges and opportunities in real‐world evidence on the renal effects of sodium‐glucose cotransporter‐2 inhibitors

“…Renal endpoints, defined by a reduction in eGFR by several different thresholds, or development of ESKD, occurred at a 30% to 50% lower rate among SGLT2 inhibitor initiators. 42 While regulatory agencies accept a 30% or 40% reduction in eGFR as a surrogate endpoint in trials exploring therapies for ESKD, 43 these endpoints may not be practical for patients in the early stages of CKD, 44 such as most of those prescribed with SGLT2 inhibitors in the clinical setting. In 2018, a workshop of the National Kidney Foundation, developed in collaboration with regulatory agencies, issued recommendations on the use of change in albuminuria and eGFR slope as alternative surrogate endpoints.…”

“…A minority of patients (8.5%) had a baseline eGFR of less than 60 mL/min/1.73 m 2 , and only one‐third had micro‐/macroalbuminuria. Renal endpoints, defined by a reduction in eGFR by several different thresholds, or development of ESKD, occurred at a 30% to 50% lower rate among SGLT2 inhibitor initiators 42 …”

“…Renal endpoints, defined by a reduction in eGFR by several different thresholds, or development of ESKD, occurred at a 30% to 50% lower rate among SGLT2 inhibitor initiators. 42 …”

Finerenone, a Novel and Safer Approach toward Management of Diabetic Kidney Disease with Heart Failure

“…In light of all the associated risks and complications, new and improved strategies are required to be developed for the prevention of such complications. [6] In recent years, novel therapeutic categories have been developed involving several drug classes such as sodium glucose cotransporter 2 (SGLT2) inhibitors, [7] glucagonlike peptide-1 (GLP-1) agonists, [8] dipeptidyl-peptidase-4 (DPP4) inhibitors, [9] and mineralocorticoid receptor antagonists (MRAs) [10,11] to improve cardiorenal outcomes in diabetic patients. SGLT2 inhibitors are found to be associated with decreased risks of cardiovascular events.…”