Background: Contemporary guidelines recommend the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) independently of glycemic control in patients with type 2 diabetes and those with kidney disease, with heart failure, or at high risk of cardiovascular disease. Using a large Israeli database, we assessed whether long-term use of SGLT2is versus dipeptidyl peptidase 4 inhibitors (DPP4is) is associated with kidney benefits in patients with type 2 diabetes overall and in those without evidence of cardiovascular or kidney disease. Methods: Patients with type 2 diabetes who initiated SGLT2is or DPP4is between 2015 and 2021 were propensity score-matched (1:1) according to 90 parameters. The kidney-specific composite outcome included confirmed ≥40% decline in eGFR or kidney failure. The kidney-or-death outcome included also all-cause mortality. Risks of outcomes were assessed using Cox proportional hazard regression models. The between-group difference in eGFR slope was also assessed. Analyses were repeated in patients' subgroup lacking evidence of cardiovascular or kidney disease. Results: Overall, 19,648 propensity score-matched patients were included; 10,467 (53%) did not have evidence of cardiovascular or kidney disease. Median follow-up was 38 months (interquartile range, 22–55). The composite kidney-specific outcome occurred at an event rate of 6.9 versus 9.5 events per 1000 patient-years with SGLT2i versus DPP4i. The respective event rates of the kidney-or-death outcome were 17.7 versus 22.1. Compared with DPP4is, initiation of SGLT2is was associated with a lower risk for the kidney-specific (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.61 to 0.86; P < 0.001) and kidney-or-death (HR, 0.80; 95% CI, 0.71 to 0.89; P < 0.001) outcomes. The respective HRs (95% CI) in those lacking evidence of cardiovascular or kidney disease were 0.67 (0.44 to 1.02) and 0.77 (0.61 to 0.97). Initiation of SGLT2is versus DPP4is was associated with mitigation of the eGFR slope overall and in those lacking evidence of cardiovascular or kidney disease (mean between-group differences 0.49 [95% CI, 0.35 to 0.62] and 0.48 [95% CI, 0.32 to 0.64] ml/min per 1.73 m² per year, respectively). Conclusions: Long-term use of SGLT2is versus DPP4is in a real-world setting was associated with mitigation of eGFR loss in patients with type 2 diabetes, even in those lacking evidence of cardiovascular or kidney disease at baseline.

This study of real‐world data from the Maccabi database in Israel compared the risk of heart failure hospitalization (HHF) or death in patients with type 2 diabetes (T2D) initiating sodium‐glucose cotransporter‐2 (SGLT2) inhibitors versus other glucose‐lowering drugs (OGLDs) according to baseline left ventricular (LV) ejection fraction (EF). After propensity‐matching patients by baseline EF there were 10 614 episodes of treatment initiation; 57% had diabetes for >10 years, the mean glycated haemoglobin level was 66 mmol/mol (8.2%), ∼43% had cardiovascular disease, ∼7% had heart failure and ∼ 20% had chronic kidney disease. A total of 2876 patients (∼9%) had reduced EF (<50%). Over a mean follow‐up of 1.5 years there were 371 HHFs or deaths, 88 (23.7%) in patients with reduced EF. Initiation of SGLT2 inhibitors versus OGLDs was associated with lower risk of HHF or death overall (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.46‐0.70]; P < 0.001) and in patients with both reduced EF (HR 0.61, 95% CI 0.40‐0.93) and preserved EF (HR 0.55, 95% CI 0.43‐0.70), with no significant heterogeneity ( P _interaction = 0.72). Our findings from real‐world clinical practice show that the lower risk of HHF and death associated with use of SGLT2 inhibitors versus OGLDs is consistent in T2D patients with both reduced and preserved EF.

Aim: To examine the renal effects of sodium‐glucose cotransporter‐2 (SGLT2) inhibition among non‐diabetic individuals with chronic kidney disease (CKD) in a real‐world setting. Methods: We collected de‐identified data on adults without diabetes and with an estimated glomerular filtration rate (eGFR) of 25–60 mL/min/1.73 m ² , who initiated the SGLT2 inhibitors dapagliflozin or empagliflozin between September 2020 and November 2022 at Maccabi Healthcare Services, an Israeli health maintenance organization. We assessed the effects of SGLT2 inhibitors on renal function (changes in eGFR slope/time). Index date was defined as the date of the first dispensing of SGLT2 inhibitors. Annual baseline slope was calculated using all eGFR measurements during the 2 years prior to index date (median = 7 measurements), while annual follow‐up slope was calculated from all evaluations during 90–900 days post index date, along with baseline measurement at index date (median = 6 measurements). Paired t tests were used to compare differences between baseline and follow‐up annual slopes. Results: Of a total of 354 participants with CKD, without diabetes, who received SGLT2 inhibitors and were followed for a median of 527 days, the mean age was 72.8 ± 11.8 years, 26% were female, and 91% used renin‐angiotensin system blockade. The mean eGFR was 45.4 ± 9.5 mL/min/1.73 m ² . The mean body mass index was 29.1 ± 5.4 kg/m ² . During the year before index date, 146 participants (41%) had a urinary albumin to creatinine ratio (UACR) 300 mg/g, and 53 (15%) had no UACR evaluation. The mean eGFR slope over time was −5.6 ± 7.7 mL/min/1.73 m ² per year at baseline, which improved to −1.7 ± 6.8 mL/min/1.73 m ² per year after SGLT2 inhibitor administration ( p <0.001). This effect was independent of UACR. Conclusion: In a real‐world study of primarily older non‐diabetic adults with CKD, SGLT2 inhibition was associated with a slower rate of kidney function decline, regardless of baseline UACR level.