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Meta-Analysis
. 2022 Mar 23;21(1):47.
doi: 10.1186/s12933-022-01476-x.

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis

Arnaud D Kaze  1 , Min Zhuo  2   3   4   5 , Seoyoung C Kim  2   3 , Elisabetta Patorno  2   3 , Julie M Paik  6   7   8   9
Affiliations
Meta-Analysis

Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: a meta-analysis

Arnaud D Kaze et al. Cardiovasc Diabetol. .

Abstract

Background: We conducted a systematic review and meta-analysis of the cardiovascular, kidney, and safety outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) among patients with diabetic kidney disease (DKD).

Methods: We searched electronic databases for major randomized placebo-controlled clinical trials published up to September 30, 2021 and reporting on cardiovascular and kidney outcomes of SGLT2i in patients with DKD. DKD was defined as chronic kidney disease in individuals with type 2 diabetes. Random-effects meta-analysis models were used to estimate pooled hazard ratios (HR) and 95% confidence intervals (CI) for clinical outcomes including major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke, and cardiovascular death), kidney composite outcomes (a combination of worsening kidney function, end-stage kidney disease, or death from renal or cardiovascular causes), hospitalizations for heart failure (HHF), deaths and safety events (mycotic infections, diabetic ketoacidosis [DKA], volume depletion, amputations, fractures, urinary tract infections [UTI], acute kidney injury [AKI], and hyperkalemia).

Results: A total of 26,106 participants with DKD from 8 large-scale trials were included (median age: 65.2 years, 29.7-41.8% women, 53.2-93.2% White, median follow-up: 2.5 years). SGLT2i were associated with reduced risks of MACE (HR 0.83, 95% CI 0.75-0.93), kidney composite outcomes (HR 0.66, 95% CI 0.58-0.75), HHF (HR 0.62, 95% CI 0.55-0.71), cardiovascular death (HR 0.84, 95% CI 0.74-0.96), MI (HR 0.78, 95% CI 0.67-0.92), stroke (HR 0.76, 95% CI 0.59-0.97), and all-cause death (HR 0.86, 95% CI 0.77-0.96), with no significant heterogeneity detected. Similar results were observed among participants with reduced estimated glomerular filtration rate (eGFR: < 60 mL/min/1.73m2). The relative risks (95% CI) for adverse events were 3.89 (1.42-10.62) and 2.50 (1.32-4.72) for mycotic infections in men and women respectively, 3.54 (0.82-15.39) for DKA, and 1.29 (1.13-1.48) for volume depletion.

Conclusions: Among adults with DKD, SGLT2i were associated with reduced risks of MACE, kidney outcomes, HHF, and death. With a few exceptions of more clear safety signals, we found overall limited data on the associations between SGLT2i and safety outcomes. More research is needed on the safety profile of SGLT2i in this population.

Keywords: Cardiovascular outcomes; Diabetic kidney disease; Kidney outcomes; Meta-analysis; SGLT2 inhibitors; Safety.

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Conflict of interest statement

No potential conflicts of interest relevant to this article were reported. EP is principal investigator of an investigator-initiated grant to the Brigham and Women’s Hospital from Boehringer Ingelheim, not related to the topic of the submitted work. SK has received research grants to the Brigham and Women’s Hospital from Pfizer, AbbVie, Roche and Bristol-Myers Squibb for studies not related to the topic of the submitted work.

Figures

Fig. 1
Fig. 1
Effects of SGLT2 inhibitors on major adverse cardiovascular events (A) and kidney composite outcomes (B) among individuals with diabetic kidney disease. CANVAS indicates Canagliflozin Cardiovascular Assessment Study, CI confidence interval, CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, DECLARE‐TIMI 58 Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58, EMPA‐REG OUTCOME Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients, I2 I-squared, MACE major adverse cardiovascular event, NR not reported, SCORED Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk, SGLT2 sodium-glucose cotransporter 2, VERTIS CV Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial
Fig. 2
Fig. 2
Effects of SGLT2 inhibitors on safety outcomes among individuals with diabetic kidney disease. CANVAS indicates Canagliflozin Cardiovascular Assessment Study, CI confidence interval, CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, eGFR estimated glomerular filtration rate, EMPA‐REG OUTCOME Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients, NR not reported; SCORED Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2, sodium-glucose cotransporter 2
Fig. 2
Fig. 2
Effects of SGLT2 inhibitors on safety outcomes among individuals with diabetic kidney disease. CANVAS indicates Canagliflozin Cardiovascular Assessment Study, CI confidence interval, CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, eGFR estimated glomerular filtration rate, EMPA‐REG OUTCOME Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients, NR not reported; SCORED Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2, sodium-glucose cotransporter 2
Fig. 2
Fig. 2
Effects of SGLT2 inhibitors on safety outcomes among individuals with diabetic kidney disease. CANVAS indicates Canagliflozin Cardiovascular Assessment Study, CI confidence interval, CREDENCE Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, eGFR estimated glomerular filtration rate, EMPA‐REG OUTCOME Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients, NR not reported; SCORED Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2, sodium-glucose cotransporter 2
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