Class effects of SGLT2 inhibitors on cardiorenal outcomes
Aaron Y Kluger1,2, Kristen M Tecson3,4,5, Andy Y Lee6,7
1Baylor Heart and Vascular Institute, 621 N. Hall #H030, Dallas, TX, 75226, USA. Aaron.Kluger@BSWHealth.org.
Background:
To summarize the four recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials: Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58), CANagliflozin CardioVascular Assessment Study (CANVAS) Program, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and explore the potential determinants for their cardiovascular, renal, and safety outcomes.
Results:
The composite renal outcome event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 3.7, 7.0, 47%; 5.5, 9.0, 40%; 6.3, 11.5, 46%; 43.2, 61.2, 30% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively (event definitions varied across trials). The major adverse cardiovascular (CV) event rates per 1000 patient-years for drug and placebo, as well as the corresponding relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14%; 38.7, 48.7, 20% for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events and CREDENCE the most. These differences were presumably due to varying inclusion criteria resulting in DECLARE-TIMI 58 having the best baseline renal filtration function and CREDENCE the worst (mean estimated glomerular filtration rate 85.2, 76.5, 74, 56.2 mL/min/1.73 m2 for DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE, respectively). Additionally, CREDENCE had considerably higher rates of albuminuria (median urinary albumin-creatinine ratios (UACR) were 927, 12.3, and 13.1 mg/g for CREDENCE, CANVAS, and DECLARE-TIMI 58, respectively; EMPA-REG OUTCOME had 59.4% UACR < 30, 28.6% UACR > 30-300, 11.0% UACR > 300 mg/g).
Conclusions:
Dapagliflozin, empagliflozin, and canagliflozin have internally and externally consistent and biologically plausible class effects on cardiorenal outcomes. Baseline renal filtration function and degree of albuminuria are the most significant indicators of risk for both CV and renal events. Thus, these two factors also anticipate the greatest clinical benefit for SGLT2i.
Insights
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) show consistent cardiorenal benefits. Baseline kidney function and albuminuria predict SGLT2i treatment response in patients with type 2 diabetes.
Area of Science:
- Cardiology
- Nephrology
- Endocrinology
Background:
- Four major trials (DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, CREDENCE) evaluated sodium-glucose cotransporter 2 inhibitors (SGLT2i).
- These trials assessed cardiovascular, renal, and safety outcomes in patients with type 2 diabetes.
Purpose of the Study:
- To summarize findings from four key SGLT2i trials.
- To explore determinants of cardiovascular, renal, and safety outcomes with SGLT2i therapy.
Main Methods:
- Analysis of data from DECLARE-TIMI 58, CANVAS, EMPA-REG OUTCOME, and CREDENCE trials.
- Comparison of composite renal and major adverse cardiovascular event rates between drug and placebo groups.
- Evaluation of baseline estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) as risk indicators.
Main Results:
- SGLT2i demonstrated significant risk reductions for renal and cardiovascular events across trials, with varying event rates.
- DECLARE-TIMI 58 showed the fewest events, while CREDENCE had the most, linked to differences in baseline renal function (eGFR) and albuminuria.
- CREDENCE enrolled patients with worse renal function (mean eGFR 56.2 mL/min/1.73 m²) and higher albuminuria (median UACR 927 mg/g) compared to other trials.
Conclusions:
- SGLT2 inhibitors exhibit consistent class effects on cardiorenal outcomes.
- Baseline renal filtration function and albuminuria are key predictors of risk and clinical benefit for SGLT2i therapy.
- These factors highlight patient selection criteria for maximizing SGLT2i efficacy in cardiorenal protection.
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