Class effects of SGLT2 inhibitors on cardiorenal outcomes

Abstract

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.

Keywords: Albuminuria; CANVAS; CREDENCE; Canagliflozin; Cardiovascular death; Cardiovascular outcome trials; Chronic kidney disease; DECLARE-TIMI 58; Dapagliflozin; EMPA–REG OUTCOME; Empagliflozin; End-stage renal disease; Estimated glomerular filtration function; Heart failure hospitalization; Mortality; SGLT2 inhibitor.

Fig. 1

Baseline estimated glomerular filtration rates (eGFRs) and prior cardiovascular disease (CVD) rates in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Prior CVD displayed as incidence (percentage)

Fig. 2

Heart failure hospitalization (HHF), HHF and cardiovascular (CV) death, and major adverse cardiovascular event (MACE) event rates per 1000 patients in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Statistical outcomes displayed as hazard ratio, 95% confidence interval, p-value. HR hazard ratio, DAPA dapagliflozin, CANA canagliflozin, EMPA empagliflozin, PLB placebo

Fig. 3

Composite renal outcome rates in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Statistical outcomes displayed as hazard ratio, 95% confidence interval, p-value. Composite renal outcomes defined as follows: DECLARE-TIMI 58: ≥ 40% reduction in estimated glomerular filtration rate (eGFR) to < 60, end-stage renal disease (ESRD) (dialysis ≥ 90 days, transplant or sustained eGFR < 15), or renal/cardiovascular (CV) death; CANVAS: ≥ 40% reduction in eGFR, renal-replacement therapy (RRT) (transplant, chronic dialysis, or sustained eGFR < 15), or renal death; EMPA–REG OUTCOME: doubling of serum creatinine (Cr) with eGFR ≤ 45, RRT, or renal death; CREDENCE: doubling of serum Cr, ESRD (eGFR < 15, dialysis, or renal transplant), renal/CV death. HR hazard ratio, DAPA dapagliflozin, CANA canagliflozin, EMPA empagliflozin

Fig. 4

Heart failure hospitalization (HHF), HHF and cardiovascular (CV) death, and major adverse cardiovascular event (MACE) relative risk reductions (RRRs) in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Statistical outcomes displayed as RRR, p-value. RRRs were calculated from hazard ratios

Fig. 5

Composite renal outcome relative risk reductions (RRRs) in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Statistical outcomes displayed as RRR, p-value. RRRs were calculated from hazard ratios. Composite renal outcomes defined as follows: DECLARE-TIMI 58: ≥ 40% reduction in estimated glomerular filtration rate (eGFR) to < 60, end-stage renal disease (ESRD) (dialysis ≥ 90 days, transplant or sustained eGFR < 15), or renal/cardiovascular (CV) death; CANVAS: ≥ 40% reduction in eGFR, renal-replacement therapy (RRT) (transplant, chronic dialysis, or sustained eGFR < 15), or renal death; EMPA–REG OUTCOME: doubling of serum creatinine (Cr) with eGFR ≤ 45, RRT, or renal death; CREDENCE: doubling of serum Cr, ESRD (eGFR < 15, dialysis, or renal transplant), renal/CV death

Fig. 6

Baseline renal risk and composite renal outcome definitions in the 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), and Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trials. Horizontal dotted lines and white arrows approximate trials averaged mean eGFRs minus 1 pooled standard deviation; vertical dotted lines and white arrows approximate trials’ quartile 3 of UACR. Data displayed as mean eGFR ± standard deviation (where available); median UACR [quartile 1, quartile 3] or percent of study population with UACR < 30, > 30–300, and > 300 (depending on trial). eGFR estimated glomerular filtration rate in mL/min/1.73 m², UACR urinary albumin-creatinine ratio in mg/g (Adapted from Ref. [60])