Table 10.3C

Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: SGLT2 inhibitors

EMPA-REG OUTCOME (8)CANVAS (9)DECLARE-TIMI 58 (164)
(n = 7,020)(n = 4,330)(n = 5,812)(n = 17,160)
InterventionEmpagliflozin/placeboCanagliflozin/placeboDapagliflozin/placebo
Main inclusion criteriaType 2 diabetes and preexisting CVDType 2 diabetes and preexisting CVD at ≥30 years of age or >2 CV risk factors at ≥50 years of ageType 2 diabetes and established ASCVD or multiple risk factors for ASCVD
A1C inclusion criteria (%)7.0–10.07.0–10.5≥6.5
Age (years)††63.163.364.0
Race (% white)72.478.379.6
Sex (% male)71.564.262.6
Diabetes duration (years)††57% >1013.511.0
Median follow-up (years)3.15.72.14.2
Statin use (%)777575 (statin or ezetimibe use)
Metformin use (%)747782
Prior CVD/CHF (%)99/1065.6/14.440/10
Mean baseline A1C (%)8.18.28.3
Mean difference in A1C between groups at end of treatment (%)−0.3^−0.58^−0.43^
Year started/reported2010/20152009/20172013/2018
Primary outcome§3-point MACE3-point MACEProgression to albuminuria** 0.73 (0.47–0.77)3-point MACE 0.93 (0.84–1.03)
0.86 (0.74–0.99)0.86 (0.75–0.97)§CV death or HF hospitalization
0.83 (0.73–0.95)
Key secondary outcome§4-point MACEAll-cause and CV mortality (see below)40% reduction in composite eGFR, renal replacement, renal death 0.60 (0.47–0.77)Death from any cause
0.93 (0.82–1.04)
Renal composite (≥40% decrease in eGFR rate to <60 mL/min/1.73m2, new ESRD, or death from renal or CV causes
0.76 (0.67–0.87)
Cardiovascular death§0.62 (0.49–0.77)0.96 (0.77–1.18)0.98 (0.82–1.17)
0.87 (0.72–1.06)#
MI§0.87 (0.70–1.09)0.85 (0.65–1.11)0.85 (0.61–1.19)0.89 (0.77–1.01)
Stroke§1.18 (0.89–1.56)0.97 (0.70–1.35)0.82 (0.57–1.18)1.01 (0.84–1.21)
HF hospitalization§0.65 (0.50–0.85)0.77 (0.55–1.08)0.56 (0.38–0.83)0.73 (0.61–0.88)
Unstable angina hospitalization§0.99 (0.74–1.34)
All-cause mortality§0.68 (0.57–0.82)0.87 (0.74–1.01)‡‡0.93 (0.82–1.04)
0.90 (0.76–1.07)##
Worsening nephropathy§||0.61 (0.53–0.70)0.60 (0.47–0.77)0.53 (0.43–0.66)
  • , not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care.

  • ** On the basis of prespecified outcomes, the renal outcomes are not viewed as statistically significant.

  • †† Age was reported as means in all trials; diabetes duration was reported as means in all trials except EMPA-REG OUTCOME, which reported as percentage of population with diabetes duration >10 years, and DECLARE-TIMI 58, which reported median.

  • AlC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).

  • § Outcomes reported as hazard ratio (95% CI).

  • || Worsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio >300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of <45 mL/min/1.73 m2, the need for continuous renal replacement therapy, or death from renal disease in EMPA-REG OUTCOME and as ≥40% decrease in estimated glomerular filtration rate to <60 mL/min/1.73 m2, ESRD, or death from renal cause in DECLARE-TIMI 58. Worsening nephropathy was a prespecified exploratory adjudicated outcome in DECLARE-TIMI 58 but not in EMPA-REG OUTCOME.

  • Truncated data set (prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program).

  • ^ Significant difference in A1C between groups (P < 0.05).

  • # Nontruncated data set.

  • ‡‡ Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R; prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program).

  • ## Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R).