Table 10.3B

Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: GLP-1 receptor agonists

ELIXA (170)LEADER (165)SUSTAIN-6 (166)*EXSCEL (171)Harmony Outcomes (168)REWIND (169)
(n = 6,068)(n = 9,340)(n = 3,297)(n = 14,752)(n = 9,463)(n = 9,901)
InterventionLixisenatide/placeboLiraglutide/placeboSemaglutide/placeboExenatide QW/placeboAlbiglutide/placeboDulaglutide/placebo
Main inclusion criteriaType 2 diabetes and history of ACS (<180 days)Type 2 diabetes and preexisting CVD, CKD, or HF at ≥50 years of age or CV risk at ≥60 years of ageType 2 diabetes and preexisting CVD, HF, or CKD at ≥50 years of age or CV risk at ≥60 years of ageType 2 diabetes with or without preexisting CVDType 2 diabetes with preexisting CVDType 2 diabetes and prior ASCVD event or risk factors for ASCVD
A1C inclusion criteria (%)5.5–11.0≥7.0≥7.06.5–10.0≥7.0≤9.5
Age (years)††60.364.364.66264.166.2
Race (% white)75.277.583.075.884.875.7
Sex (% male)69.364.360.76269.453.7
Diabetes duration (years)††9.312.813.91213.810.5
Median follow-up (years)2.13.82.13.21.65.4
Statin use (%)9372737484.066
Metformin use (%)6676737773.681
Prior CVD/CHF (%)100/2281/1860/2473.1/16.2100/20.232/9
Mean baseline A1C (%)7.78.78.78.08.77.4
Mean difference in A1C between groups at end of treatment (%)−0.3^−0.4^−0.7 or – 1.0^−0.53^−0.52^−0.61^
Year started/reported2010/20152010/20162013/20162010/20172015/20182011/2019
Primary outcome§4-point MACE3-point MACE3-point MACE3-point MACE3-point MACE3-point MACE
1.02 (0.89–1.17)0.87 (0.78–0.97)0.74 (0.58–0.95)0.91 (0.83–1.00)0.78 (0.68–0.90)0.88 (0.79–0.99)
Key secondary outcome§
  • Expanded MACE

  • (0.90–1.11)

  • Expanded MACE

  • 0.88 (0.81–0.96)

  • Expanded MACE

  • 0.74 (0.62–0.89)

Individual components of MACE (see below)Expanded MACE (with urgent revascularization for unstable angina)Composite microvascular outcome (eye or renal outcome)
0.78 (0.69–0.90)0.87 (0.79–0.95)
CV death or HF hospitalization
0.85 (0.70–1.04)
Individual components of MACE (see below)
Cardiovascular death§0.98 (0.78–1.22)0.78 (0.66–0.93)0.98 (0.65–1.48)0.88 (0.76–1.02)0.93 (0.73–1.19)0.91 (0.78–1.06)
MI§1.03 (0.87–1.22)0.86 (0.73–1.00)0.74 (0.51–1.08)0.97 (0.85–1.10)0.75 (0.61–0.90)0.96 (0.79–1.15)
Stroke§1.12 (0.79–1.58)0.86 (0.71–1.06)0.61 (0.38–0.99)0.85 (0.70–1.03)0.86 (0.66–1.14)0.76 (0.61–0.95)
HF hospitalization§0.96 (0.75–1.23)0.87 (0.73–1.05)1.11 (0.77–1.61)0.94 (0.78–1.13)0.93 (0.77–1.12)
Unstable angina hospitalization§1.11 (0.47–2.62)0.98 (0.76–1.26)0.82 (0.47–1.44)1.05 (0.94–1.18)1.14 (0.84–1.54)
All-cause mortality§0.94 (0.78–1.13)0.85 (0.74–0.97)1.05 (0.74–1.50)0.86 (0.77–0.97)0.95 (0.79–1.16)0.90 (0.80–1.01)
Worsening nephropathy§||0.78 (0.67–0.92)0.64 (0.46–0.88)0.85 (0.77–0.93)
  • , not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care.

  • * Powered to rule out a hazard ratio of 1.8; superiority hypothesis not prespecified.

  • †† Age was reported as means in all trials; diabetes duration was reported as means in all trials except EXSCEL, which reported medians.

  • A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide.

  • § 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 LEADER and SUSTAIN-6 and as new macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or more from baseline, or chronic renal replacement therapy in REWIND. Worsening nephropathy was a prespecified exploratory adjudicated outcome in LEADER, SUSTAIN-6, and REWIND.

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