Table 10.4

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

DPP-4 inhibitorsGLP-1 receptor agonistsSGLT2 inhibitors
SAVOR-TIMI 53 (168) (n = 16,492)EXAMINE (175) (n = 5,380)TECOS (171) (n = 14,671)ELIXA (161) (n = 6,068)LEADER (159) (n = 9,340)SUSTAIN-6 (160)* (n = 3,297)EXSCEL (162) (n = 14,752)EMPA-REG OUTCOME (8) (n = 7,020)CANVAS (9) (n = 4,330)CANVAS-R (9) (n = 5,812)
InterventionSaxagliptin/placeboAlogliptin/placeboSitagliptin/placeboLixisenatide/placeboLiraglutide/placeboSemaglutide/placeboExenatide QW/placeboEmpagliflozin/placeboCanagliflozin/placebo
Main inclusion criteriaType 2 diabetes and history of or multiple risk factors for CVDType 2 diabetes and ACS within 15–90 days before randomizationType 2 diabetes and preexisting CVDType 2 diabetes and history of ACS (<180 days)Type 2 diabetes and preexisting CVD, kidney disease, or HF at ≥50 years of age or cardiovascular risk at ≥60 years of ageType 2 diabetes and preexisting CVD, HF, or CKD at ≥50 years of age or cardiovascular risk at ≥60 years of ageType 2 diabetes with or without preexisting CVDType 2 diabetes and preexisting CVDType 2 diabetes and preexisting CVD at ≥30 years of age or >2 cardiovascular risk factors at ≥50 years of age
A1C inclusion criteria (%)≥6.56.5–11.06.5–8.05.5–11.0≥7.0≥7.06.5–10.07.0–10.07.0–10.5
Age (years)††65.161.065.460.364.364.66263.163.3
Diabetes duration (years)††10.37.111.69.312.813.91257% >1013.5
Median follow-up (years)2.11.53.02.13.82.13.23.15.72.1
Statin use (%)789180937273747775
Metformin use (%)706682667673777477
Prior CVD/CHF (%)78/13100/2874/18100/2281/1860/2473.1/16.299/1065.6/14.4
Mean baseline A1C (%)8.08.07.27.78.78.78.08.18.2
Mean difference in A1C between groups at end of treatment (%)−0.3˄−0.3˄−0.3˄−0.3˄−0.4˄−0.7 or – 1.0˄−0.53˄−0.3˄−0.58˄
Year started/reported2010/20132009/20132008/20152010/20152010/20162013/20162010/20172010/20152009/2017
Primary outcome§3-point MACE3-point MACE4-point MACE4-point MACE3-point MACE3-point MACE3-point MACE3-point MACE3-point MACEProgression to albuminuria**
1.00 (0.89–1.12)0.96 (95% UL ≤1.16)0.98 (0.89–1.08)1.02 (0.89–1.17)0.87 (0.78–0.97)0.74 (0.58–0.95)0.91 (0.83–1.00)0.86 (0.74–0.99)0.86 (0.75–0.97)§0.73 (0.47–0.77)
Key secondary outcome§Expanded MACE4-point MACE3-point MACEExpanded MACEExpanded MACEExpanded MACEIndividual components of MACE (see below)4-point MACEAll-cause and cardiovascular mortality (see below)40% reduction in composite eGFR, renal replacement, renal death
1.02 (0.94–1.11)0.95 (95% UL ≤1.14)0.99 (0.89–1.10)1.00 (0.90–1.11)0.88 (0.81–0.96)0.74 (0.62–0.89)0.89 (0.78–1.01)0.60 (0.47–0.77)
Cardiovascular death§1.03 (0.87–1.22)0.85 (0.66–1.10)1.03 (0.89–1.19)0.98 (0.78–1.22)0.78 (0.66–0.93)0.98 (0.65–1.48)0.88 (0.76–1.02)0.62 (0.49–0.77)0.96 (0.77–1.18)
0.87 (0.72–1.06)#
MI§0.95 (0.80–1.12)1.08 (0.88–1.33)0.95 (0.81–1.11)1.03 (0.87–1.22)0.86 (0.73–1.00)0.74 (0.51–1.08)0.97 (0.85–1.10)0.87 (0.70–1.09)0.85 (0.65–1.11)0.85 (0.61–1.19)
Stroke§1.11 (0.88–1.39)0.91 (0.55–1.50)0.97 (0.79–1.19)1.12 (0.79–1.58)0.86 (0.71–1.06)0.61 (0.38–0.99)0.85 (0.70–1.03)1.18 (0.89–1.56)0.97 (0.70–1.35)0.82 (0.57–1.18)
HF hospitalization§1.27 (1.07–1.51)1.19 (0.90–1.58)1.00 (0.83–1.20)0.96 (0.75–1.23)0.87 (0.73–1.05)1.11 (0.77–1.61)0.94 (0.78–1.13)0.65 (0.50–0.85)0.77 (0.55–1.08)0.56 (0.38–0.83)
Unstable angina hospitalization§1.19 (0.89–1.60)0.90 (0.60–1.37)0.90 (0.70–1.16)1.11 (0.47–2.62)0.98 (0.76–1.26)0.82 (0.47–1.44)1.05 (0.94–1.18)0.99 (0.74–1.34)
All-cause mortality§1.11 (0.96–1.27)0.88 (0.71–1.09)1.01 (0.90–1.14)0.94 (0.78–1.13)0.85 (0.74–0.97)1.05 (0.74–1.50)0.86 (0.77–0.97)0.68 (0.57–0.82)0.87 (0.74–1.01)‡‡
0.90 (0.76–1.07)##
Worsening nephropathy§1.08 (0.88–1.32)0.78 (0.67–0.92)0.64 (0.46–0.88)0.61 (0.53–0.70)0.60 (0.47–0.77)
  • —, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event; MI, myocardial infarction; SGLT2, sodium–glucose cotransporter 2; UL, upper limit. Data from this table was adapted from Cefalu et al. (176) in the January 2018 issue of Diabetes Care.

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

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

  • †† Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all but four trials, with SAVOR-TIMI 58, EXAMINE, and EXSCEL reporting medians and EMPA-REG OUTCOME reporting as percentage of population with diabetes duration >10 years.

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

  • 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, LEADER, and SUSTAIN-6 and as doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL (530 μmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53, LEADER, and SUSTAIN-6 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).