Table 10.3A.
Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: DPP-4 inhibitors
| SAVOR-TIMI 53 (224) | EXAMINE (235) | TECOS (226) | CARMELINA (193,236) | CAROLINA (193,237) | |
|---|---|---|---|---|---|
| (n = 16,492) | (n = 5,380) | (n = 14,671) | (n = 6,979) | (n = 6,042) | |
| Intervention | Saxagliptin/placebo | Alogliptin/placebo | Sitagliptin/placebo | Linagliptin/placebo | Linagliptin/glimepiride |
| Main inclusion criteria | Type 2 diabetes and history of or multiple risk factors for CVD | Type 2 diabetes and ACS within 15–90 days before randomization | Type 2 diabetes and preexisting CVD | Type 2 diabetes and high CV and renal risk | Type 2 diabetes and high CV risk |
| A1C inclusion criteria (%) | ≥6.5 | 6.5–11.0 | 6.5–8.0 | 6.5–10.0 | 6.5–8.5 |
| Age (years)† | 65.1 | 61.0 | 65.4 | 65.8 | 64.0 |
| Race (% White) | 75.2 | 72.7 | 67.9 | 80.2 | 73.0 |
| Sex (% male) | 66.9 | 67.9 | 70.7 | 62.9 | 60.0 |
| Diabetes duration (years)† | 10.3 | 7.1 | 11.6 | 14.7 | 6.2 |
| Median follow-up (years) | 2.1 | 1.5 | 3.0 | 2.2 | 6.3 |
| Statin use (%) | 78 | 91 | 80 | 71.8 | 64.1 |
| Metformin use (%) | 70 | 66 | 82 | 54.8 | 82.5 |
| Prior CVD/CHF (%) | 78/13 | 100/28 | 74/18 | 57/26.8 | 34.5/4.5 |
| Mean baseline A1C (%) | 8.0 | 8.0 | 7.2 | 7.9 | 7.2 |
| Mean difference in A1C between groups at end of treatment (%) | −0.3‡ | −0.3‡ | −0.3‡ | −0.36‡ | 0 |
| Year started/reported | 2010/2013 | 2009/2013 | 2008/2015 | 2013/2018 | 2010/2019 |
| Primary outcome§ | 3-point MACE 1.00 (0.89–1.12) | 3-point MACE 0.96 (95% UL ≤1.16) | 4-point MACE 0.98 (0.89–1.08) | 3-point MACE 1.02 (0.89–1.17) | 3-point MACE 0.98 (0.84–1.14) |
| Key secondary outcome§ | Expanded MACE 1.02 (0.94–1.11) | 4-point MACE 0.95 (95% UL ≤1.14) | 3-point MACE 0.99 (0.89–1.10) | Kidney composite (ESRD, sustained ≥40% decrease in eGFR, or renal death) 1.04 (0.89–1.22) | 4-point MACE 0.99 (0.86–1.14) |
| Cardiovascular death§ | 1.03 (0.87–1.22) | 0.85 (0.66–1.10) | 1.03 (0.89–1.19) | 0.96 (0.81–1.14) | 1.00 (0.81–1.24) |
| MI§ | 0.95 (0.80–1.12) | 1.08 (0.88–1.33) | 0.95 (0.81–1.11) | 1.12 (0.90–1.40) | 1.03 (0.82–1.29) |
| Stroke§ | 1.11 (0.88–1.39) | 0.91 (0.55–1.50) | 0.97 (0.79–1.19) | 0.91 (0.67–1.23) | 0.86 (0.66–1.12) |
| HF hospitalization§ | 1.27 (1.07–1.51) | 1.19 (0.90–1.58) | 1.00 (0.83–1.20) | 0.90 (0.74–1.08) | 1.21 (0.92–1.59) |
| Unstable angina hospitalization§ | 1.19 (0.89–1.60) | 0.90 (0.60–1.37) | 0.90 (0.70–1.16) | 0.87 (0.57–1.31) | 1.07 (0.74–1.54) |
| All-cause mortality§ | 1.11 (0.96–1.27) | 0.88 (0.71–1.09) | 1.01 (0.90–1.14) | 0.98 (0.84–1.13) | 0.91 (0.78–1.06) |
| Worsening nephropathy§ǁ | 1.08 (0.88–1.32) | — | — | Kidney composite (see above) | — |
—, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiovascular event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu et al. (238) in the January 2018 issue of Diabetes Care.
Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians.
Significant difference in A1C between groups (P < 0.05).
Outcomes reported as hazard ratio (95% CI).
Worsening nephropathy is defined as a doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53.