Novel Antidiabetic Drugs

Opportunities of Antidiabetic Drugs in Cardiovascular Medicine: A Meta-Analysis and Perspectives for Trial Design

To identify potential application of GLP1‑RAs and SGLT2‑Is in cardiovascular medicine, we performed PubMed search updated until November 30, 2019 and selected placebo-controlled randomized trials (RCTs) in T2DM patients.  24-H ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in HbA1c and body weight (BW) were aggregated across RCTs using random-effect models.  In 2238 patients (7 RCTs), SGLT2‑Is lowered 24‑h systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4–5.5/1.2–2.6 mm Hg), whereas two GLP1-RAs RCTs produced contradictory BP results.  Over 1.3–5.4 years of follow-up of 56,004 patients (7 RCTs), aggregate hazard ratios (HRs) associated with GLP1-RA treatment were 0.88 (0.84–0.93) for MACE, 0.84 (0.74–0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE endpoints (P≤0.01).  Across five SGLT2-Is RCTs, including 43,467 patients with 1.5–4.2 years follow-up, HRs were 0.87 (0.82–0.93) for MACE, 0.68 (0.62–0.75) for HF, 0.82 (0.72–0.93) for cardiovascular death, 0.87 (0.79–0.96) for myocardial infarction, and 0.61 (0.56–0.67) for worsening CKD.  The effects of GLP1‑RAs on HF (P=0.08) and of SGLT2‑Is on stroke (P=0.78) were weak.  The risk of HF and CKD, but not MACE, decreased with more BP lowering, but stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD.  The aggregate effect sizes on systolic BP, BW and HbA1c were ‑1.61 mm Hg, ‑2.40 kg and ‑0.69% for GLP1-RAs, and ‑2.53 mm Hg, ‑1.15 kg and ‑0.24%, for SGLT2-Is (P<0.001).  In conclusion, GLP1‑RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles. 

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