p.26 抽出テキスト

MI, and stroke compared with placebo. A meta-analysis of seven of the eight completed GLP-1 RA trials, excluding the ELIXA trial results (due to a very short pharmacodynamic half-life [3 h] of once a day [o.d.] lixisenatide, and the very high-risk population post-ACS differentiating it from all others), showed that a pooled estimate for GLP-1 RA vs. placebo for the primary outcome was reduced by 15% (HR 0.85; 95% CI, 0.80–0.90; Figure 6).164 Results from pooled analyses of the effects of GLP-1 RA vs. placebo on individual CV outcomes included CV death (HR 0.85; 95% CI, 0.78–0.93), MI (HR 0.88; 95% CI, 0.81–0.96), stroke (HR 0.81; 95% CI, 0.74–0.90), and hospitalization for HF (HR 0.88; 95% CI, 0.79–0.98). Notably, the point estimate in the seven trials was lower (HR = 0.85) in those with established ASCVD than in those without (HR = 0.94), with Pint = 0.068, suggesting but not conclusively proving that GLP-1 RAs may reduce risks more in those with established ASCVD. As absolute risks are greater in those with established CV disease, the absolute benefits are also expected to be greater. Based on these aggregate results, along with the SGLT2 inhibitors (see above) GLP-1 RAs are a preferred glucose-lowering therapy for patients with T2DM and ASCVD, independent of glucose control considerations, and independent of background metformin use. In patients with T2DM without ASCVD or severe TOD, but with a calculated 10-year CVD risk ≥10% in the SCORE2-Diabetes algorithm (Section 4), treatment with GLP-1 RAs and/or SGLT2 inhibitors may be considered to reduce CV risk, independent of glucose control considerations. This recommendation is a consensus within the Task Force based on the assumption that some level of predicted CVD risk appears to be equivalent to ‘severe TOD risk’, acknowledging it is a Level C recommendation. Of note, it is in line with recommendations from EASD and ADA.1,156,157

5.3.1.3 Pioglitazone

The PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) randomized CVOT assessed the CV effects of the thiazolidinedione (TZD) pioglitazone vs. placebo, independent of glucose control, in patients with T2DM and ASCVD. It failed to achieve statistical significance for its primary composite outcome of all-cause death, MI, stroke, unstable angina, coronary or peripheral revascularization, and amputation (HR 0.90; 95% CI, 0.80–1.02).165 However, for the principal secondary outcome evaluating the goldstandard, three-point composite outcome of CV death, MI, and stroke, there was a nominally significant 16% relative risk (RR) reduction (HR 0.84; 95% CI, 0.72–0.98).165 Results from subsequent meta-analyses and observational studies have supported the suggested efficacy of pioglitazone in persons with ASCVD.166–169 Notably, the magnitude of the estimated treatment benefit with pioglitazone across these studies aligns with contemporary meta-analyses estimates of the effects of SGLT2 inhibitors and GLP-1 RAs on the same composite MACE outcome.155,164 TZDs enhance fluid retention and the risk of peripheral oedema, especially with concomitant insulin use and in the context of kidney dysfunction. In addition, TZDs increase the risk of HF, with the incremental risk of HF with pioglitazone at an estimated 0.4% annualized, absolute increase.170 HF associated with TZDs appears to be attributable to expanded plasma volume, with no evidence of myocardial toxicity.171 TZDs induce weight gain due to adipose tissue expansion, but with weight redistributed predominantly to less metabolically active adipose tissue; weight gain may be the greatest concern of patients and clinicians with the TZD class. Based on the data and net benefit-risk assessment, it is reasonable to consider using pioglitazone to mitigate ASCVD risk in patients with T2DM and prevalent ASCVD.

5.3.2 Glucose-lowering medications with

cardiovascular safety but not incremental efficacy demonstrated in dedicated cardiovascular outcomes trials 5.3.2.1. Dipeptidyl peptidase-4 inhibitors Five randomized CV safety trials in populations with T2DM with or at high risk of ASCVD have assessed the CV effects of dipeptidyl peptidase-4 (DPP-4) inhibitors (Supplementary data online, Table S9): saxagliptin, alogliptin, sitagliptin, and linagliptin each vs. placebo, and linagliptin vs. glimepiride.172–175 All four of the placebo-controlled trials demonstrated statistical non-inferiority but not superiority for the DPP-4 inhibitors in the primary MACE endpoint. In the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus—Thrombolysis in Myocardial Infarction 53) trial, saxagliptin statistically significantly increased the risk of hospitalization for HF vs. placebo.176 Numerically, more HF events occurred with alogliptin vs. placebo in the EXAMINE (Cardiovascular Outcomes Study of Alogliptin in Patients With Type 2 Diabetes and Acute Coronary Syndrome) trial, though this difference was not nominally significant.177 These observations led to the development and regulatory filing of prospective HF analysis plans for the TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) and CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus) trials, each of which revealed no increased risk of HF with either sitagliptin or linagliptin compared with placebo.178,179 In the CAROLINA (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes) trial, linagliptin was compared with the active comparator glimepiride, demonstrating no difference in any assessed CV or kidney outcome, though noting a higher risk of hypoglycaemia with glimepiride.180

5.3.2.2 Lixisenatide and exenatide

Of the eight GLP-1 RAs evaluated in CVOTs, two have demonstrated safety but not incremental efficacy. In the ELIXA trial, lixisenatide 10 or 20 μg o.d. was non-inferior to placebo, but did not significantly affect a four-point MACE (three-point MACE plus hospitalization for unstable angina) in patients with T2DM post-ACS.158 In the EXSCEL trial of patients with T2DM in whom 73% had experienced a previous CV event, exenatide extended-release 2 mg once weekly showed non-inferiority but not superiority to placebo for the primary outcome of CV death, MI, and stroke.159

5.3.2.3 Insulin

Two basal insulins have been formally evaluated in dedicated CVOTs. In the ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial, 12 537 patients (mean age 63.5 years) at high CVD risk with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or T2DM were randomized to insulin glargine titrated to a fasting blood glucose level of ≤5.3 mmol/L (≤95 mg/dL) or standard care.86 After a median follow-up of 6.2 years, the incidence of CV outcomes did not differ between the two groups. Downloaded from academic.oup.com/eurheartj/article/44/39/4043/7238227 by guest on 07 October 2026