p.51 抽出テキスト

SGLT2 inhibitor use among GLP-1 RA trials. Data from an exploratory analysis of the AMPLITUDE-O trial suggest that the efficacy and safety of efpeglenatide was independent of concurrent SGLT2 inhibitor use, including HF hospitalization.546 Only three small RCTs of GLP-1 RAs have been conducted in patients with HFrEF.547 The LIVE trial randomly assigned 241 patients with chronic, stable HFrEF with or without DM to placebo or liraglutide.548 While no changes in LVEF, quality of life, or functional class were noted after 24 weeks of treatment, more serious adverse cardiac events (sustained ventricular tachycardia, AF requiring intervention, and aggravation of IHD; 12 [10%] vs. 3 [3%] for liraglutide and placebo, respectively; P = 0.04) occurred in the liraglutide group. The FIGHT trial (Functional Impact of GLP1 for HF Treatment) randomly assigned 300 patients with and without DM with HFrEF and a recent hospitalization for HF to liraglutide or placebo. Following 180 days of treatment, the primary outcome (time to death, time to re-hospitalization for HF, and time-averaged proportional change in NT-proBNP level from baseline to 180 days) was not different between groups. In addition, there was a non-significant between-group difference in the number of rehospitalizations for HF (63 [41%] in the liraglutide group vs. 50 [34%] in the placebo group; HR 1.30, 95% CI, 0.89–1.88; P = 0.17).549 The third trial was a small (n = 82), randomized study evaluating 12 weeks of albiglutide vs. placebo in patients with HFrEF. No significant differences were seen in LVEF, 6 min walk test, myocardial glucose utilization, or oxygen use.550 The study was too small and too short to evaluate clinical outcomes.

7.5.3 Dipeptidyl peptidase-4 inhibitors

Four DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin, and linagliptin) have been examined in dedicated placebo-controlled CV safety trials in patients with T2DM with or at high risk of ASCVD. Saxagliptin significantly increased the risk of HF hospitalization172 and is not recommended in patients with DM with or at increased risk of HF. Alogliptin was associated with a non-significant trend towards an increase in HF hospitalization.173 Sitagliptin and linagliptin had a neutral effect.174,178–180 Vildagliptin, not tested in a CVOT, had no significant effect on LVEF but led to an increase in LV volumes in a small trial.551

7.5.4 Insulin

In patients with T2DM and advanced HF, insulin use is independently associated with a significantly worse prognosis.552 Two basal insulins have been formally evaluated in dedicated CV outcomes trials. In the ORIGIN trial, 12 537 patients (mean age 63.5 years) at high CV risk, with IFG, 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. After a median follow-up of 6.2 years, insulin glargine was neutral in its effect on HF hospitalizations.553 The DEVOTE randomized trial, a double-blind comparison of the ultra-long-acting, oncedaily insulin degludec vs. insulin glargine U100, enrolled 7637 patients with T2DM with ASCVD or at high CV risk.181 Treatment with insulin degludec vs. insulin glargine did not differ with respect to HF hospitalization; prior HF was independently associated with future HF hospitalization.554

7.5.5 Metformin

Metformin is suggested to be safe at all stages of HF with preserved or stable, moderately reduced kidney function (i.e. eGFR >30 mL/min/ 1.73 m2). It is associated with a lower risk of death and HF hospitalization compared with insulin and sulphonylureas in observational studies, though dedicated randomized, controlled, CVOTs evaluating safety and efficacy of metformin have not been conducted.555–557 Concerns regarding lactic acidosis have not been substantiated.558,559

7.5.6 Sulphonylureas

Data on the effects of sulphonylureas on HF are inconsistent. Data from two retrospective cohort studies, including 111 971 patients with diabetes, suggest an adverse safety profile showing ∼20–60% higher death rate and ∼20–30% higher risk of HF compared with metformin.560,561 However, in the UKPDS, NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research), and ADOPT trials, there were no increased HF signals.127,562–564 In addition, data from the CAROLINA trial comparing linagliptin (shown to not increase the risk of HF hospitalization vs. placebo in the CARMELINA trial) vs. glimepiride did not show an elevated risk of HF hospitalization by this sulphonylurea.179

7.5.7 Thiazolidinediones

Thiazolidinediones increased the risk of HF hospitalization in several trials and are not recommended in patients with diabetes and symptomatic HF.165,565–567

7.5.8 Special consideration: hypoglycaemia and risk

of heart failure hospitalization Although severe hypoglycaemic events were associated with higher HF hospitalization in some but not all studies, there is no clear evidence for causality.139,140,554,568 Recent analyses have demonstrated bi-directional associations between hypoglycaemia and CV outcomes, including HF, suggesting that this is not causal, but rather reflects underlying frailty and risk of adverse outcomes.139,140 Figure 16 summarizes glucose-lowering treatment of patients with HF and T2DM.

ESC Guidelines                                                                                                                                                                                          4093

Downloaded from academic.oup.com/eurheartj/article/44/39/4043/7238227 by guest on 07 October 2026