Steven E. Nissen

Aims: The impact of tirzepatide and dulaglutide on major adverse cardiovascular events (MACE) and heart failure (HF) outcomes according to HF status is unknown. Methods and results: Patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease were treated with tirzepatide up to 15 mg or dulaglutide 1.5 mg weekly (average 4 years). The incidence of MACE-3 [cardiovascular (CV) death, myocardial infarction (MI), stroke], MACE-4 (CV death, MI, stroke, coronary revascularization) and composite of all-cause or CV death and hospitalization or urgent visits for HF were analysed in patients with and without a history of HF. A history of HF (20.3%) was associated with more coronary artery disease and prior MI. Incidences of event categories were higher in the HF group. The hazard ratio (HR) for all-cause death or hospitalization or urgent visits for HF on tirzepatide vs. dulaglutide was 0.83 [95% confidence interval (CI) 0.70–0.99] in patients with HF and 0.88 (95%CI 0.78–1.00) without HF. The HR for CV death or hospitalization or urgent visits for HF was 0.85 (95%CI 0.70–1.03) and 0.96 (95%CI 0.83–1.12), for MACE-3 0.90 (95%CI 0.76–1.08) and 0.93 (95%CI 0.83–1.04), and for MACE-4 0.81 (95%CI 0.69–0.95) and 0.91 (95%CI 0.83–1.00) in patients with and without HF, respectively. The patient-reported outcomes of APPADL and EQ-5D-5L visual analogue scores improved and were higher on tirzepatide in both groups. Conclusion: With overall non-inferiority established, this exploratory analysis revealed lower rates of the composite of all-cause death or HF events, or MACE-4 among patients with T2D and HF treated with tirzepatide compared with dulaglutide.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Recently, bempedoic acid was shown to reduce MACE in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS: CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13 970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALE, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS: A total of 1624 of the enrolled patients (mean±SD age, 63.9±9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALE over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALE by 36% (hazard ratio, 0.64 [95% CI, 0.44–0.93]; P =0.018). Bempedoic acid reduced total MALE by 45% (relative risk, 0.55 [95% CI, 0.35–0.85]; P =0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80–0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64–1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79–0.86]; P _interaction =NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73–0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54–0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73–0.92]; P _interaction =NS). CONCLUSIONS: Patients with PAD are at high risk of MALE and MACE. Bempedoic acid reduces both MACE and MALE in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.

Background: Lowering low‐density lipoprotein cholesterol (LDL‐C) reduces the risk of major vascular events across all age groups. We analyzed phase 3 studies of bempedoic acid to characterize the safety and efficacy in patients aged ≥75 years with and without a concomitant statin. Methods: Post hoc analysis of bempedoic acid in high‐risk patients with cardiovascular disease by age from phase 3 placebo‐controlled, randomized clinical trials: two 52‐week primary hyperlipidemia studies with maximal background statin (“max‐statins pool”), and 1 cardiovascular outcomes trial (“statin‐intolerant pool”). Efficacy (LDL‐C, non–high‐density lipoprotein cholesterol, total cholesterol, high‐sensitivity C‐reactive protein) and safety were evaluated. Results: The max‐statins pool included 3009 (2010 bempedoic acid, 999 placebo) patients. The statin‐intolerant pool included 13 970 patients (6992 bempedoic acid, 6978 placebo). In total 7022 patients were aged 18 to <65 years; 7372 were aged 65 to <75 years; 2585 were aged ≥75 years. Placebo‐corrected mean percentage change in LDL‐C at week 12 in the max‐statin pool with bempedoic acid was −18.4% (95% CI, −21.3 to −15.6) for patients aged 18 to <65 years, −18.6% (95% CI, −21.2 to −16.1) for 65 to <75 years, and −18.3% (95% CI, −22.2 to −14.5) for ≥75 years. In the statin‐intolerant pool, LDL‐C change was −21.9% (95% CI, −23.1 to −20.7) for patients aged 18 to <65 years, −22.9% (95% CI, −24.0 to −21.8) for 65 to <75 years, and −24.5% (95% CI, −26.2 to −22.7) for ≥75 years. Frequency of adverse events compared with placebo was similar across the ages, but more frequent among patients ≥75 years regardless of background statin. Cardiovascular event reduction was statistically comparable across all ages. Conclusions: Bempedoic acid was well tolerated in patients aged ≥75 years with efficacy and safety comparable with younger subgroups regardless of background statin usage. Bempedoic acid may be considered a viable strategy for managing hypercholesterolemia in adults, regardless of age.