Pemafibrate fails to reduce cardiovascular events in diabetes but may benefit the liver

Pemafibrate did not reduce the risk for cardiovascular events in patients with type 2 diabetes and dyslipidaemia, despite lowering the levels of triglycerides, very-low-density lipoprotein-cholesterol (VLDL-C), remnant cholesterol, and apolipoprotein (apo)-CIII. Nevertheless, an exploratory analysis showed that pemafibrate may decrease the risk of hepatic adverse events and non-alcoholic fatty liver disease.

Post-hoc analyses of fibrate trials indicated that patients with type 2 diabetes, hypertriglyceridaemia, and low high-density lipoprotein-cholesterol (HDL-C) may benefit from fibrate therapy in terms of a reduced risk for cardiovascular events [1]. The multinational, randomised, double-blind, placebo-controlled PROMINENT trial (NCT03071692) examined this issue by randomising participants with type 2 diabetes and mild-to-moderate hypertriglyceridaemia (TG >200 to 499 mg/dl) and HDL-C <40 mg/dl who were treated with guideline-directed LDL-C lowering therapies (n=10,497) 1:1 to pemafibrate 0.2 mg twice daily or placebo. The primary efficacy outcome was a composite of myocardial infarction, ischaemic stroke, coronary revascularisation, or cardiovascular death. Dr Aruna Pradhan (Brigham and Women’s Hospital, MA, USA), the first author of the study, noted that 96% of the participants were treated with statins at baseline [2].

Pemafibrate lowered triglycerides, VLDL-C, remnant cholesterol, and apo-CIII significantly more than the placebo did, with reductions of 26.2%, 25.8%, 25.6%, and 27.6%, respectively. Interestingly, levels of apolipoprotein B and LDL-C increased on pemafibrate relative to placebo. After a median follow-up of 3.4 years, there was no difference between the 2 study groups regarding the primary endpoint (HR 1.03; 95% CI 0.91–1.15; P=0.67). Additionally, secondary endpoints and subgroup analyses revealed no potential benefits of pemafibrate over placebo concerning cardiovascular outcomes.

Dr Pradhan highlighted that the rate of serious adverse events was similar for the 2 arms of the study (HR 1.04; 95% CI 0.98–1.11) but that renal adverse events (HR 1.12; 95% CI 1.04–1.20) and venous thromboembolism (HR 2.05; 95% CI 1.35–3.17) were more common in the intervention arm. Notably, the risk for liver disease (HR 0.83; 95% CI 0.69–0.99) and non-alcoholic fatty liver disease in particular (HR 0.78; 95% CI 0.63–0.96) was lower in the pemafibrate arm compared with the placebo arm.

Prof. Karol Watson (University of California, Los Angeles, CA, USA) commented that fibrates have indeed not been demonstrated to reduce the risk for cardiovascular events in clinical trials since the introduction of statins. “On the bright side, there will be studies evaluating the effects of fibrates in liver conditions, given the encouraging data from the PROMINENT trial”.

1. 
   
   1. Saely CH, et al. N Engl J Med 2010;363(7):692–695.
   2. Pradhan AD, et al. PROMINENT: pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes. LBS.01, American Heart Association Meeting 2022, 05–07 November, Chicago, USA.

 

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Posted on 11 January 202313 June 2024