Novel hypolipidemic bempedoic acid safe in diabetics, may overcome shortcomings of statins: Lancet

Statins reduce LDL cholesterol and cardiovascular events among those with or without diabetes but have been reported to increase new-onset diabetes. A prespecified analysis of CLEAR outcomes trial published recently in The Lancet journal has shown that unlike statins, bempedoic acid is not associated with an increased risk of new-onset diabetes, even in those in the pre-diabetic stage.

More than a decade ago, the US Food and Drug Administration mandated that statins carry a warning about reports of increased blood sugar and HbA1c levels with treatment.

In the 2008 JUPITER trial, for example, rosuvastatin was associated with a significantly increased risk of new-onset diabetes. That risk was confirmed in Sattar et al’s meta-analysis of 13 randomized trials involving more than 90,000 patients showing that statin use was associated with a small, but statistically significant, 9% higher relative risk of new-onset diabetes compared with placebo.

The CLEAR Outcomes trial demonstrated that bempedoic acid reduced the risk of MACE among statin-intolerant patients at high cardiovascular risk. In the present prespecified analysis, the authors aimed to evaluate the cardiovascular benefits of bempedoic acid, in individuals with diabetes, and to evaluate the risk of new-onset diabetes and HbA1c among those without diabetes in the CLEAR Outcomes trial.

The CLEAR Outcomes is a randomised, double-blind, placebo-controlled trial. Patients with or without cardiovascular disease who were unwilling or unable to take guideline-recommended doses of statins and an LDL cholesterol of 2·59 mmol/L or more were randomly assigned (1:1) in a double-blinded manner to either bempedoic acid 180 mg once per day or placebo.

In this prespecified analysis, the efficacy endpoint was a time-to-event analysis of four-component major adverse cardiovascular event (MACE-4), which is the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularisation, using the intention-to-treat population stratified by baseline glycaemia status.

The prespecified analysis of risk of new-onset diabetes and HbA1cincrease was evaluated in patients without diabetes at baseline.

The authors found that:

1. Over a median of 3·4 years follow up, patients with diabetes had significant relative and absolute cardiovascular risk reductions in MACE-4 endpoints with bempedoic acid compared to placebo.

2. The proportion of patients who developed new-onset diabetes were similar between the bempedoic acid and placebo groups.

3. HbA1c levels at 12 months and the end of the study were similar between randomised groups in patients who had prediabetes and normoglycaemia.

4. Placebo-corrected LDL cholesterol concentrations and high-sensitivity C-reactive protein at 6 months were reduced in each glycaemic stratum (diabetes, prediabetes, and normoglycaemia) for patients randomly assigned to bempedoic acid.

Importantly, among those without diabetes at baseline, the use of bempedoic acid over 3.4 years of follow-up did not lead to an increase in new-onset diabetes or worsening HbA1c levels, which is a concern with statin therapy. The agent also was linked to a small amount of weight loss.

To conclude, among patients with diabetes, bempedoic acid reduces LDL cholesterol and high-sensitivity C-reactive protein and risk of cardiovascular events. Patients without diabetes had no increase in new-onset diabetes or worsening HbA1c with bempedoic acid. The efficacy and cardiometabolic safety profile of bempedoic acid makes it a clinical option for those with and without diabetes.

SOURCE: The Lancet : https://doi.org/10.1016/S2213-8587(23)00316-9