Aims

Bempedoic acid inhibits ATP-citrate lyase (ACL), an enzyme in the cholesterol synthesis pathway. Mendelian randomization and genetic studies suggest decreased HMG-CoA reductase activity is associated with increased risk for type 2 diabetes, whereas decreased ACL activity is not. We evaluated the effect of bempedoic acid on glycaemic and lipid parameters in patients with hypercholesterolemia.

Methods

A patient-level pooled analysis of 4 phase 3, randomized, double-blind, placebo-controlled trials evaluated changes in glycemia, change from baseline in LDL-C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycemia).

Results

The annual rate of new-onset diabetes for bempedoic acid vs placebo in patients with normoglycemia at baseline (n = 618) was 0.3% vs 0.8% and for patients with prediabetes at baseline (n = 1,868) was 4.7% vs 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P<.0001) reduced HbA1c by −0.12% and −0.06%, respectively, and did not worsen fasting glucose vs placebo. Bempedoic acid significantly and consistently lowered LDL-C levels vs placebo, regardless of baseline glycaemic status (placebo-corrected difference range, −17.2% to −29.6%; P<.001 for each stratum). Safety of bempedoic acid was comparable to placebo and similar across glycaemic strata.

Conclusions

Bempedoic acid significantly lowered LDL-C across glycaemic strata and did not worsen glycaemic parameters nor increase incidence of new-onset diabetes vs placebo over a median follow-up of 1 year.

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