In an analysis of four phase 3 trials, the oral lipid-lowering drug bempedoic acid (Nexletol; Esperion) did not worsen glycemic control or increase the incidence of type 2 diabetes.
As previously reported, this first-in-class drug, which acts by inhibiting ATP-citrate lyase, was approved by the Food and Drug Administration in February 2020.
Lawrence A. Leiter MD, from the University of Toronto, delivered the findings of this latest analysis in an oral presentation at the virtual American Diabetes Association 80th Scientific Sessions.
“The current study is important as it shows overall consistent efficacy and safety regardless of glycemic status and no increase in new-onset diabetes,” Dr. Leiter said in an interview.
There is interest in how lipid-lowering drugs might affect glycemia because “meta-analyses have shown about a 10% increased risk of new-onset diabetes in statin users, although the absolute increased risk is 1 extra case per 255 treated patients [in whom one would expect 5.4 cardiovascular events to be prevented by the statin],” he noted.
In a comment, John R. Guyton, MD, from Duke University Medical Center, Durham, N.C., agreed that the new study demonstrates that “patients with diabetes and prediabetes respond to bempedoic acid with LDL cholesterol lowering that is similar to that in patients with normal glucose tolerance.”
Although “statins have a slight effect of worsening glucose tolerance and a modest effect of increasing cases of new-onset diabetes,” the current research shows that “bempedoic acid appears to be free of these effects,” said Dr. Guyton, who discussed this drug in another symposium at the meeting where he also discussed how the agent will “fit” into prescribing patterns.
How do patients with diabetes, prediabetes fare?
“Current guidelines support aggressive LDL cholesterol lowering in patients with diabetes, given the increased risk of cardiovascular morbidity and mortality,” said Dr. Leiter.
Bempedoic acid was approved as an adjunct to diet and maximally tolerated statin therapy to treat adults with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL cholesterol, although its effect on cardiovascular morbidity and mortality has not been determined, the prescribing information states.
However, it has been unknown how bempedoic acid affects LDL cholesterol or hemoglobin A1c levels in patients with diabetes, prediabetes, or normoglycemia.
To examine this, the researchers pooled data from four phase 3 trials in 3623 patients with ASCVD or HeFH who had been randomized 2:1 to bempedoic acid 180 mg/day or placebo for 12 or 24 weeks (if they were statin intolerant) or 52 weeks (if they were also on statins).
In the pooled sample, about half the patients had prediabetes (52%), and the rest had diabetes (31%) or normoglycemia (17%). Overall, 75%-84% of patients had a history of ASCVD.
Mean LDL cholesterol levels were higher in patients with normoglycemia (119 mg/dL) or prediabetes (115 mg/dL) than in patients with diabetes (110 mg/dL).
The primary outcome was percent change in LDL cholesterol from baseline to week 12.
In the two types of patients (all with ASCVD or HeFH) – those on statins and those with statin intolerance – LDL cholesterol at 12 weeks was significantly lower in patients who received bempedoic acid, compared with placebo, regardless of whether they had no diabetes, prediabetes, or diabetes (all P < .001).
Similarly, patients who received bempedoic acid also had significant reductions in total cholesterol, non–HDL cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (hsCRP) at 12 weeks, compared with patients who received placebo (all P < .01).
The safety profile of bempedoic acid was similar to placebo and did not vary by glycemic status.
“Of course, with any lipid-lowering therapy, there’s lots of interest in changes in glycemic parameters,” said Dr. Leiter. “A1c did not increase. In fact, it was significantly lower in patients with prediabetes and diabetes on bempedoic acid versus placebo.”
In addition, “statin trials have shown small increases in body weight. We did not observe this,” he reported.