Lipid-Lowering Bempedoic Acid Does Not Hasten or Worsen Diabetes

Marlene Busko

June 17, 2020

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 adenosine triphosphate-citrate lyase (ACL), was approved by the US Food and Drug Administration in February 2020.

Lawrence A. Leiter MD, from the University of Toronto, Ontario, Canada, delivered the findings of this latest analysis in an oral presentation June 12 at the virtual American Diabetes Association (ADA) 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," Leiter told Medscape Medical News in an email.

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 one extra case per 255 treated patients (in whom one would expect 5.4 cardiovascular events to be prevented by the statin)," he noted.

Invited to comment, John R. Guyton, MD, from Duke University Medical Center, Durham, North Carolina, 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 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 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 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% to 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).

Change in LDL-C at 12 Weeks in Patients With ASCVD or HeFH on Statins

  Bempedoic Acid Group Placebo Group 
Baseline Glycemic Status n Change in LDL-C, % n Change in LDL-C, %
No diabetes 314 –14.0 157 3.2
Prediabetes 994 –16.4 504 2.1
Diabetes 614 –18.6 317 0.6

 

Change in LDL-C at 12 Weeks in Statin Intolerant Patients With ASCVD or HeFH 

  Bempedoic Acid Group  Placebo Group 
Baseline Glycemic Status n Change in LDL-C, % n Change in LDL-C, %
No diabetes 76 –25.2 46 –1.6
Prediabetes 215 –25.0 91 4.7
Diabetes 108 –20.9 52 –1.9

 

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 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.

Where Does Bempedoic Acid "Fit"?

"Bempedoic acid will be a useful add-on to any patient who requires additional LDL-cholesterol lowering," according to Leiter.

"It will typically be used as an add-on to statins, but will also be very useful in the statin-intolerant patient, especially when used in combination with ezetimibe," he said.

The fixed-dose combination of bempedoic acid plus ezetimibe (Nexlizet, Esperion), was also approved in the United States in February, just days after bempedoic acid as a solo agent was cleared for marketing.

"Bempedoic acid would not be chosen in preference to a statin, ezetimibe, or PCSK9 inhibitor," Guyton said.

Rather, "its chief use will be in patients with statin intolerance and either FH or ASCVD when LDL-cholesterol is poorly controlled despite maximum tolerated lipid-lowering therapy."

According to Guyton, "use of bempedoic acid should be undertaken only when provider-patient discussion acknowledges that it has not been shown to reduce cardiovascular events, although preliminary evidence from genetic analysis (Mendelian randomization study) suggests that it will," as previously reported.

The CLEAR Outcomes cardiovascular outcomes trial of bempedoic acid completed enrollment in August 2019, involving 14,032 patients with hypercholesterolemia and high CVD risk according to a company statement.

The study was funded by Esperion. Leiter has reported being on advisory panels for Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novo Nordisk, Sanofi, and Servier, receiving research support from Amgen, AstraZeneca, Kowa Pharmaceuticals, and The Medicines Company, and being on speakers bureaus for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, HLS Therapeutics, Janssen, Medscape, Merck, Novo Nordisk, Sanofi, and Servier. Disclosures for the other authors are listed with the abstract. Guyton has reported being a consultant for Amarin and receiving research support form Regeneron Pharmaceuticals.

ADA 80th Scientific Sessions. June 12, 2020. Abstract 185-OR.

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