Bempedoic Acid Reassures in Patients With and Without Diabetes: CLEAR Outcomes

The use of bempedoic acid (Nexletol; Esperion) safely lowers LDL cholesterol levels and reduces cardiovascular events in statin-intolerant patients with and without diabetes, according to results of a new CLEAR Outcomes analysis.

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. 

“There are going to be people who are more concerned about the risk of diabetes with statins, and these are going to be people who are overweight or who have metabolic syndrome,” lead investigator Kausik K. Ray, MD, MPhil (Imperial College London, England), told TCTMD. “While they obviously have to [adopt a healthy] lifestyle, knowing that this drug is giving you benefits like cardiovascular risk reduction, and not making your glucose levels worse, particularly in someone who might be prone to that, might be why some people could choose this [drug].”

In a diabetic patient unable to tolerate statins, bempedoic acid is an excellent alternative, particularly if combined with ezetimibe, said Ray.

Naveed Sattar, MD, PhD (University of Glasgow, Scotland), who led a large meta-analysis that provided firm evidence statin use was associated with a higher risk of diabetes, said that he is “reasonably confident” bempedoic acid does not increase the risk of new-onset diabetes in treated patients.

“But the context is that it’s not without risks because it has previously been shown, even in the outcomes’ trial, it increased the risk of gout,” Sattar told TCTMD, pointing to a higher 1% absolute risk with bempedoic acid in CLEAR Outcomes. “There's something about targeting this pathway that affects some other metabolic pathway. In the case of bempedoic acid, it looks like it's the uric-acid pathway and gout. In the case of statins, it looks like it's the glycemia pathway and diabetes risk.”

The new analysis was published this week in the Lancet Diabetes & Endocrinology.

Metabolic Safety of Bempedoic Acid

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.

Given that the risk of new-onset diabetes emerged long after statins were approved, subsequent trials with other lipid-lowering therapies have sought to clarify whether these newer drug classes were also associated with risk.

Bempedoic acid is an ATP citrate lyase inhibitor that targets the production of cholesterol upstream of the enzyme inhibited by statins. The drug is approved by both the FDA and the European Medicines Agency as an adjunct to diet and lifestyle changes for lowering LDL cholesterol but does not yet have an indication for cardiovascular event reduction.

The CLEAR Outcomes study—the cardiovascular outcomes trial—included 13,970 primary- and secondary-prevention patients deemed intolerant to statins. In the main trial, treatment reduced the relative risk of the primary four-component MACE endpoint (CV death, nonfatal MI, nonfatal stroke, or coronary revascularization), as well as the three-component MACE endpoint that excluded revascularization, by 13% and 15%, respectively.

Of those included in the trial, 6,373 had diabetes and 5,796 had prediabetes. Over 3.4 years of follow-up, the primary four-component MACE endpoint occurred in 11.9% of patients with normoglycemia, 12.6% of those with prediabetes, and 14.2% of those with diabetes, with a similar graded relationship observed for the three-component MACE endpoint by diabetes status.

In those with diabetes, bempedoic acid reduced the relative risk of the four-component MACE endpoint by 17% compared with placebo, with similar trends seen in those with prediabetes and normal glycemic levels (P = 0.42 for interaction). The three-component MACE endpoint was reduced 20% among those with diabetes, with similar trends again seen in those with prediabetes and normoglycemia (P = 0.10 for interaction). In terms of absolute risk reduction, the largest benefit was seen in those with diabetes (2.4% and 2.1% reduction for MACE-4 and MACE-3, respectively).

“We wanted look at the benefit in people with diabetes because they're at a higher cardiovascular risk,” said Ray. “The same percentage reduction in LDL and same reduction in CRP levels gets you similar relative risk reductions in those with and without diabetes. However, you get a much bigger absolute cardiovascular benefit [in those with diabetes] because absolute risk is much higher. The higher the risk in the population, the greater the benefit.”

No New-Onset Diabetes

The second goal of the analysis was to assess the metabolic safety of treatment. Here, use of bempedoic acid did not result in new-onset diabetes in patients without diabetes at baseline, nor did it result in new-onset diabetes in those with normoglycemia or prediabetes. Similarly, treatment did not impact mean HbA1c levels at 12 months or study completion in those without diabetes, those with normoglycemia, and those with prediabetes. Similar results were observed for mean fasting glucose levels.

For patients with diabetes, weight changes were larger with bempedoic acid when compared with placebo (-0.64 kg at study completion; P < 0.0001).

While CLEAR Outcomes is relatively short at 3.4 years, Ray pointed to their mendelian randomization study of ACLY, the gene encoding for ATP citrate lyase, and HMGCR, the gene that encodes 3-hydroxy-3-methylglutaryl–coenzyme A reductase, which is the target of statins. They showed ACLY and HMGCR were associated with similar changes in the concentration of plasma lipoproteins and had a similar effect on the risk of cardiovascular events for each unit decrease in LDL cholesterol. Importantly, the ACLY genetic risk score was not associated with the risk of diabetes while the HMGCR risk score was.

“With statins, you see weight gain, you see an increased risk of new-onset diabetes,” said Ray. “The genetics show exactly the same thing. Targeting ACLY—the genetics and the trials—show small weight loss and no increased risk of diabetes. So, what that means is if you're treating with bempedoic acid for 40 years, it probably should be safe.”

Sattar said the increased risk of diabetes with statins is “relatively modest,” noting that it’s most likely to occur in people close to the diagnostic threshold and could be mitigated with an increase in exercise and adherence to a better diet. The new data, he said, shouldn’t elevate bempedoic acid over statin therapy as first-line treatment for at-risk patients in need of LDL cholesterol-lowering. Nonetheless, bempedoic acid is reassuring from the standpoint that it doesn’t result in muscle pain and/or weakness and does not affect metabolic risk, said Sattar.

“There may be some physicians who are worried about the diabetes risk in some individuals, and a very, very small minority might think about a combination of ezetimibe plus bempedoic acid to not expose their patients to a slightly higher risk of diabetes,” he said. “But I think that it's going to be a negligible number of people, I would imagine, at this moment in time.”