Bempedoic Acid: A Statin-Intolerance Savior?

Cardiovascular disease remains one of the leading causes of death in patients with type 2 diabetes in the United Kingdom. Sadly, these patients are twice as likely to suffer or die from a cardiovascular event, compared with patients without type 2 diabetes. Therefore, mitigating future cardiovascular risk is a key priority for me in supporting patients with type 2 diabetes.

Kevin Fernando, MBChB, MSc

Recently updated UK NICE guidance covering the management of type 2 diabetes in adults has encouraged healthcare professionals to think beyond glycemia and address overall cardiovascular risk. The guidance recommends that clinicians choose cardioprotective therapies irrespective of baseline glycemic control and according to the presence of specific comorbidities such as atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. This change in guidance has been driven by several positive cardiorenal outcome trials for SGLT2 inhibitors and GLP-1 receptor agonists. The trials demonstrated significant reductions in major adverse cardiovascular and kidney events, including cardiovascular mortality, following treatment with these drugs.

Despite the use of cardioprotective therapies, however, many of my patients with type 2 diabetes have significant residual cardiovascular risk that results from factors such as dyslipidemia. Elevated LDL cholesterol is a proven direct cause of atherosclerotic cardiovascular disease. Moreover, for every 39-mg/dL reduction in LDL cholesterol, there is a 23% reduction in major vascular events.

The recently updated European Society of Cardiology/European Atherosclerosis Society lipid guidance now recommends very tight LDL cholesterol targets for our highest-risk patients, including those with type 2 diabetes. For my patients with type 2 diabetes without target organ damage (eg, microalbuminuria or retinopathy) and with diabetes duration of at least 10 years or an additional risk factor (eg, hypertension), it is now recommended to aim for an LDL cholesterol target of < 70 mg/dL and a 50% reduction from baseline. If there is evidence of end-organ damage or three or more risk factors, then the LDL cholesterol target is < 54 mg/dL and a 50% reduction from baseline.

Clearly, these targets are challenging for many of my patients, particularly those who are statin intolerant. In the UK, public opinion of statins varies widely, largely because of conflicting headlines in the press. While it is increasingly accepted that most side effects attributed to statins result from a nocebo effect (that is, an expectation of adverse side effects rather than actual adverse events), it is estimated that around 9% of patients are truly statin intolerant.

For my statin-intolerant patients, I usually will try a lower dose of the current statin (eg, atorvastatin, 10 mg or 20 mg). If it is not tolerated, I will switch to an alternative hydrophilic statin, such as pravastatin or rosuvastatin, that has a weaker association with muscle symptoms. Rosuvastatin has the additional advantage of having a relatively long half-life (19 hours vs 2-3 hours with simvastatin), which allows alternate-day dosing to improve compliance and concordance with statin therapy.

In patients who do not tolerate even this infrequent dosing strategy, I was hitherto limited in my further oral treatment options.

Ezetimibe is one option in this context but has modest cardiovascular outcome data (and only alongside simvastatin) from the IMPROVE-IT trial. The drug has no effect on cardiovascular mortality or all-cause mortality. But it does what it says on the tin and reduces LDL cholesterol by around 20% from baseline (only when added on to a statin).

A newer oral medication to reduce LDL cholesterol is bempedoic acid. This prodrug inhibits liver cholesterol synthesis upstream of statins. Bempedoic acid is activated in the liver, however, and not in the peripheral muscle. Therefore, it is not associated with significant muscle-related adverse effects. This is, in my opinion, one of the key clinical advantages of bempedoic acid. My patients agree.

The phase 3 clinical trial program investigating bempedoic acid demonstrated 17%-28% reductions in LDL cholesterol with bempedoic acid alone and a 38% reduction when used with ezetimibe. In the clinical trial program, bempedoic acid was generally well tolerated. Commonly reported adverse effects included hyperuricemia, pain in extremities, anemia, and constipation.

The CLEAR Outcomes trial that was published earlier this year provided positive cardiovascular outcomes data for bempedoic acid in a population of high-risk patients (mixed primary and secondary prevention) who were statin intolerant. The primary endpoint of the trial (4-point MACE) was significantly reduced by 13%, which equates to a number needed to treat (NNT) of 63 over 40 months to prevent one composite event. Of note, no mortality benefit was observed.

A prespecified subgroup analysis of the CLEAR Outcomes trial was published during the recent ADA 2023 congress. This analysis explored the impact of bempedoic acid on cardiovascular outcomes in the primary prevention cohort of participants (30% of total participants) who were statin intolerant. Two thirds of this primary prevention cohort had type 2 diabetes. In this cohort, 4-point MACE was reduced by 30%, which equates to an NNT of just 43 over 40 months to prevent one composite event.

I have several patients on bempedoic acid now, predominantly in the context of type 2 diabetes and secondary prevention. Specifically, I have patients with type 2 diabetes and comorbid atherosclerotic cardiovascular disease optimized on metformin, an SGLT2 inhibitor, a GLP-1 receptor agonist, aspirin, a statin at the maximally tolerated dose (eg, atorvastatin, 80mg), and ezetimibe. I have initiated bempedoic acid for these patients if they are still above their LDL cholesterol target of 54 mg/dL.

The aforementioned results have given me confidence to widen my prescribing of bempedoic acid to my higher-risk primary-prevention patients (with or without type 2 diabetes) who are truly statin intolerant.

However, I do not consider bempedoic acid a replacement for statins, with their potent LDL cholesterol–lowering efficacy, established mortality benefits (with compellingly lower trial NNTs), and associated beneficial cardiovascular pleiotropic effects.

In addition, the current cost of bempedoic acid is significantly more than that of statins and ezetimibe, which are widely available as generics. For these reasons, I would still consider rechallenging my highest-risk patients with a statin, even several years down the line. Nevertheless, I welcome this additional evidence-based option to reduce the risk for major vascular events in primary and secondary prevention.

Dr Fernando is a general practitioner near Edinburgh, Scotland, with a specialist interest in diabetes; cardiovascular, renal, and metabolic diseases; and medical education.

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Cite this: Bempedoic Acid: A Statin-Intolerance Savior? - Medscape - Jun 29, 2023.