Lipid-Lowering Therapies Beyond Statins: ESC 2024

For patients who cannot reach guideline-recommended low-density lipoprotein cholesterol levels on statins alone or who are statin intolerant, additional lipid-lowering therapies are needed.

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While statins are commonly prescribed to lower low-density lipoprotein (LDL) cholesterol, and they can have other benefits for the heart, blood vessels, and other organs, not all patients can reach guideline-recommended LDL cholesterol goals while other patients may be intolerant to statins. Research at the European Society of Cardiology Congress 2024 evaluated lipid-lowering therapy in addition to statins.

Bempedoic Acid for MACE Reduction

A systematic review of randomized controlled trials comparing bempedoic acid with placebo in patients with hyperlipidemia found the intervention significantly reduced 3-point major adverse cardiovascular events (MACE) consisting of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.¹ However, this reduction was largely driven by a lower rate of nonfatal myocardial infarction.

Bempedoic acid was first approved in the US in February 2020 as bempedoic acid and ezetimibe (Nexlizet) to lower LDL cholesterol in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease.² It was the first nonstatin agent approved in the US. Earlier this year, its label was expanded to not only include both primary and secondary prevention patients for lowering LDL cholesterol but also to reduce cardiovascular risk.³

The researchers conducted a systematic search of PubMed, Web of Science, and Embase for published research until March 20, 2023. They identified 10 papers, with 18,200 (9765 on bempedoic acid and 8435 on placebo) patients included. While bempedoic acid significantly reduced MACE compared with placebo (OR, 0.84; 95% CI, 0.76-0.96; P < .001; I² = 0%), it did not have a significant effect on stroke (OR, 0.86; 95% CI, 0.69-1.08; P = .20; I² = 0%) or all-cause mortality (OR, 1.19; 95% CI, 0.73-1.93; P = .49; I² = 18%).

Lipid Lowering Beyond Statins

Other research analyzed the findings of 15 randomized controlled trials to evaluate how well ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduced LDL cholesterol in addition to statins.⁴ Because a minority of patients on statin therapy reach suggested LDL thresholds, additional medications are added on to intensify therapy.

The researchers conducted a meta-analysis of IMPROVE-IT, FOURIER, ODYSSEY Outcomes, ODYSSEY LONG TERM, EWTOPIA 75, PACMAN-AMI, RACING, SPIRE I, SPIRE II, OSLER-1, OSLER-2, CLEAR HARMONY, CLEAR OUTCOMES, CLEAR SERENITY, and CLEAR WISDOM.

They found ezetimibe and PCSK9 inhibitors were associated with:

• 19% risk reduction in cardiovascular events (OR, 0.81; 95% CI, 0.75-0.86)
• 19% risk reduction in myocardial infarction (OR, 0.81; 95% CI, 0.74-0.89)
• 23% risk reduction in ischemic stroke (OR, 0.77; 95% CI, 0.70-0.84)

Similarly, this research found all-cause mortality was not improved by intensified lipid-lowering therapy, even when comparing follow-up of less than 3 years with 3 years or more.

“Intensified LDL-lowering therapy with ezetimibe, bempedoic [acid,] or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality,” the researchers concluded.

Lipid Lowering in High-Risk Patients

Finally, researchers from the United Kingdom analyzed lipid management in high-risk patients and found that real-world practice had not been updated to reflect changes in lipid guidelines, which advocate for the use of combination lipid-lowering therapy to achieve very low LDL cholesterol.⁵

The study included 102 very high-risk patients with a prior history of acute coronary syndrome (ACS) or stroke who had a subsequent ACS or stroke between January 2022 and December 2022. The patients had been treated at a United Kingdom district general hospital.

Prior to admission, 15% of the patients had been on no lipid-lowering therapy. A total of 77.4% of patients had received a lipid profile in the 18 months prior to admission and only 19.6% were compliant with the standard secondary prevention guidelines of receiving high-intensity statins. A significant number of the patients still received no lipid profile in the 12 months after admission (21% in the ACS group and 57% in the stroke group).

Only 5 patients were escalated to receive high-intensity statin plus ezetimibe and 1 patient escalated to receive a statin plus ezetimibe plus a PSCK9 inhibitor. Only 45% of patients reached the guideline target of LDL less than 1.8 mmol/L in 1 year of follow up.

“A majority of our ACS patients did not have a lipid profile blood test during their admission highlighting the fact that whilst guidelines have progressed significantly over the last few years the clinical importance of lipid optimisation in practice has not been appreciated by many of the clinicians,” they wrote.

References

1. Mutschlechner D, Tscharre M, Huber K, Gremmel T. Cardiovascular events in patients treated with bempedoic acid vs. placebo: systematic review and meta-analysis. Presented at: ESC 2024; August 30, 2024; London, England.

2. New tablets for lowering cholesterol granted FDA approval. Pharmacy Times^®. February 27, 2020. Accessed August 29, 2024. https://www.pharmacytimes.com/view/new-combination-tablet-for-lowering-cholesterol-granted-fda-approval

3. Gallagher A. FDA expands label for bempedoic acid to reduce cardiovascular risk, with or without statins. Pharmacy Times. March 22, 2024. Accessed August 29, 2024. https://www.pharmacytimes.com/view/fda-expands-label-for-bempedoic-acid-to-reduce-cardiovascular-risk

4. Dykun I, Khoury M, Rassaf T, Mahabadi AA. Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events. Presented at: ESC 2024; August 30, 2024; London, England.

5. Ghazanfar A, Campbell R, Randall R, Child N. The difference between guideline based lipid optimisation and real-world practice in a very high risk population. Presented at: ESC 2024; August 30, 2024; London, England.