Background
Lipid lowering therapy have been the mainstay treatment for primary and secondary cardiovascular disease prevention. While robust data shows that high intensity statin therapy can lower LDL-cholesterol (LDL-C) about 50%, few large-scale trials, until recently, supported the use of adjunct lipid-lowering agents to further reduce LDL-C.¹

Despite optimal reduction in LDL-C, patients with coronary artery disease have a residual risk of experiencing additional cardiovascular events.² Hence, adjunct lipid lowering strategy with triglyceride (TG) reduction can provide additional risk reduction on top of maximally tolerated statin therapy.

Mechanism of Action: Ezetimibe inhibits the absorption of biliary and intestinal absorption by binding to Niemann-Pick C1-Like 1 is now largely used to further reduce LDL-C.³

Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (P04103) (IMPROVE-IT) trial randomized 18,144 patients who were hospitalized for an acute coronary syndrome within the preceding 10 days; subjects had LDL-C levels of 50 to 100 mg/dl and were receiving lipid-lowering therapy or 50 to 125 mg/dL if they were not receiving lipid-lowering therapy.⁴

The combination of simvastatin 40 mg and ezetimibe 10 mg was compared to the control arm of simvastatin 40 mg monotherapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke with a median follow-up of 6 years.

Ezetimibe when added to simvastatin resulted in incremental lowering of LDL-C compared to simvastatin alone (54 compared to 70 mg per deciliter). More importantly, ezetimibe improved cardiovascular outcomes even with a such baseline LDL-C. The Kaplan–Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin–ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (HR: 0.936; 95% CI, 0.89 to 0.99; P=0.016). A subsequent analysis by Dr. Erin Bohula showed that there was substantial benefit in the high-risk subgroup with a modified TIMI risk score of at least 3.⁵

The safety of ezetimibe has been questioned with results from the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial in 2008 which randomized 1,873 patients with mild-to-moderate asymptomatic aortic stenosis (AS) to simvastatin/ezetimibe compared to simvastatin alone.³ The study did not find significant benefits from intensive lipid-lowering therapy in progression of AS but reported incidental findings of increased total cancer occurrence and cancer-associated death with simvastatin/ezetimibe compared to simvastatin alone (11.1% vs. 7.5% p = 0.01). Other smaller studies since SEAS did not corroborate these results (SHARP Study of Heart and Renal Protection).⁶

Given the lack of power in many of these studies, a subgroup analysis of the IMPROVE-IT trial sought to evaluate the association of ezetimibe with cancer incidence in a much larger study population. This study may guide current practice in safely prescribing ezetimibe as an adjunct lipid lowering agent.

Study Design
Over a median 6-year follow-up period, 17,708 patients were followed, and suspected tumors (benign and malignant) were reported.⁷ An independent panel of oncologists who were blinded to randomization evaluated these tumors to determine malignancy. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies), and secondary endpoint was death due to malignancy.

Results
Within IMPROVE-IT 1,470 (8.3%) patients developed the primary malignancy endpoint during the median 6-year follow-up. Among the 1,470 patients who met the primary endpoint, 1,370 (7.7%) had new malignancy, 53 had progressive malignancy and 47 had relapses. The most common malignancies were prostate (18.9%), lung (16.8%), and bladder (8.8%) and no differences were observed between treatment arms (p >0.05).

Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe/simvastatin and simvastatin alone (10.2% vs. 10.3% HR: 1.03; 95% CI: 0.93 to 1.14, p =0.56) as were rates of death from malignancy (3.8% vs. 3.6%; HR: 1.04; 95% CI: 0.88 to 1.23; p = 0.68). There was no significant sex difference.

Significance
As more data supports the association between cardiovascular disease and the development cancer, it is essential to understand any potential carcinogenicity of lipid lowering agents as they are being routinely used in clinical practice.⁸ The SEAS trial serves as an example of an underpowered study that found a statistically significant association between ezetimibe and increased incidence of cancer.

The IMPROVE-IT trial randomized nearly 10 times the number of patients, was more ethnically diverse, and prospectively followed patients. It used an independent panel of expert oncologists to support findings that disproved earlier claims of ezetimibe's carcinogenicity.

Compared to the SEAS trial and smaller retrospective studies examining this topic, IMPROVE-IT had a more diverse patient population. Limitations of the study include the follow-up period of only 6 years (cancers may take more time to develop) and the power of cancer subgroups as the rates of cancers were low making it possible to not identify differences related to cancer subtype.⁹

IMPROVE-IT confirmed there is no link between ezetimibe and cancer, and it can be safely used as a lipid lowering agent. As the relationship between cardiovascular disease and oncology is better understood, it is essential to study both cardiovascular and oncologic endpoints of pharmacologic intervention and incorporate expert oncologists into study design.

References

1. Adams SP, Tsang M, Wright JM. Lipid lowering efficacy of atorvastatin. Cochrane Database Syst Rev 2012;12:CD008226.
2. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012;14:1-10.
3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;Mar 17:[Epub ahead of print].
4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;375:2387-97.
5. Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359:1343-56.
6. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92.
7. Giugliano RP, Gencer B, Wiviott SD, et al. Prospective evaluation of malignancy in 17,708 patients randomized to ezetimibe vs. placebo: analysis from the IMPROVE-IT. J Am Coll Cardiol CardioOnc 2020;3:385-96.
8. Van't Klooster CC, Ridker PM, Cook NR, et al. Prediction of lifetime and 10-year risk of cancer in individual patients with established cardiovascular disease. J Am Coll Cardiol CardioOnc 2020;2:400-10.
9. Lewis EF, Rhee JW. IMPROVE-IT: A final closure to carcinogenicity of ezetimibe? J Am Coll Cardiol CardioOnc 2020;2:397–99.

Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Dyslipidemias, Cholesterol, LDL, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Acute Coronary Syndrome, Retrospective Studies, Cardiovascular Diseases, Prostate, Urinary Bladder, Follow-Up Studies, Incidental Findings, Random Allocation

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