Why Athletes Might Need Ezetimibe

Ezetimibe is often mentioned on sports forums as a «mild» cholesterol drug that does not hit the muscles. This is partly true: its mechanism of action is not related to skeletal muscle. However, ezetimibe is not a performance enhancer and does not compensate for the harm from hormonal drugs. The editorial team examines the situations in which ezetimibe really makes sense for people who train, and what should not be expected of it.

Why athletes are interested in ezetimibe

The main reason for the interest is the drug's reputation as being neutral for the muscles. People who train intensively fear statin-associated muscle symptoms and want to lower cholesterol without risk to recovery. Ezetimibe acts in the intestine and does not affect the mevalonate pathway in muscle cells.

The second reason is the prevalence of dyslipidemia among athletes in certain disciplines. Veterans of strength sports and older amateurs, like the general population, have hereditary lipid metabolism disorders. In some of them LDL levels remain high despite training and diet.

The third reason is specific: in the bodybuilding community ezetimibe is sometimes viewed as a «companion» when using anabolic steroids. The editorial team addresses this approach separately below, since it is based on mistaken ideas about the mechanisms of cardiovascular risk.

Let us note right away: there is no data that ezetimibe improves strength, endurance or recovery. Its only proven role is lowering LDL and, in combination with a statin, reducing the risk of cardiovascular events in people with the appropriate indications.

Statin intolerance and combination therapy

For people who genuinely develop muscle symptoms on statins, the ESC/EAS guidelines (2019) propose several steps: changing the statin, reducing the dose, and if that is not enough — adding ezetimibe or using it as monotherapy. For a physically active patient such a strategy often turns out to be optimal.

The Korean RACING trial (Kim et al., 2022) compared two approaches in patients with atherosclerotic disease: a moderate-intensity statin plus ezetimibe versus a high-intensity statin. The combination was not inferior in the frequency of cardiovascular events, reached the target LDL more often, and discontinuation or dose reduction due to intolerance occurred less frequently — approximately 4.8% versus 8.2%.

For people who train, this means there is an evidence-based alternative to maximal statin doses. A doctor can choose a moderate dose of atorvastatin combined with ezetimibe, obtaining a comparable LDL reduction with a lower risk of muscle complaints.

When statins are impossible altogether, ezetimibe as monotherapy lowers LDL on average by about a fifth. This may be insufficient for patients at very high risk, and then the doctor considers other drugs, in particular PCSK9 inhibitors or bempedoic acid.

Athletes' nutrition and cholesterol absorption

The diet of many athletes contains a large amount of animal protein: eggs, meat, dairy products. The LDL response to dietary cholesterol is highly individual: in some people it is minimal, while in others, so-called «hyper-absorbers», it is pronounced. Ezetimibe acts precisely on this link.

At the same time, the drug is not a «license» for any diet. Saturated fats affect LDL mainly through hepatic mechanisms, not through intestinal cholesterol absorption. So the quality of the diet remains the basis of lipid control regardless of medication.

An interesting practical nuance: phytosterols and ezetimibe act on the same stage — intestinal absorption. So combining the drug with plant sterol supplements has limited sense; the advisability of such a combination should be discussed with a doctor.

Athletes are often also concerned about the effect on fat-soluble vitamins. Unlike drugs that bind fats, ezetimibe acts selectively on sterols, and according to available data it does not cause a clinically significant deficiency of vitamins A, D, E and K. Nevertheless, a balanced diet and, if necessary, monitoring of vitamin D remain a sensible practice.

Ezetimibe on top of anabolic steroids: the limits of what is possible

Anabolic-androgenic steroids cause a complex of changes: a sharp decrease in HDL, an increase in LDL, an increase in pressure, erythrocytosis, myocardial hypertrophy and impairment of its function. A statement from the American Heart Association (Baggish et al., 2017) describes these mechanisms as interrelated.

Ezetimibe can affect only one of these components — LDL. Moreover, the drug does not eliminate the decrease in HDL, which is caused primarily by the effect of androgens on hepatic lipase. It also does not affect pressure, hematocrit or structural changes in the heart.

Therefore, the notion of ezetimibe as «insurance» during a cycle is just as mistaken as the analogous notion about statins. The most effective way to normalize the lipid profile in this situation is to stop steroids under a doctor's supervision; in most people the indicators gradually recover.

If a person consults a doctor with dyslipidemia and has a history of steroid use, it is important to report this frankly. The interpretation of tests, the choice of therapy and the assessment of cardiac risk all depend on it.

Anti-doping status and practical nuances

Ezetimibe is not on the WADA Prohibited List and has no ergogenic properties. Its use for medical indications does not require a therapeutic use exemption. However, an athlete must declare any medications on the doping control form.

• The drug is taken once a day, regardless of food and the time of training.
• Bile acid sequestrants reduce the absorption of ezetimibe, so a time-separated intake is needed on a doctor's recommendation.
• LDL is monitored several weeks after the start of therapy, as with statins.
• In combination with a statin, all the restrictions and precautions characteristic of the statin apply.

Although myopathy on ezetimibe monotherapy occurs extremely rarely, such cases have been described in post-marketing data. So new pronounced muscle symptoms, especially against the background of a combination with a statin, should be a reason to consult a doctor and test CK.

And finally, about quality. Ezetimibe is an affordable generic drug sold in pharmacies by prescription. Buying it through unofficial channels has no advantages and carries the risk of counterfeits.

Editorial conclusions

Ezetimibe does not improve athletic performance, but it may be appropriate for physically active people with proven dyslipidemia, especially in cases of intolerance to high doses of statins.

The RACING trial showed that a combination of a moderate statin dose with ezetimibe is not inferior to high-intensity monotherapy and less often requires discontinuation due to intolerance.

On top of anabolic steroids, ezetimibe affects only one link of the risk and does not make steroid use safe.

We also recommend reading «Ezetimibe: mechanism of action», «Side effects and contraindications of Ezetimibe» and «Why athletes might need Atorvastatin».

References

1. Kim BK, Hong SJ, Lee YJ, et al. Long-term efficacy and safety of moderate-intensity statin with ezetimibe combination therapy versus high-intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING). Lancet. 2022;400(10349):380–390.
2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111–188.
3. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397.
4. Baggish AL, Weiner RB, Kanayama G, et al. Cardiovascular toxicity of illicit anabolic-androgenic steroid use. Circulation. 2017;135(21):1991–2002.
5. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel Statement. Eur Heart J. 2015;36(17):1012–1022.
6. Zetia (ezetimibe) tablets. Prescribing information. U.S. Food and Drug Administration.
7. World Anti-Doping Agency. The Prohibited List. Montreal: WADA; оновлюється щороку.