Get urgent medical help for severe muscle pain or weakness with dark (tea- or cola-coloured) urine or passing much less urine (possible rhabdomyolysis); for yellow skin or eyes (possible liver injury); or for swelling of the face, lips or throat, or trouble breathing (possible serious allergic reaction).
Key points
- Statins are the foundation of LDL lowering. Ezetimibe, PCSK9 inhibitors, inclisiran and bempedoic acid are added when LDL stays high or statins cannot be taken.
- Statin muscle damage is uncommon and rhabdomyolysis is very rare. NICE advises checking creatine kinase (CK) only for unexplained muscle symptoms.
- Simvastatin and lovastatin are contraindicated with strong CYP3A4 inhibitors and have dose limits with amlodipine, amiodarone, diltiazem and verapamil.
- The first oral PCSK9 inhibitor, enlicitide (Lipfendra), was FDA-approved in July 2026 to lower LDL in adults, including those with heterozygous familial hypercholesterolaemia.
- In 2021 the FDA asked for the statin pregnancy contraindication to be removed. Most people should still stop a statin once pregnancy is recognised, and breastfeeding is not recommended while taking one.
How each medicine lowers LDL
- Statins (atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin and others) block HMG-CoA reductase, a key enzyme in the liver's cholesterol production.
- Ezetimibe blocks the intestinal sterol transporter NPC1L1, reducing absorption of cholesterol and plant sterols from the gut. The dose is 10 mg once daily, with or without food.
- PCSK9 monoclonal antibodies (evolocumab, alirocumab) bind PCSK9, a protein that destroys LDL receptors on liver cells, so the liver clears more LDL. They are injected under the skin every 2 to 4 weeks (evolocumab 140 mg every 2 weeks or 420 mg monthly; alirocumab usually starts at 75 mg every 2 weeks or 300 mg every 4 weeks and can be raised to 150 mg every 2 weeks).
- Enlicitide is a macrocyclic peptide that binds PCSK9 in the same way, but by mouth. It was approved by the FDA on 15 July 2026 (NDA 220848). The dose is one 20 mg tablet once daily. Take it in the morning on an empty stomach with water, black coffee or plain tea. Swallow it whole and wait at least 30 minutes before other food or drink.
- Inclisiran is a small interfering RNA (siRNA) that makes liver cells produce less PCSK9. A health professional injects 284 mg, repeats it at 3 months, then gives it every 6 months.
- Bempedoic acid blocks ATP-citrate lyase, an enzyme that acts earlier in the same cholesterol pathway as statins. The dose is 180 mg once daily.
Who uses them
Statins are used for primary and secondary prevention of cardiovascular disease (targets are covered in our high LDL cholesterol article). US approvals for the add-ons differ:
- Evolocumab and alirocumab: lower LDL, and also reduce the risk of major cardiovascular events (such as heart attack and stroke) in adults at increased risk.
- Bempedoic acid: lowers LDL, and reduces cardiovascular events in adults at increased risk who cannot take recommended statin therapy.
- Inclisiran and enlicitide: approved to lower LDL. Their labels cite outcome trials of statins and PCSK9 antibodies but do not include their own cardiovascular-event indication. A cardiovascular outcomes trial of enlicitide is ongoing.
In the UK, NICE recommends ezetimibe when statins are contraindicated or not tolerated, bempedoic acid with ezetimibe when ezetimibe alone is not enough, and considering ezetimibe, a PCSK9 antibody (alirocumab or evolocumab) or inclisiran, as set out in its technology appraisals, when the maximum tolerated statin does not reach the secondary-prevention target. Access rules differ between countries.
Statin muscle symptoms and rhabdomyolysis
NICE advises telling people that the risk of statin-related muscle pain, tenderness or weakness is small and that rhabdomyolysis is extremely rare. The FDA labels list these risk factors for myopathy:
- age 65 or over
- untreated (uncontrolled) hypothyroidism
- kidney impairment
- interacting medicines
- higher statin doses
The simvastatin label also notes a higher risk in Chinese patients. Rosuvastatin should start at 5 mg in Asian patients.
- Before starting: NICE advises measuring CK in anyone with persistent, unexplained generalised muscle symptoms. If CK is more than 5 times the upper limit of normal, re-check after 7 days. If it is still that high, do not start a statin. If it is raised but below 5 times, start at a lower dose.
- During treatment: measure CK if unexplained muscle pain, tenderness or weakness develops, not in people without symptoms. With CK below 5 times the upper limit, the statin is unlikely to be the cause, so look for other causes.
- Options if side effects occur (NICE): stop the statin and retry once symptoms resolve, to see whether they are linked; switch to another statin of the same intensity (for example from atorvastatin to rosuvastatin); lower the dose; or use a lower-intensity statin.
- Stopping: stop the statin if CK is markedly raised or myopathy is suspected, and pause it during acute illness with a high risk of rhabdomyolysis-related kidney failure.
- Immune-mediated necrotising myopathy is a rare autoimmune myopathy with anti-HMG-CoA reductase antibodies. Proximal weakness and raised CK persist after stopping the statin.
Liver tests and blood glucose
Statins can raise transaminases, and liver failure is rare. The labels advise considering liver tests before starting and stopping promptly for serious liver injury or jaundice. Simvastatin and atorvastatin are contraindicated in acute liver failure or decompensated cirrhosis. NICE advises checking transaminases at baseline, at 2 to 3 months and at 12 months, then only if clinically indicated. A raised level below 3 times the upper limit of normal is not a reason to withhold a statin.
Statins can raise HbA1c and fasting glucose. NICE advises against stopping a statin for this reason.
CYP3A4 interactions and label dose limits
CYP3A4 inhibitors raise simvastatin, lovastatin and atorvastatin levels and myopathy risk. Key US label limits:
| Statin | Contraindicated with | Dose limits |
|---|---|---|
| Simvastatin | Strong CYP3A4 inhibitors (some azole antifungals, macrolides such as clarithromycin, some antivirals, nefazodone); cyclosporine; danazol; gemfibrozil | Maximum 10 mg with verapamil, diltiazem or dronedarone; 20 mg with amiodarone, amlodipine or ranolazine. Usual maximum 40 mg; 80 mg only for people who have taken it for 12 months or more without muscle toxicity |
| Lovastatin | Strong CYP3A4 inhibitors (such as itraconazole, ketoconazole, clarithromycin, erythromycin, HIV protease inhibitors, cobicistat) | Maximum 20 mg with danazol, diltiazem, dronedarone or verapamil; 40 mg with amiodarone |
| Atorvastatin | No drug contraindications; cyclosporine, gemfibrozil, tipranavir plus ritonavir, and glecaprevir plus pibrentasvir are not recommended | Maximum 20 mg with clarithromycin, itraconazole and several HIV/HCV antivirals; 40 mg with nelfinavir |
| Rosuvastatin | No drug contraindications; avoid gemfibrozil and tafamidis | Maximum 5 mg with cyclosporine or darolutamide; 10 mg with teriflunomide, enasidenib, capmatinib, regorafenib, gemfibrozil (if used at all) and several HIV/HCV antivirals; 20 mg with febuxostat, fostamatinib |
Also:
- Grapefruit juice: raises simvastatin levels; avoid it with simvastatin.
- Warfarin: check the INR before starting simvastatin and during dose changes.
- Bempedoic acid: raises simvastatin and pravastatin levels. Avoid simvastatin above 20 mg or pravastatin above 40 mg with it.
Safety: what to check
- Before starting a statin: lipid profile, diabetes status, kidney function, transaminases, TSH if thyroid symptoms (NICE), all medicines and supplements, and previous muscle symptoms.
- Kidney function: in severe kidney impairment, start simvastatin at 5 mg (creatinine clearance 15 to 29 mL/min). Start rosuvastatin at 5 mg and keep it at 10 mg or less (CrCl below 30 mL/min/1.73 m², not on dialysis). Ezetimibe needs no kidney dose change.
- Liver: ezetimibe is not recommended in moderate or severe liver impairment (Child-Pugh B or C). Combinations with a statin carry the statin's own liver contraindications.
- Ezetimibe: consider stopping it if ALT or AST stays at 3 times the upper limit or more. Take it at least 2 hours before or 4 hours after a bile acid sequestrant, and monitor cyclosporine levels if both are used.
- PCSK9 antibodies and inclisiran: serious hypersensitivity reactions, including angioedema, have been reported with evolocumab, alirocumab and inclisiran, and a previous serious reaction is a contraindication. Injection-site reactions are common.
- Enlicitide: the US label lists no contraindications (pregnancy advice is below). In the familial hypercholesterolaemia study, diarrhoea (7% vs 2% on placebo) and dizziness (9% vs 4%) were more frequent than with placebo. Never take 2 doses in one day.
- Bempedoic acid: raises uric acid and can trigger gout. It has also caused tendon rupture: avoid it in people with previous tendon disorders and stop it at the first sign of rupture.
- Pregnancy: the FDA's July 2021 safety communication asked for the class-wide contraindication to be removed so that very high-risk patients can decide individually. Examples are homozygous familial hypercholesterolaemia or a previous heart attack or stroke. Most patients should still stop a statin when pregnancy is recognised, since treating cholesterol during pregnancy is generally not needed. The enlicitide label gives the same advice. Some generic lovastatin labels still list pregnancy as a contraindication, so follow the local product information.
- Breastfeeding: breastfeeding is not recommended while taking a statin. Many people can pause the statin until breastfeeding ends. Those who need ongoing treatment should use alternatives such as formula. Enlicitide's presence in human milk is unknown.
- Older adults: age 65 and over is a myopathy risk factor. Review interacting medicines and kidney function.
Frequently asked questions
Can I take my statin with amlodipine?
Yes, but the simvastatin dose must not go above 20 mg a day. Atorvastatin and rosuvastatin labels have no amlodipine limit. Ask your prescriber or pharmacist to check the dose.
Does my statin cause diabetes?
Statins can raise blood glucose and HbA1c slightly. NICE advises not stopping the statin for this reason, and the label advises healthy eating, regular exercise and weight control.
Is the new PCSK9 pill a replacement for statins?
No. Enlicitide is approved to lower LDL, usually alongside other treatment. Its effect on heart attacks and strokes is still being studied, while statins have proven outcome benefits.
I have muscle aches on a statin. Should I stop it?
Tell your clinician first, who may check CK and look for other causes. Options include a break and retrial, a different statin or a lower dose. Seek urgent care for severe weakness or dark urine.
Sources
- NICE. Cardiovascular disease: risk assessment and reduction, including lipid modification (NG238). nice.org.uk/guidance/ng238
- US FDA. Drug Safety Communication: FDA requests removal of strongest warning against using statins during pregnancy (20 July 2021). fda.gov
- US FDA. Drugs@FDA approval letter, Lipfendra (enlicitide), NDA 220848, July 2026. accessdata.fda.gov
- ClinicalTrials.gov. CORALreef Outcomes, enlicitide cardiovascular outcomes study (NCT06008756). clinicaltrials.gov
- US FDA-approved labeling, enlicitide (Lipfendra). DailyMed
- US FDA-approved labeling (DailyMed), statins: simvastatin, atorvastatin, rosuvastatin, lovastatin
- US FDA-approved labeling (DailyMed), other LDL-lowering medicines: ezetimibe, evolocumab, alirocumab, inclisiran, bempedoic acid
This article is for education and does not replace advice from a doctor or pharmacist who knows the person's history and other medicines.
