What statins, available in Canada, have the lowest risk of muscle soreness for an adult patient with high cholesterol or at risk of cardiovascular disease?

Statins Available in Canada with Lowest Risk of Muscle Soreness

Pitavastatin and fluvastatin are the preferred statins for minimizing muscle-related adverse events, with pitavastatin demonstrating superior tolerability in patients with statin-induced myalgia. 1

First-Line Recommendations for Muscle Symptom Avoidance

Pitavastatin (Preferred Option)

• Pitavastatin is the top choice for patients concerned about muscle symptoms, demonstrating superior tolerability compared to other statins in patients with statin-induced myalgia 1
• This statin has minimal dependence on CYP3A4 metabolism and is lipophilic, which contributes to its lower muscle-related adverse event profile 1, 2
• Pitavastatin has a long half-life (up to 12 hours) and selective uptake into hepatocytes, with minimal metabolism by cytochrome P450 enzymes, decreasing the likelihood of drug-drug interactions that could increase myopathy risk 3
• Clinical trials demonstrate that pitavastatin 1-4 mg once daily is well tolerated and provides effective LDL-C reduction comparable to atorvastatin and simvastatin 4, 5

Fluvastatin (Second-Line Alternative)

• Fluvastatin is the second-line alternative statin, with lower muscle-related adverse event rates compared to most other statins, though it still carries a 74% relative risk compared to rosuvastatin for muscle symptoms 1
• Fluvastatin is lipophilic but has minimal CYP3A4 dependence, which may contribute to its improved tolerability profile 1

Additional Lower-Risk Options

Pravastatin

• Pravastatin is hydrophilic and non-CYP3A4 dependent, with a lower myopathy risk profile and different metabolism than atorvastatin 2
• This statin has been shown to have lower muscle-related adverse events in clinical practice 1

Rosuvastatin

• Rosuvastatin is hydrophilic with minimal CYP3A4 metabolism, making it another strong option for patients concerned about muscle symptoms 2
• However, rosuvastatin is more potent than atorvastatin at equivalent doses, which should be considered when prescribing 2

Important Context About Muscle Symptoms

True Incidence of Statin-Induced Myalgia

• In randomized clinical trials, the difference in muscle symptoms between statin-treated and placebo-treated participants is less than 1%, suggesting that most muscle symptoms are not pharmacologically caused by the statin 6
• True statin intolerance is very uncommon (only 1% of patients), and most muscle pain may be subjective or nocebo-related 2, 6
• The SAMSON trial demonstrated that 90% of adverse symptoms with statins can be attributed to nocebo effects 1

Risk Factors for Muscle Symptoms

• Advanced age (>65 years), female sex, small body frame or frailty, chronic renal insufficiency, hypothyroidism, vitamin D deficiency, and polypharmacy increase the risk for statin-associated muscle symptoms 2, 7
• Concomitant medications that alter drug metabolism, particularly CYP3A4 inhibitors (macrolide antibiotics, antifungals, cyclosporine, gemfibrozil), substantially increase myopathy risk 1, 2

Alternative Dosing Strategies if Muscle Symptoms Develop

• Alternate-day dosing with long half-life statins (atorvastatin or rosuvastatin at the lowest dose) can be considered for patients who cannot tolerate daily statin therapy 1, 2
• De-escalation dosing (alternating between 40 mg and 20 mg every other day) or lower daily doses than previously attempted are recommended strategies 1
• Starting with the lowest approved dose of any statin and gradually titrating up as tolerated minimizes the risk of muscle symptoms 2

Critical Pitfalls to Avoid

• Do not permanently discontinue statin therapy without establishing causality through rechallenge, as most muscle symptoms are not pharmacologically caused by the statin 1, 7
• Avoid combinations of statins with fibrates (especially gemfibrozil), high-dose niacin (>1 gram/day), or cyclosporine, which substantially increase myopathy risk 1
• Do not assume true statin intolerance until the patient has failed at least 2-3 different statins, preferably ones metabolized by different pathways 1, 2

When to Consider Non-Statin Therapies

• Non-statin therapies (ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran) should only be considered if the patient has failed at least 3 different statins, including one at the lowest approved dose 1, 2
• Combining a low-dose tolerated statin with ezetimibe is strongly preferred over ezetimibe monotherapy for cardiovascular outcomes 2