How to manage side effects in patients taking statins (HMG-CoA reductase inhibitors)?

From the Guidelines

Statin side effects should be managed by first assessing the severity and type of symptoms, and then considering a systematic approach that includes temporary discontinuation, rechallenge with a lower dose or alternative statin, and combination with non-statin therapies if necessary, as recommended by the 2022 ACC expert consensus decision pathway 1. When patients experience side effects, it is essential to evaluate the symptoms and determine the best course of action. For mild to moderate myalgias, temporarily discontinuing the statin for 2-4 weeks to see if symptoms resolve, and then rechallenging with the same statin at a lower dose or switching to a different statin, such as fluvastatin, pitavastatin, or rosuvastatin, which may be better tolerated, is a reasonable approach 1. Some key points to consider when managing statin side effects include:

• Assessing the severity and type of symptoms, with muscle-related complaints being most common
• Temporarily discontinuing the statin for 2-4 weeks to see if symptoms resolve, and then rechallenging with the same statin at a lower dose or switching to a different statin
• Considering alternative dosing strategies, such as every-other-day or twice-weekly regimens, especially with longer-acting statins like atorvastatin or rosuvastatin
• Ruling out contributing factors like hypothyroidism, vitamin D deficiency, or drug interactions (particularly with medications metabolized by cytochrome P450 3A4)
• Regular monitoring of liver enzymes and creatine kinase levels is recommended for patients with persistent symptoms, as suggested by the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1. The use of non-statin therapies, such as ezetimibe or PCSK9 inhibitors, may be considered for patients who have failed to achieve adequate reduction in LDL-C or non-HDL-C on maximally tolerated statin therapy, as recommended by the 2022 ACC expert consensus decision pathway 1.

From the FDA Drug Label

Atorvastatin calcium may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Rosuvastatin may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis.

Managing Side Effects in Patients Taking Statins: To manage side effects in patients taking statins, the following steps can be taken:

• Monitor liver enzymes: Consider liver enzyme testing before statin initiation and when clinically indicated thereafter.
• Monitor muscle symptoms: Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the statin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.
• Adjust dosage: Rosuvastatin dosage modifications are recommended for patients taking certain antiviral medications, darolutamide, and regorafenib. Atorvastatin calcium dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications.
• Discontinue statin: Discontinue statin if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Temporarily discontinue statin in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.
• Consider alternative treatments: Consider if the benefit of use of certain products (e.g. lipid modifying doses of niacin, fibrates, colchicine) outweighs the increased risk of myopathy and rhabdomyolysis. 2 3

From the Research

Statin Side Effects

• The most common side effect of statins is statin-associated muscle symptoms, with myalgia being the most commonly reported [(4,5,6,7)].
• Other side effects include new-onset diabetes mellitus, elevation in liver enzymes, and increased risk of diabetes mellitus [(4,8,6,7)].
• Rhabdomyolysis is a rare but serious side effect of statin use [(8,6)].
• Derangement in liver function tests is common, but the clinical significance is unknown 6.

Management of Statin Side Effects

• Strategies for managing statin intolerance include changing statins, intermittent dosing, intensification of lifestyle modifications, and using other LDL-C-lowering agents 5.
• Identifying patients with true statin-associated side effects and proactive utilization of available diagnostic tests to rule out alternate etiologies is essential for accurate diagnosis 4.
• Timely intervention with modified statin or non-statins is beneficial in patients with true statin-associated side effects 4.
• Alternative strategies should be identified to avoid an increased risk of atherosclerotic cardiovascular disease in patients who discontinue statin therapy due to intolerance 7.

Risk Factors for Statin Side Effects

• Risk factors for statin-related myopathy include hypothyroidism, polypharmacy, and alcohol abuse 6.
• Patients with multiple medical co-morbidities are at increased risk of adverse effects from long-term statin use 6.
• Certain statin drugs, such as pitavastatin, have not been associated with an increased risk of diabetes 6.