What is the onset of adverse effects associated with HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, commonly referred to as statins?

From the Guidelines

Side effects from statins can occur at any time during therapy, but most commonly develop within the first few weeks of starting treatment. According to the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1, the majority of symptoms are subjective and definitive diagnostic criteria do not exist. The clinical diagnosis of statin-associated muscle symptoms (SAMS) remains challenging, given that the majority of symptoms are subjective.

Some key points to consider when evaluating side effects from statins include:

• Muscle pain (myalgia) is a common side effect, and can develop within 4-6 weeks of starting the medication, but some patients may notice effects within days while others might not experience them for months or even years 1.
• Statins can also cause liver enzyme elevations, digestive issues, and increased blood sugar, with the timing varying based on the specific statin, dosage, individual metabolism, and genetic factors 1.
• Some side effects are dose-dependent, meaning higher doses increase the risk, and the benefits of statins for cardiovascular risk reduction often outweigh the potential side effects for most patients 1.
• If you experience concerning symptoms like severe muscle pain, weakness, or dark urine while taking statins, contact your healthcare provider immediately rather than discontinuing the medication on your own, as many side effects are manageable through dose adjustments, switching to a different statin, or changing the dosing schedule 1.

In terms of specific management strategies, the guideline recommends a approach of reassess, rediscuss, and rechallenge for patients experiencing SAMS, and notes that a majority of patients will be able to be successfully treated with at least one or several statins 1. Additionally, the guideline suggests that patients with statin-associated autoimmune myopathy may benefit from seeing a neurologist specializing in neuromuscular disorders, and that statins are not contraindicated in patients with increased ASCVD risk with chronic, stable liver disease 1.

From the FDA Drug Label

The maximum LDL-C reduction of pravastatin is usually achieved by 4 weeks and is maintained after that. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: hepatic transaminase elevations, nausea, anxiety/depression, and dizziness

• Time to onset of side effects: The exact time to onset of side effects is not specified in the label, but it is mentioned that the maximum LDL-C reduction is usually achieved by 4 weeks.
• Common side effects: The common side effects of pravastatin include nausea, diarrhea, headache, upper respiratory infection, and dizziness.
• Serious side effects: Serious side effects such as myopathy, rhabdomyolysis, and increased liver enzymes have been reported with pravastatin use 2.

From the Research

Side Effects of Statins

• The risk of hepatic injury caused by statins is estimated to be about 1 percent, similar to that of patients taking a placebo 3.
• Myalgias are common with statin use, but myositis and rhabdomyolysis are rare 3, 4.
• Myopathic symptoms usually resolve approximately two months after discontinuing the statin 3.
• Plasma levels of CoQ10 are lowered in the course of statin treatment, which could be related to the fact that statins lower plasma LDL levels 4.
• CoQ10 depletion during statin therapy might be associated with subclinical cardiomyopathy, and this situation is reversed upon CoQ10 treatment 4.

Timing of Side Effects

• The exact timing of side effects is not specified in the studies, but it is mentioned that myopathic symptoms resolve approximately two months after discontinuing the statin 3.
• It is not clear when the side effects of statins, such as liver enzyme abnormalities and muscle toxicity, typically occur, as this information is not provided in the studies 3, 4.

Factors Affecting Side Effects

• Coexisting elevations of transaminase levels from nonalcoholic fatty liver disease and stable hepatitis B and C viral infections are not contraindications to statin use 3.
• Clinically important drugs that interact with statins and increase the risk of adverse effects include fibrates, diltiazem, verapamil, and amiodarone 3.
• The incidence of myopathy is similar to that of placebo when statins are prescribed at one-half the recommended maximal dosage or less 3.