What are the systemic effects of statins (HMG-CoA reductase inhibitors) beyond hepatotoxicity (liver damage)?

From the Guidelines

Statins have several systemic effects beyond hepatotoxicity, including muscle-related complications, neurological effects, metabolic impacts, and potential benefits for certain conditions, with the most common adverse effect being myopathy, ranging from mild myalgia to severe rhabdomyolysis, affecting approximately 5-20% of patients, as reported in the 2022 ACC expert consensus decision pathway 1. The systemic effects of statins can be categorized into several areas, including:

• Muscle-related complications, such as myopathy and rhabdomyolysis, which can occur in 5-20% of patients, with true complete statin intolerance being uncommon 1
• Neurological effects, such as peripheral neuropathy, cognitive changes, and sleep disturbances, which can occur in some individuals
• Metabolic impacts, such as an increased risk of new-onset diabetes by 9-12%, particularly in predisposed individuals
• Potential benefits for certain conditions, including anti-inflammatory properties, improved endothelial function, and potential neuroprotection The risk of adverse effects varies by specific statin, with lipophilic statins (atorvastatin, simvastatin) generally having more systemic effects than hydrophilic ones (rosuvastatin, pravastatin) 1. Some patients may experience gastrointestinal disturbances, such as constipation, diarrhea, and abdominal pain, while others may have an increased risk of hemorrhagic stroke, although the overall risk is not significantly increased 1. The approach to managing statin-associated side effects should include discontinuation of statin therapy until resolution of symptoms and subsequent rechallenge to verify recurrence of muscle-related symptoms, with the goal of finding the highest tolerated statin dose that is as close to the guideline recommendation as possible 1. In patients with clinical ASCVD and possible statin-associated side effects, nonstatin therapies, such as ezetimibe or a PCSK9 mAb, may be considered as first-line therapy, depending on the patient's clinical scenario, with referral to a lipid specialist recommended for patients with LDL-C ≥190 mg/dL who have not achieved adequate lowering of LDL-C on maximally tolerated statin therapy 1.

From the FDA Drug Label

The most common adverse reactions that led to treatment discontinuation were: elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0. 5% on 4 mg). Adverse reactions reported in ≥ 2% of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis. Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with pitavastatin tablets. The following laboratory abnormalities have been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose Gastrointestinal disorders:abdominal discomfort, abdominal pain, dyspepsia, nausea General disorders:asthenia, fatigue, malaise, dizziness Hepatobiliary disorders:hepatitis, jaundice, fatal and non-fatal hepatic failure Immune system disorders:angioedema, immune-mediated necrotizing myopathy associated with statin use Metabolism and nutrition disorders:increases in HbA1c, fasting serum glucose levels Musculoskeletal and connective tissue disorders:muscle spasms, myopathy, rhabdomyolysis Nervous system disorders:hypoesthesia, peripheral neuropathy. There have been rare reports of new onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. Psychiatric disorders:insomnia, depression Reproductive system and breast disorders:erectile dysfunction Respiratory, thoracic and mediastinal disorders:interstitial lung disease Skin and subcutaneous tissue disorders:lichen planus

The systemic effects of statins beyond hepatotoxicity (liver damage) include:

• Musculoskeletal effects: myalgia, muscle spasms, myopathy, rhabdomyolysis
• Nervous system effects: hypoesthesia, peripheral neuropathy, cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion)
• Metabolic effects: increases in HbA1c, fasting serum glucose levels
• Gastrointestinal effects: abdominal discomfort, abdominal pain, dyspepsia, nausea
• Dermatological effects: rash, pruritus, urticaria, lichen planus
• Respiratory effects: interstitial lung disease
• Psychiatric effects: insomnia, depression
• Reproductive effects: erectile dysfunction
• Immune system effects: angioedema, immune-mediated necrotizing myopathy associated with statin use 2 3

From the Research

Systemic Effects of Statins Beyond Hepatotoxicity

The systemic effects of statins, beyond their potential to cause liver damage, are numerous and varied. Some of the key effects include:

• Myopathy, which is the most frequent side effect of statins, and in some cases may have a form of severe rhabdomyolysis 4
• Peripheral neuropathy, which is a less common adverse effect 4
• Impaired myocardial contractility, which can occur due to the depletion of coenzyme Q involved in mitochondrial electron transport and antioxidant protection 4
• Autoimmune diseases, which have been reported as a rare side effect of statin use 4

Pleiotropic Effects of Statins

Statins have been found to have pleiotropic effects, which are independent of their cholesterol-lowering effect. These effects include:

• Antifibrotic effects in patients with advanced liver disease, possibly through the prevention of hepatic sinusoidal microthrombosis 5
• Decreased hepatic vein pressure gradient in patients with portal hypertension, which can improve survival after variceal bleeding 5
• Lower rates of infections in patients with cirrhosis who receive statin treatment 5
• Decreased risk of hepatocellular carcinoma (HCC) in patients with advanced liver disease, particularly in patients with chronic hepatitis B and C 5

Use of Statins in Patients with Liver Disease

The use of statins in patients with liver disease is generally considered safe, with some exceptions. These include:

• Patients with decompensated cirrhosis and acute liver failure, who should not receive statin therapy due to their grave prognosis 6
• Patients with stable/compensated cirrhosis, who can safely receive statin therapy 6
• Patients with nonalcoholic fatty liver disease (NAFLD), primary biliary cirrhosis, and hepatitis C virus, who can also safely receive statin therapy 6

Monitoring and Safety

Monitoring for adverse effects is crucial when prescribing statins, particularly in patients with underlying liver disease. This includes:

• Routine hepatic biochemical test monitoring, although the cost-effectiveness of this approach has been questioned 6
• Careful follow-up to rapidly recognize the onset of further liver damage in patients with chronic hepatitis 7
• Caution when prescribing statins to patients with liver disease, with careful consideration of the potential risks and benefits 7, 8