Adverse Effects During Statin Therapy

Introduction

Statins are the first-line therapy for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Statins have also been shown to be safe and well-tolerated in properly selected patients, similar to those who participated in the randomized trials. However, these trials did exclude patients with a history of statin-associated side effects (SASE), or conditions or concomitant drug therapy that could increase the potential for SASE (Table 19-1; see also Statins).

Many patients will experience muscle and other symptoms during statin therapy. The challenge is to determine if the symptoms are actually due to the statin. In randomized trials in patients with well-documented SASE, on rechallenge with a statin, the majority (55%-90%) did not develop muscle symptoms that led to statin discontinuation, while a substantial proportion (>10%-20%) developed muscle symptoms while receiving a placebo.

The previous (2013 American College of Cardiology and American Heart Association (ACC/AHA)) cholesterol guideline provided an expert recommendation for the management of muscle symptoms during statin therapy (Table 19-2). The 2018 multi-society cholesterol guideline contains similar, though less detailed, recommendations. Other expert panels recommend a similar approach of statin dosing interruption and rechallenge for muscle and other symptoms.

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Clinical Highlight I

• Most patients tolerate statin therapy. Discuss with the patient the potential to benefit from statin therapy and the desirability of finding some dose of statin in order to reduce their risk of coronary heart disease, stroke, and death. Work together on a cycle of statin withdrawal and rechallenge until a tolerable intensity of statin therapy can be found.
• Avoid using simvastatin 80 mg.
• Nonstatin therapy can be used to further reduce ASCVD risk in patients with statin-associated side effects. Ezetimibe, PCSK9 inhibitors, and bempedoic acid all appear to be reasonably well tolerated in patients with statin-associated side effects.
• Patients with predisposing factors are likely also to be candidates for ASCVD risk reduction therapy with statins. A reasonable approach would be to:
• Identify a statin with the least likelihood of drug interactions or compromised metabolism.
• Carefully educate the patient on the potential for myopathy.
• Start at a low to moderate intensity and increase as tolerated.

Statin Adverse Effects: Predisposing Factors

Characteristics that predispose patients to the development of SASE fall into roughly two groups (Table 19-1):

• Conditions that increase statin blood levels/decrease metabolism
• Conditions that lower the threshold for muscle symptoms.

Not uncommonly, statins may unmask another condition that is causing the myopathy. Once that condition resolves or is treated, statin therapy can usually resume without causing muscle symptoms.

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Genetics of Statin-Associated Side Effects

A number of genetic polymorphisms associated with statin uptake and metabolism and muscle metabolic pathways have been associated with increased risk of statin myopathy. Genotyping is not routinely recommended. Most patients with a genetic polymorphism never develop SASE. However, in patients with a family history of SASE or muscle disorders, genetic testing may determine an etiology. Nonetheless, patients with a genetic polymorphism should still be managed according to the withdrawal-rechallenge strategy outlined below.

Managing Muscle Symptoms

Patients may report a variety of muscle symptoms of varying intensity described as muscle soreness, aching, stiffness, tenderness, cramping, weakness, or fatigue unassociated with exercise. Often these symptoms may occur proximally, in the neck, shoulders, upper arms, back, buttocks, or thighs, but may occur distally as well. Other manifestations include focal or generalized tendon tenderness. The challenge is to determine if these are indeed due to the statin. A standardized definition of statin myalgia has been used in clinical trials in patients with SASE:

• New onset or increased muscle symptoms unassociated with recent exercise
• Symptoms persist for at least 2 weeks
• Symptoms begin resolving within 2 weeks of stopping the statin
• Symptoms recur within 4 weeks of restarting the statin

In patients with mild-moderate muscle symptoms, statin myalgia can only be established by withdrawing the statin, and once symptoms resolve, rechallenging with a statin to determine whether symptoms recur (Table 19-2; Figure 19-1). Statin-associated muscle symptoms will have begun resolving within 2 weeks and be entirely resolved within 2 months of withdrawing the statin. If the muscle symptoms persist >2 month after withdrawing the statin, evaluate for another cause of myopathy (see below).

If the patient is willing, rechallenge with the same statin at the same dose or a lower dose, titrating upward as tolerated. Alternatively, rechallenge with a different statin at a lower dose and titrate to the desired statin intensity as tolerated.

Continue the withdrawal/rechallenge cycle until a tolerable dose of statin is found.

Alternate dosing strategies include less than daily dosing. For example, rosuvastatin 5 to 10 mg once a week lowers LDL-C by about 25% to 30%. Patients can then be uptitrated as tolerated.

Patients who develop symptoms after a defined period of therapy can try taking the statin up to 2 weeks before the usual interval, stop the statin, then resume in 2 weeks (e.g., symptoms after 3 months: stop statin at 2.5 months, resume after 2 weeks).

Patients with severe muscle symptoms and/or weakness should be evaluated with a creatine kinase (CK) test as well. Patients with normal CK levels can be managed as recommended in Table 19.2/Figure 19.1.

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Reduced Exercise Tolerance

Some patients who engage in strenuous physical activity may notice decreased exercise capacity or muscle soreness during statin therapy. There is some evidence that statins can attenuate cardiorespiratory adaptations to exercise. Marathon runners on statins were observed to have higher CK levels than those not on a statin. In the STOMP trial, participants randomized to atorvastatin 80 mg had similar muscle strength and exercise performance as the placebo group after 6 months of treatment. However, the atorvastatin 80 mg group did have slightly more myalgias than the placebo group (who reported myalgias, too) and slightly higher CK levels.

Immune-Mediated Statin Myopathy

Very rarely, a patient whose symptoms persist for more than 2 months off the statin will have an immune-mediated inflammatory myopathy related to statin therapy. This may be due to unmasking an underlying condition (e.g., polymyositis, dermatomyositis, or necrotizing myopathy). Some of these patients will have anti-HMG CoA reductase antibodies. These patients respond to immunosuppressive therapy.

Other Causes of Myopathy

Numerous conditions common in an aging population can predispose to statin myopathy and cause persistent muscle symptoms once the statin has been withdrawn. These include rheumatologic disorders such as polymyalgia rheumatica or rheumatoid arthritis, hypothyroidism, reduced renal or hepatic function, steroid myopathy, severe vitamin D deficiency, or primary muscle diseases. Once these conditions are treated or resolve, statins are often again well tolerated.

In patients whose muscle symptoms persist off statin therapy, laboratory evaluation can include creatine kinase (CK), thyroid-stimulating hormone (TSH), creatinine, ALT, erythrocyte sedimentation rate (ESR) and possibly 25-OH vitamin D testing. Additional testing should be guided by other symptomatology. Referral to a rheumatologist and a muscle biopsy may be needed to determine a diagnosis.

Simvastatin 80 mg has the highest potential for myopathy and should not be initiated; the dose should be reduced if symptoms occur in patients already taking simvastatin 80 mg.

Statin Rechallenge

Most patients with SASE will tolerate the same statin on rechallenge. Among those who do not, an alternative statin at some dose can be found for almost all patients. Start with low doses and/or weekly dosing then increase the dosing interval/dose as tolerated. The addition of a nonstatin therapy may be tolerated.

Nonstatin Therapy in Patients with Statin-Associated Side Effects

For patients who have tried at least a low dose of every available statins, one or more nonstatins may be tolerated. See Nonstatins: Evolving Role in ASCVD Prevention for recommendations regarding the consideration of nonstatins in patients with statin-associated side effects.

Ezetimibe, PCSK9 inhibitors and bempedoic acid are all reasonably well tolerated in randomized, double-blind trials.

Ezetimibe has been shown to further reduce ASCVD events when added to background statin therapy in the IMPROVE-IT trial, as have PCSK9 inhibitors in the ODYSSEY OUTCOMES (alirocumab) and FOURIER (evolocumab)trials. Inclisiran has been shown to lower LDL-C in the ORION-9, ORION-10 and ORION-11 trials. The LDL-C-lowering efficacy of bempedoic acid has been shown in the CLEAR Wisdom and CLEAR Harmony trials, as well as in a trial of bempedoic acid in combination with ezetimibe. A cardiovascular outcomes trial of bempedoic acid is ongoing. Bile acid sequestrants, niacin, fenofibrate and gemfibrozil have been shown to reduce ASCVD or CAD events in limited clinical trial populations. However, they are not as well tolerated either due to gastrointestinal adverse effects (bile acid sequestrants) or increased muscle or other adverse effects (i.e., gemfibrozil, fenofibrate and niacin).

Supplements/Vitamins

Vitamin D—Low vitamin D levels are common in patients with SASE. They are also common in patients who are obese, diabetic, sedentary, have low quality diets, or ASCVD. No randomized trials have evaluated whether vitamin D supplementation improves muscle symptoms in patients with SASE.

Coenzyme Q10—Although some open-label studies suggest CoQ10 improves muscle symptoms in patients with SASE, a randomized trial of a high dose of CoQ10 (600 mg/d) had no effects on muscle symptoms in these patients. The 2018 multi-society cholesterol guideline does not recommend the use of CoQ10 in patients treated with statins or for the treatment of statin-associated muscle symptoms.

Red yeast rice—Red yeast rice contains a fungal form of lovastatin and has mild cholesterol-lowering effects. However, commercially available products have varying amounts, if any, of the active ingredient. Red yeast rice is not approved for sale in the United States.

Managing Creatine Kinase Elevations

No Indication for Routine CK Monitoring

Damaged muscles, either skeletal or cardiac, release CK into the blood. Since the vast majority of patients with statin-related muscle symptoms had normal CK levels in the statin randomized trials, routine monitoring is not recommended by the 2018 multi-society cholesterol guideline. However, a CK test may be reasonable to further evaluate muscle symptoms.

Selective CK Monitoring

Selective evaluation of baseline CK prior to initiating statin therapy is reasonable to consider in patients with a history of muscle symptoms or SASE. CK evaluation may also be considered in patients whose mild-moderate muscle symptoms recur on statin therapy. In patients with severe muscle symptoms or profound fatigue in whom a diagnosis of rhabdomyolysis or severe myopathy is being considered, CK should be evaluated, along with creatinine and urine myoglobin.

Managing Elevated CK Levels

• Unexplained CK elevation <5 times the upper limit of normal (ULN) without muscle symptoms. Average normal CK levels are higher in African American men and women. If the CK level is asymptomatic there is no concern for SASE. Recheck CK at the next visit.
• Unexplained CK elevation <5 times the ULN with muscle symptoms. Withdraw the statin and manage according to the algorithm above.
• CK levels ≥5 to <10 times the ULN with or without skeletal muscle symptoms. This level of CK elevation occurs with some frequency in individuals who engage in unaccustomed or intermittent strenuous physical activity, especially under hot or humid conditions. These patients should vigorously hydrate with oral fluids. If they have muscle symptoms, they may wish to discontinue the statin until muscle symptoms resolve and CK returns to normal, and then resume the statin. If muscle symptoms return or the CK elevation occurred without explanation, follow the muscle symptom management algorithm above.
• CK levels ≥10 times the ULN without skeletal muscle symptoms. Recheck within 1 week. If CK remains elevated, withdraw the statin until the CK levels return to normal or a cause is identified.
• CK levels ≥10 times the ULN or CK >10,000 mg/dL with skeletal muscle symptoms. Consider severe myopathy or rhabdomyolysis. Check creatinine and urine myoglobin. Discontinue the statin and hydrate. If a new substantial decrease in glomerular filtration rate occurs, the patient should be admitted as an inpatient for hydration with carefully monitoring of fluid and renal status.

Clinical Highlight II

• There is no need to routinely monitor CK levels.
• Check CK levels if a patient has recurrent muscle symptoms on statin rechallenge or has severe muscle symptoms suggesting rhabdomyolysis.

Managing Liver Function Test Elevations

Hepatic alanine aminotransferase (ALT or SGOT) is the most sensitive test for drug hepatotoxicity, although it can be elevated in other liver diseases. The 2013 ACC/AHA cholesterol guideline could find no evidence for statin hepatoxicity in the systematic review of statin safety. Nor is there concern about statin hepatoxicity in a report by muscle experts or in a review of adverse event reports to the US Food and Drug Administration. The 2018 multi-society cholesterol guideline states that liver transaminases (aspartate aminotransferase and alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) should be evaluated if there are signs or symptoms suggesting hepatotoxicity. Check Baseline Liver Transaminases Only

Both the 2018 multi-society cholesterol guideline and the FDA recommend obtaining liver transaminase level prior to initiating statin therapy. In the statin cardiovascular outcomes trials, baseline ALT levels <1.5 times the ULN were required for randomization. Rates of persistent ALT elevations >3 times the ULN were uncommon, and similar in both statin and placebo/control groups during the trial. Therefore, statins can be used with confidence of their safety in patients with ALT <1.5 times the ULN prior to initiating treatment.

• Individuals with ALT levels ≥1.5 times the ULN were excluded from the statin trials. Many patients with ALT 1.5-3 times the ULN have fatty liver, a complication of obesity, metabolic syndrome and insulin resistance. These conditions identify a patient at increased ASCVD risk with the potential to benefit from statin therapy. As a rule of thumb, as long as the alkaline phosphatase and direct bilirubin are normal (e.g., no evidence of obstructive liver disease), a moderate-intensity statin can be started in patients with ALT ≤3 times the ULN without concern for adverse hepatic effects. Atorvastatin 80 mg, simvastatin 80 mg, and statin-ezetimibe therapy can uncommonly cause persistent elevations of ALT >3 times the ULN. These regimens should be used with more caution when baseline ALT is two to three times the ULN, and follow-up ALT levels should be assessed periodically.
• Patients with ALT >3 times the ULN, elevated alkaline phosphatase and/or direct bilirubin should be evaluated for other hepatic conditions, including viral hepatitis. Once an etiology is established and/or treated, a low- to moderate-intensity statin can be started, with careful periodic monitoring (e.g., at 2, 4 and 8 weeks, then monitoring at every visit thereafter).

No Indication for Routine ALT or Other LFTs Monitoring Unless Other Clinical Symptoms

Statins do not cause serious or irreversible hepatic toxicity. The Food and Drug Administration (FDA) has concluded that “serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.” The 2018 multi-society guideline recommends against routine liver function tests (LFT) due to the lack of hepatoxicity in randomized trials and the support of the FDA for this approach.

Symptomatic patients on a statin who develop abdominal pain, nausea, vomiting, jaundice, dark urine, or change in bowel habits should have an ALT as well as other LFTs evaluated.

Incidental Elevated LFTs During Statin Therapy

• ALT 1.5-3 times the upper limit of normal occurs with some frequency in statin-treated patients. The cause is usually related to intercurrent illness, excessive alcohol consumption (often an unaccustomed amount such as during a vacation), or intake of over-the-counter analgesics, decongestants, acetaminophen, or nonsteroidal anti-inflammatory drugs. Numerous prescription drugs cause ALT elevations. The potential offending agent should be discontinued and the ALT monitored until it returns to baseline. The statin can be continued during this time. Patients on long-term statin therapy may develop fatty liver as a result of gaining weight or worsening insulin resistance. See Baseline LFT section for further discussion.
• An unexplained ALT >3 times the upper limit of normal should be rechecked in 1 to 2 weeks. If the ALT remains >3 times the upper limit of normal, the statin should be discontinued until the cause is determined and ALT levels return to baseline. Atorvastatin 80 mg, simvastatin 80 mg, and statin-ezetimibe in combination uncommonly cause persistent ALT >3 times the upper limit of normal. The dose of atorvastatin or simvastatin should be reduced or the ezetimibe discontinued and the ALT monitored until it returns to baseline. Rosuvastatin 20 mg does not appear to increase ALT levels more than placebo.
• An ALT >10 times the upper limit of normal may indicate a serious intercurrent illness, such as acute viral hepatitis and should be immediately evaluated to determine the etiology. The statin should be discontinued until cause is identified and the ALT returns to baseline.

Clinical Highlight III

• If baseline ALT is <1.5 times the upper limit of normal, there is no need to monitor ALT at subsequent visits.
• ALT elevations during statin therapy are almost always due to something other than the statin.
• Patients who develop unexplained, persistent ALT elevations >3 times the upper limit of normal, jaundice, or abdominal pain should be evaluated for causes of acute hepatitis or obstructive liver disease.

Managing Blood Glucose Elevations

Patients treated with statins had a slightly higher excess risk of developing type 2 diabetes (T2D) than those not receiving a statin in randomized trials and observational studies. High-intensity statins have a modestly higher excess risk of diabetes than moderate- or low-intensity statins. However, the excess risk of diabetes occurs only in patients with risk factors for diabetes. Indeed, statins simply move up the date of diabetes diagnosis by 2 to 4 months compared to patients not treated with a statin. The potential mechanisms for statin-associated diabetes include slight weight gain, slightly worsened insulin resistance and/or slightly decreased insulin secretion. There appear to be no long-term consequences to statin-associated diabetes. The number of ASCVD events prevented with statins in patients with diabetes risk factors far exceeds the number of cases of excess diabetes.

Given the relatively high prevalence of transition to diabetes in individuals with diabetes risk factors, it is impossible to determine whether the statin contributed to a patient developing diabetes during therapy.

The 2018 multi-society cholesterol guideline recommends screening for and treating diabetes according to current diabetes guidelines. All patients receiving statin therapy should be counseled on the importance of healthy lifestyle habits to prevent ASCVD as well as diabetes.

Controlling weight, eating a healthy diet and engaging in regular physical activity have been shown to prevent progression to diabetes in randomized trials.

Clinical Highlight VI

• All patients on a statin should control their weight, exercise regularly and eat a healthy diet.
• Patients who develop diabetes while on statin therapy were already going to develop it; the statin just tipped them over a little earlier.
• Patients who develop diabetes while on statin therapy are at high ASCVD risk and should be treated with a statin to reduce that risk.