Since most lipid-lowering guidelines emphasize the use of statin therapy and at potent doses in the highest-risk individuals, it is important to recognize side effects. Clinically significant adverse effects of statins include all of the following except:
Renal insufficiency. Statins have not been shown to worsen renal function. There was concern raised when proteinuria was noted in clinical trials with rosuvastatin. However, in analyses of RCTs, creatinine has not been shown to worsen and may improve. The other adverse effects listed above have all been noted with statins. In a meta-analysis by Naci et al. in 2013 comparing statins to placebo, the odds ratio for elevation in LFTs was 1.51, diabetes development 1.09, myalgia 1.07, CPK abnormality 1.13, and cancer 0.96, statistically significant only for liver test abnormalities and diabetes. Concerns have been raised about memory loss but there is a lack of large prospective trials designed to address this question and limited. A recent report in fact suggests a reduction in dementia with statin therapy.
You see a 68-year-old woman recently started on a statin for a calculated FRS of 18% 10-year risk and elevated usCRP. She returns in 6 weeks complaining of left lower extremity aching, which she had not experienced before.
Regarding muscle-related side effects with statin drugs, all of the following statements are true except that:
Myalgia symptoms reported in prescribing information range from 5% to 10%. Definitions specified by the ACC/AHA NHLBI (National Heart, Lung, and Blood Institute) 2002 Clinical Advisory offer the following terminology to describe muscle injury: myalgias (muscle ache/weakness without CPK elevation), myopathy (muscle symptoms with CPK levels more than 10 times ULN), rhabdomyolysis (muscle symptoms with marked CPK elevation typically more than 10 times ULN with creatinine elevation and often with urinary myoglobin). Myalgia is reported in prescribing information at 1.2% to 3.2% but up to 11% in registries. Myopathy occurs in 0.1% to 0.5% of patients in a dose-dependent fashion. Fortunately, the risk of rhabdomyolysis is quite rare and reported <0.1%. Meta-analysis has reported rates of 0.03% to 0.05%. Muscle symptoms are more likely to occur at higher doses and doses should not exceed those recommended to achieve treatment goals. Attention should be paid to factors that may increase risk for myopathy. Concomitant medications such as fibrates, nicotinic acid (rarely), cyclosporine, azole antifungals, itraconazole, ketoconazole, macrolide antibiotics, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (>1 qt/day), and alcohol abuse may increase drug exposure and increase myopathy risk. This may be particularly true for simvastatin (metabolized via CYP3A) prompting an FDA advisory not to exceed 40 mg dose in general and reduce dose to 10 to 20 mg with concomitant use of drugs such as high-dose niacin, verapamil, ranolazine, and amiodarone. Other factors contributing to a higher likelihood of muscle symptoms include advanced age (especially >80 years; women more than men), small body frame, frailty, multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes), and perioperative periods.
You see a 68-year-old woman recently started on a statin for a calculated FRS of 18% 10-year risk and elevated usCRP. She returns in 6 weeks complaining of left lower extremity aching, which she had not experienced before. You obtain a creatine phosphokinase (CPK) which is 282 (upper normal in laboratory of 220 U/L). No baseline CPK is available for comparison. She has no reproducible pain or weakness on examination. She denies darkening of the urine.
Should you stop the statin?
No. Routine measurement of CPK on statin therapy is not recommended but it is reasonable to obtain at baseline prior to therapy in individuals at higher risk for myopathy and if new symptoms develop on treatment. When a patient presents with complaints of pain, tenderness, stiffness, cramping, weakness, or fatigue the first approach should be to document the severity of the symptoms, obtain CPK, creatinine, and urinalysis to exclude rhabdomyolysis, and search for other causes (such as hypothyroidism, rheumatologic disorders, vitamin D deficiency, and steroid use). If there are clinical signs of severe pain, new muscle weakness, CPK greater than 10 times ULN, or myoglobinuria the statin should be stopped. If symptoms are mild to moderate and CPK is less than three times ULN it is reasonable to hold the statin until symptoms can be evaluated. If symptoms resolve rechallenge with the same or lower dose of the statin to establish whether a causal relationship exists. If so starting a low dose of a different statin is reasonable followed by slow titration. If an asymptomatic individual on statin therapy has an elevated CPK, complete a thorough muscular examination and if unremarkable check for other causes. If greater than 10 times ULN, hold statin and evaluate for other primary or secondary myopathies. If a baseline CPK is known to be elevated prior to therapy, it is not an absolute contraindication to initiate statin therapy if less than three times ULN and asymptomatic. If higher, a search for other causes such as hypothyroidism, recent injury, and other myopathies would be prudent before initiating therapy with a statin and consideration of referral to a rheumatologist for further evaluation.
You see a 49-year-old obese, sedentary woman with type 2 DM, hypertension, and family history of coronary stent in her father at age 53. LDL-C was 173 mg/dL. Based on NCEP ATP III and 2013 ACC/AHA guidelines she is a candidate for intensive statin therapy. Laboratory values obtained 3 months after treatment with 40 mg of atorvastatin revealed alanine transaminase (ALT)/aspartate transaminase (AST) of 102/96 (upper normal in laboratory of 50/42 U/L).
Which of the following regarding liver abnormalities with statin use is not true?
Statins have been shown to worsen the outcome in persons with chronic transaminase elevations due to hepatitis B or C. Dose-related elevation in AST or ALT has been reported between 0.1% and 2%. Statins have not been shown to worsen the outcome in persons with chronic transaminase elevations due to hepatitis B or C. A search for other causes of LFT elevations is essential including review of prescription and over-the-counter drugs and supplements, recent infections, and alcohol use. In this patient with LFT less than three times ULN, it is reasonable to repeat in 6 to 12 weeks on the same or a lower dose. If LFTs greater than three times ULN repeat in 2 weeks and if continued elevation stop statin, recheck in 2 to 4 weeks and if improving consider rechallenge with a lower-dose or different statin. Reversal of transaminase elevation is frequently noted with a reduction in statin dose, and elevations do not often recur with either readministration or selection of another statins.
Later that afternoon you are referred a 58-year-old man with waist circumference of 42 inches, fasting glucose of 112 mg/dL, hypertension, current smoker with brother with MI at age 54. LDL-C is 163 mg/dL, TG 275 mg/dL, and HDL-C 47 mg/dL. When first seen prior to initiation of any therapy, he had LFTs similar to those reported for the patient in the previous question (approximately two times upper limit of normal [ULN]). The patient is very worried about taking statins due to concerns of liver failure.
Which of the following can you tell him? 10 year risk by Framingham Risk Score is >30% and ACC/AHA calculator score is 21.2.
Statin therapy may lower LFTs in patients with fatty liver infiltration. Prior to initiation of statin therapy it is reasonable to exclude other causes for LFT elevation. However, there are small studies supporting the safety of use in appropriate patients. Kiyici et al. examined 44 patients with biopsyproven NASH (nonacoholic steatosis) and found that on atorvastatin 10 mg for 6 months there was a decrease in cholesterol, AST, ALT, AP (alkaline phosphatase), and GGT (gammaglutaryl transferase). Chalasani et al. examined the effect of statins over 6 months in patients with baseline moderate elevations in LFTs. In patients with normal LFTs placed on statin, the incidence of mild/moderate or severe elevation in LFTs was 1.9% and 0.2%, respectively, in those with baseline elevations placed on statin (4.7% and 0.6%) compared with those not placed on statin (6.4% and 0.4%). Progression to liver failure due to statins is not zero but exceedingly rare reported at 0.02 to 0.07 per million treated. In this patient, an ultrasound of the liver confirmed fatty infiltration. Manufacturer’s prescribing information lists unexplained ALT greater than three times ULN as a contraindication to statin therapy. The best approach is to counsel on a diet program low in sugar and carbohydrates, weight loss, and exercise, and start statin therapy following the LFTs more closely.
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