Pub Date: Monday, Dec 10, 2018
Author: Francoise A. Marvel, MD and Roger S. Blumenthal, MD
Affiliation: Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
Atherosclerotic cardiovascular disease (ASCVD) continues to be the leading cause of mortality worldwide with approximately 17.7 million deaths annually, the majority of which are preventable1. The latest guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) recommend that for optimal ASCVD risk reduction the first-line therapies are adherence to a heart healthy lifestyle2 and consideration of evidence-based doses of 3-Hydroxy-3-MethylGlutaryl-Coenzyme A reductase inhibitors (HMG-CoA reductase inhibitors or statins) based on 10-year ASCVD risk estimation and a clinician-patient risk discussion3. About 1 in 3 American adults age 40 and older have hypercholesterolemia with total cholesterol levels of 200 mg/dL or higher4. The Center for Disease Control and Prevention (CDC) estimate that 78 million U.S. adults have an indication for statin therapy5.
High quality evidence from large randomized control trials (RCTs) have shown statins effectively reduce LDL-C and cardiovascular risk6, are generally well-tolerated with low rates of adverse effects7, and are easily accessible to patients as generic drugs for about $11 per patient per year8. Furthermore, literature is accumulating on potential for additional benefits of statins beyond reducing LDL-C particularly anti-inflammatory, antiangiogenic, and antifibrotic effects that suggest statins may have pleiotropic effects with novel applications in the future9.
Although statins are among the most commonly used pharmaceuticals in clinical practice with 200 million patients on this therapy worldwide9, adherence to these cardiovascular morbidity and mortality-reducing medications has been challenging. One major limitation to statin adherence is the persistent concern about adverse effects largely from case reports and reports on the internet. Given that statin therapy is a cornerstone of ASCVD prevention, it is essential for clinicians to understand statin safety issues and the available evidence supporting the incorrect perception that statins have common adverse effects.
To address this important issue, a 2018 Scientific Statement from the American Heart Association10 has provided a comprehensive overview and interpretation of the available evidence on statin safety, adverse events, and tolerability. Nine specific adverse events were reviewed, including muscle, diabetes mellitus, liver, neurological, steroidogenesis, cataracts, renal, tendon disorders, and cancer, as well as drug-drug interactions, and approach to specific demographic groups. The main conclusions from the 2018 Scientific Statement are: (1) only a small minority of symptoms are likely to be due to statin therapy as the majority would occur just as frequently on placebo in randomized trials; (2) statins are safe for the majority of patients including demographics of patients with HIV, chronic kidney disease, elderly, children, and East Asian patient populations; and (3) the benefits of statin therapy in reducing cardiovascular disease risk greatly outweigh the very small risks associated with statin use.
Safety Profile of Statins
1. Muscle-related Symptoms
The most common anticipatory guidance from health care providers given to patients before starting a statin is warning them of the “fairly high risks” of developing muscle symptoms, including myalgia (muscle pain or aches), myopathy (muscle pain or weakness with CK >10x ULN), or rhabdomyolysis (severe myopathy, CK>40x ULN). Although there are risks of muscle symptoms that are important to counsel patients about, including factors of dose, agent, and demographics, it is equally important to share the relatively rare occurrence of these symptoms to support informed decision-making.
The 2018 Scientific Statement from the American Heart Association reviewed multiple double-blind statin randomized control trials (RCTs) evaluating effects on cardiovascular outcomes and the incidence of statin intolerance and found no significant difference in muscle symptoms between patients on statins or placebo. Furthermore, a meta-analysis by Collins et al11 that pooled results of 12 trials with 100,000 patients found no significant difference in muscle symptoms in statins vs. placebo in RCTs. The HOPE-312, JUPITER13, and ASPEN14 RCTs had a small statistically significant difference in muscle symptoms for placebo vs. statin (up to 1.4% absolute risk); however, it was negligible across pooled results. The AHA Statement also includes double-blind RCTs with patients classified as having intolerant statin-associated muscle symptoms (SAMS), which are defined as muscle symptoms reported during statin therapy but not necessarily caused by the statin.
In GAUSS-315 and ODYSSEY ALTERNATIVE RCTs16,17, the majority of patients with documented SAMS enrolled under double-blind conditions had no reproducible muscle symptoms. These findings suggest statin intolerance may be closely related to patient expectations, a hypothesis which was tested in ASCOT-LLA study18; this trial compared a blinded randomized phase of atorvastatin vs placebo-allocated patients to the unblinded phase when patients were aware they were taking a statin. The only significant difference between statin users and non-users during the unblinded phase was muscle adverse events (p=0.0059).
The AHA Statement’s conclusion is the most likely explanation for a difference in muscle symptoms between randomized clinical trials and observational studies is the “nocebo effect” defined as expressed or internal expectations of harm from a therapy generated from clinician warning and media. Although muscle symptoms rarely occur with statin therapy, the clinical approach should be to first support the patient’s concerns, check a CK to assess for evidence of myopathy or rhabdomyolysis, evaluate for alternative causes of muscle symptoms like hypothyroidism or Vitamin D deficiency; if there is no evidence of muscle injury, clinicians can rechallenge with the same statin, perhaps with every other day dosing for the first month.
2. Diabetes Mellitus
The Scientific Statement from the American Heart Association presents evidence for a minimal risk (0.2% per year) of developing newly diagnosed diabetes mellitus on statin therapy, which is predominately among patients with pre-existing risk factors for developing diabetes (e.g. adults with pre-diabetes/metabolic syndrome). The mechanisms of the diabetogenic effect of statins remain unclear. The JUPITER Trial13,19 was the first prospective study evaluating statins and newly diagnosed diabetes mellitus among 17,802 patients without known diabetes at the beginning of the study. In the rosuvastatin group 0.6% more patients were reported to have diabetes by their physician over a median of 1.9 years with a small but statistically significant HbA1c difference of median values of 5.9% for rosuvastatin vs. 5.8% for placebo, with no significant difference in fasting glucose.
A large meta-analysis with pooled data of 32,572 patients showed over a median of 4.9 years on statin therapy that 2 cases of diabetes occurred per 1000 patient-years of treatment and 6.5 cardiovascular events (stroke, myocardial infarction, revascularization) per 1000 patient-years were prevented20. Additionally, patients with diabetes on statin-therapy have a negligible increase in HbA1c as shown in AFORRD21 (atorvastatin 20mg vs. placebo; N = 800) and CARDS (atorvastatin 10mg daily vs. placebo N = 2,838) 22,23 RCTs with increases in HbA1c of 0.3% and 0.1% respectively at 4 years.
The Scientific Statement from the American Heart Association raises the question if statin therapy accelerates the development of diabetes in those patients with metabolic syndrome, who would otherwise likely develop it. Among patients on high-intensity statin with risk factors for diabetes, it is prudent to continue aggressive prevention with lifestyle modification (weight loss if indicated and better exercise habits) and periodic screening for diabetes.
The safety profile of statins for liver injury has a historical precedence in animal studies, which has promoted a misconception of statins leading to hepatocellular injury. Randomized control trials show very low rates of liver injury including the EXCEL RCT24 evaluating 8000 with lovastatin vs placebo where there were no cases of clinically symptomatic hepatitis and JUPITER13 in which 18,000 with rosuvastatin vs placebo patients were followed for about two years and there were equivalent rates of “hepatic disorder” across groups.
The Food and Drug Administration (FDA) in post-marketing reviews of statins and hepatoxicity also supported low reporting rates with less than or equal to 2 per one million patient-years, and it was unclear if the reported cases were directly caused by statin therapy. Furthermore, monitoring liver function studies is now not recommended as it has not proven useful in preventing hepatoxcity in statin-users given its rare occurrence. Overall, the American Heart Association Statement concluded that statins pose minimal risk for hepatocellular injury and severe liver injury is extremely rare occurring in about 0.001% of patients, and it does not advise monitoring liver function studies.
4. Other Adverse Effects
The concern for adverse effects associated with statin use and cognitive dysfunction, sleep disturbances, Alzheimer’s Disease, Parkinson’s disease, tendonitis, cancer and peripheral neuropathy lack evidence to support a causal link to statin therapy. Statins have not been shown to cause hypogonadism; although they might slightly lower testosterone levels, there is no adverse effect on erectile dysfunction (ED) and conversely statins may have benefits in ED.
Although cataracts were an early concern of statin adverse effects in animal studies, the majority of large RCTs including EXCEL24, JUPITER13, Scandinavian Simvastatin Survival Study (4S)25,26 found no difference in rates of lens opacities across groups. Moreover, there is no evidence that acute kidney injury is an adverse effect of statins; however, rosuvastatin at maximal doses can cause transient proteinuria and microscopic hematuria.
5. Drug-Drug Interactions
Statin metabolism and drug interactions are addressed in depth by the 2016 American Heart Association Clinical Science Statement, Recommendations for The Management of Clinically Significant Drug-Drug Interactions with Statins and Selected Agents Used in Patients with Cardiovascular Disease27. The 2018 Scientific Statement emphasizes that metabolic pathways differ among statins as do bioavailability, particularly with simvastatin and lovastatin which are pro drugs and they have the lowest bioavailability of 5% compared to pitavastatin which has the highest (about 50%) bioavailability in the class27.
Statins have multiple drug-drug interactions due to being “victims” of other “perpetrator” drugs (ex. fluconazole), which alter the pharmacokinetics by inhibition of one or more of CYP3A4, OAT1B1, and P-glycoprotein. In the case of warfarin, there is evidence that simvastatin, lovastatin, and to a greater extent rosuvastatin have a moderate potentiation of the anticoagulation effect through an unclear mechanism. Clinicians must be cognizant of statin bioavailability, “perpetrator” drugs which can produce large increases in the plasma concentrations of statins leading to muscle-related adverse effects, and for some statins it is advised to monitor anticoagulation effects of warfarin more closely.
Elderly patients are a vulnerable group for medication complications due to lower glomerular filtration rates, multiple comorbidities, and polypharmacy. Statins have been studied in many subjects who were 65 years old or older; PROSPER28, GISSI-HF Trials29, CORONA30, CARDS22,23 JUPITER13 found no significant differences in rates of adverse events between older and younger patients. In contrast, the SEARCH RCT31 with 12,000 patients found age 65 or greater was associated with double the rate of statin-induced myopathy/incipient myopathy.
Overall, clinicians must share in decision-making with older individuals to balance their health benefits with risks of statin therapy, which includes an increased risk of myopathy. On the other spectrum of age, the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) have both recommended consideration of statin therapy for children with very high risk lipid abnormalities as young as age 8 years old32-34. The AHA Scientific Statement supports selective statin use in children with marked hyperlipidemia and did not find evidence of growth or developmental delay associated with statin use. In the case of East Asian patients, who are likely to have a pharmacogenetic factor that influences statin metabolism thereby increasing active statin metabolites, it is recommended to reduce doses of statins in this population. For pregnant patients, definitive evidence from trials are unable to be obtained; therefore, all statins are contraindicated in pregnancy.
7. Specific Diseases
Patients with familial hypercholesterolemia (FH) were pioneers in helping to test lovastatin in humans in early trials and had documented safety and tolerability of the statins. Patients with Chronic Kidney Disease (Stages 2-4) studied in the UK-HARP-1 RCT (simvastatin 20mg vs. placebo)35 and SHARP (ezetimibe 10mg vs simvastatin 20mg vs, placebo)36 and dialysis patients with AURORA (rosuvastatin 10mg vs. placebo)37 showed no evidence of harm for statin therapy. Statins are also safe in liver disease patients with non-alcoholic fatty liver disease (NAFLD) or hepatitis with stable or modestly elevated transaminases (up to 3x ULN), and the data does not suggest progression of liver disease in this population if statin therapy is initiated.
Adults with HIV on ART require careful selection of statin to avoid pharmacokinetic interactions with a preference for pitavastatin or other hydrophilic statin. One population to consider avoiding statin therapy is patients with prior intracranial hemorrhage given limited evidence from the SPARCL study,38 which showed reduction in Quality Adjusted Life Years.
In summary, the 2018 Scientific Statement from the American Heart Association provides a comprehensive analysis of the most up-to-date evidence of potential adverse effects and tolerability of statins. From the totality of available evidence, it is prudent to advise patients who are recommended to take statin therapy that this therapy can provide a major benefit in risk reduction with infrequent risks. The adverse effects of statins are generally minor and the majority of evidence does not support the misguided perception of frequent adverse-effects. Improved awareness and recognition of the rarity of adverse effects with statin use among clinicians and patients will bolster cardiovascular prevention efforts as well as support patient adherence to guideline-directed therapy.
Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell PB, Brinton EA, Pollak A, Braun LT, Welty FK, on behalf of the American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health, Council on Lifelong Congenital Heart Disease and Heart Health in the Young, Council on Clinical Cardiology, and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association [published online ahead of print December 10, 2018]. Arterioscler Thromb Vasc Biol. DOI: 10.1161/ATV.0000000000000073
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