HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.

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Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism

Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is bene- ficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypo- cholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients.

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Effects of thyroid dysfunction on lipid profile.

https://www.onlinecjc.ca/article/S0828-282X(16)00007-6/pdf

Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016)

Approximately 95% of statin-treated patients tolerate this form of cholesterol management without any adverse effects. However, given their efficacy in reducing low density lipoproteins and cardiovascular events large numbers of patients are selected for statin therapy. Therefore muscle complications are, in fact, quite common. Limited understanding of the underlying pathophysiology has hampered physicians' ability to identify patients at risk for developing statin myotoxicity. A growing number of published case reports/series have implicated statins in the exacerbation of both acquired and genetic myopathies. A clinical management algorithm is presented which outlines a variety of co-morbidities which can potentiate the adverse effects of statins on muscle. In addition, a rational approach to the selection of those patients most likely to benefit from skeletal muscle biopsy is discussed. Ongoing work will define the extent to which statin-intolerant patients represent carriers of recessive metabolic myopathies or pre-symptomatic acquired myopathies. The expanding importance of pharmacogenomics will undoubtedly be realized in the field of statin myopathy research within the next few years. Such critical information is needed to establish more definitive management and diagnostic strategies.

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A neuromuscular approach to statin-related myotoxicity.

Despite major progress in the prevention and treatment of cardiovascular diseases, women remain an underdiagnosed and insufficiently treated group, with higher hospitalization and death rates compared to men. Obesity, more frequently encountered in women, raises the risk of metabolic syndrome and cardiovascular diseases as women age. There are some differences based on sex regarding the screening, diagnosis, and treatment of dyslipidemia, as it has been observed that women are less frequently prescribed statins and, when they are, they receive lower doses, even after myocardial infarction or coronary revascularization. Real-life data show that, compared to men, women are at higher risk of non-adherence to statin treatment and are more predisposed to discontinue treatment because of side effects. Statin metabolism has some particularities in women, due to a lower glomerular filtration rate, higher body fat percentage, and overall faster statin metabolism. In women of fertile age, before initiating statin treatment, contraception methods should be discussed because statins may have teratogenic effects. Older women have a higher likelihood of polypharmacy, with greater potential for drug interactions when prescribing a statin.

Cardiovascular Risk and Statin Therapy Considerations in Women.

Serious side effects of statins, including severe myopathy and rhabdomyolysis, are rare but important in general practice. Hypothyroidism can cause secondary hypercholesterolemia and myopathy. There have been few reports on the risk of statins in patient with unnoticed hypothyroidism. We analyzed the characteristics of 77 patients with primary hypothyroidism in our hospital. Nine patients (11%) accidentally received statins in the treatment of hypercholesterolemia without diagnosis of hypothyroidism. In such patients, free T4 (FT4) levels were lower, and those of LDH, CK were higher than those in patients not receiving statins. In patients accidentally receiving statins, an inverse correlation between CK and FT4 could not be shown (which was recognized in patients not receiving them). Even after FT4 levels were matched, levels of CK were still higher in the patients accidentally receiving statins. Patients with high CK levels over 1000 U/L were 5 times more frequent (56%) in patients accidentally receiving statins than in those not receiving statins (11%). The present study confirms that statins enhances levels of CK in patients with hypothyroidism. We must not begin and continue to use these drugs without checking the possibility of hypothyroidism.

HMG-CoA Reductase Inhibitors (statins) might Cause High Elevations of Creatine Phosphokinase (CK) in Patients with Unnoticed Hypothyroidism

The fasting blood glucose concentration in type 1 diabetes may vary without being much affected by diet and exercise. This study aimed to identify association of morning fasting blood glucose concentration variability with insulin antibodies and clinical factors. The subjects in this study were 54 patients with type 1 diabetes who had high variation of fasting blood glucose. The insulin antibody level was measured, and correlations of glycemic variability with antibody levels, binding rates, and other clinical factors were investigated. The standard deviation (SD) of the 30-day morning self-monitored fasting blood glucose concentration (FBG SD) was evaluated as an index of glycemic variability. The mean glucose level was 159.8±42.1 mg/dL and the FBG SD was 47.5±22.0 mg/dL. Glycemic variability (FBG SD) was positively correlated with insulin antibody level, but not with insulin antibody binding rate, and had a negative correlation with C-peptide immunoreactivity/plasma glucose (CPR/PG) and positive correlations with diabetes duration, basal insulin dose and bolus insulin dose. Glycemic variability was not correlated with BMI, HbA1c or age. In multiple regression analysis of glycemic variability, CPR/PG was the only significant related factor. The results showed that glycemic variability was mainly influenced by endogenous insulin secretion capacity and was high in patients with high insulin antibody levels. In some patients with a high insulin antibody titer, the antibody may have an effect on the variability of the fasting glucose concentration in type 1 diabetes.

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Yoshifumi Suzuki

Papers

HMG-CoA Reductase Inhibitors (statins) might Cause High Elevations of Creatine Phosphokinase (CK) in Patients with Unnoticed Hypothyroidism

Association of morning fasting blood glucose variability with insulin antibodies and clinical factors in type 1 diabetes