Hypothyroidism as a risk factor for statin intolerance

doi:10.1016/j.jacl.2014.05.005

Journal of Clinical Lipidology

Volume 8, Issue 4, July–August 2014, Pages 401-407

https://doi.org/10.1016/j.jacl.2014.05.005 Get rights and content

Highlights

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We provide a large cohort analysis of statin intolerance and hypothyroidism.
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We provide a sex-specific analysis of the cohort.
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We evaluate for a statin prescription at follow-up for the cohort.
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Hypothyroidism is more prevalent in people with statin intolerance.
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Statin intolerance is a risk factor for lack of statin prescription at follow-up.
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Hypothyroidism is a risk factor for lack of statin prescription at follow-up.

Background

Three-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are one of the most commonly prescribed classes of medications because of their proven cardiovascular benefits. However, statin intolerance occurs in 5% to 20% of patients. Understanding the basis for statin intolerance remains a key issue in preventive medicine.

Objectives

To evaluate the association of statin intolerance with hypothyroidism in a large integrated health care system, including its sex-specific relationship and subsequent statin rechallenge and prescription history.

Methods

The Intermountain Healthcare electronic medical record database identified patients (n = 2686; males = 1276, females = 1410) with a documentation of intolerance (“allergy”) to at least 1 statin. Age and sex similar controls (n = 8103; males = 3892, females = 4211) were identified among patients prescribed statins without documented intolerance. Patients were evaluated for a history of hypothyroidism, development of hypothyroidism, and statin prescription history up to 5 years of follow-up.

Results

A total of 30.2% patients (210 males, 16.5%; 602 females, 42.7%) with statin intolerance had a history of hypothyroidism compared with 21.5% of statin-tolerant patients (475 males, 12.2%; 1266 females, 30.1%), for an odds ratio (OR) in the total population of 1.49 (95% confidence interval [CI] 1.34–1.65; P < .0001); in males, OR was 1.29 (CI 1.07–1.55; P = .001); in females, OR was 1.60 (CI 1.41–1.82; P < .0001). During follow-up, patients with statin intolerance and hypothyroidism were less likely to be on a statin than their statin-intolerant counterparts without hypothyroidism (hazard ratio 0.84; 95% CI 0.75–0.94; P = .002).

Conclusions

Hypothyroidism is more prevalent in those with statin intolerance, both in males and, especially, in females. People with hypothyroidism are less likely to have a prescription for a statin at follow-up than those without hypothyroidism.

Section snippets

Methods

Data from the electronic medical record database of the Intermountain Healthcare system (Murray, UT) were studied to address 4 objectives in a general health care population: (1) to determine the prevalence of hypothyroidism in patients with documented intolerance to at least 1 statin; (2) to provide sex-specific analysis of the relationship between statin intolerance and hypothyroidism; (3) to evaluate the development of hypothyroidism in persons with and without statin intolerance; and (4) to

Results

Demographics are presented in Table 1. A study population of n = 10,789 subjects was identified with 47.9% males and 52.1% females. The mean age of all subjects was 67.2 ± 11.4 years. Males were older than females (P < .0001). Overall, 2686 subjects had statin intolerance matched 3:1 to 8103 controls with no history of statin intolerance. Persons with statin intolerance were more likely to have hypertension (P < .0001), diabetes (P < .0001), coronary artery disease (P = .0001), a history of

Summary of study findings

In the present study, we demonstrate that people who have an established diagnosis of hypothyroidism are more likely to have statin intolerance, and females more than males. We also show that those who have statin intolerance without a history of hypothyroidism are more likely to subsequently develop hypothyroidism. Additionally, statin intolerance and hypothyroidism appear to be independent and additive negative predictors of the likelihood that a person will be on a statin at follow-up. We

Conclusions

In conclusion, in a large health care system's database, we found hypothyroidism to be more prevalent in those with statin intolerance, both in males and, especially, in females. People with hypothyroidism are less likely to have a prescription for a statin at follow-up than those without hypothyroidism. Recognizing this interaction may lead to improved, more personalized care in these patients.

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In fact, high-level exercising usually interferes with taking statin [10,11]. There is no clear evidence explaining why patients develop muscle pain, but several studies suggest that it might be a combination of factors that are usually patient-specific [12,13]. These factors are age, body size, gender, ethnicity, genetic background, the presence of other metabolic diseases, and alcohol abuse [12,13].
Statins are the first-line treatment for hypercholesterolemic patients. Herein, the effects of three statins on complex formation between proprotein convertase subtilisin-kexin 9 (PCSK9) and the low density lipoprotein receptor (LDLR), a critical step for the PCSK9-dependent degradation of LDLR in the lysosome, were examined. Human hepatocyte-like C3A cells grown in control (containing 10% fetal bovine serum) or MITO+ (supplemented with BD™ MITO + serum extender) medium were also treated with atorvastatin (Atorv), lovastatin (Lov), or pravastatin (Prav) for 24 h. RNA and protein expression studies and determinations of PCSK9/LDLR complex formation were performed. As expected, the statins increased the expression of PCSK9 and LDLR independently of the medium employed. Interestingly, Atov and Lov caused increases in PCSK9/LDLR complex formation, whereas Prav decreased complex formation when compared to cells treated without drugs. These results may explain why Prav works better for statin intolerant patients than other statins such as Atorv and Lov.
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Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates.
Development and Validation of Algorithms to Identify Statin Intolerance in a US Administrative Database
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The study, however, focused only on statin discontinuation and analyzed only the first-reported statin-related event. Similarly, Robison et al. [34] used the Intermountain Healthcare EMR database to identify patients with a documented history of SI with and without hypothyroidism. The algorithm, however, was not validated and had numerous other limitations: patients were not required to have a minimum duration of statin therapy; there was no requirement to attempt therapy with more than one statin; the analysis was conducted in a predominantly white population; and the study did not collect information on the specific statins taken by patients or on statin dosage.
To develop and validate algorithms to define statin intolerance (SI) in an administrative database using electronic medical records (EMRs) as the reference comparison.
One thousand adults with one or more qualifying changes in statin therapy and one or more previous diagnoses of hyperlipidemia, hypercholesterolemia, or mixed dyslipidemia were identified from the Henry Ford Health System administrative database. Data regarding statin utilization, comorbidities, and adverse effects were extracted from the administrative database and corresponding EMR. Patients were stratified by cardiovascular (CV) risk. SI was classified as absolute intolerance or titration intolerance on the basis of changes in statin utilization and/or the occurrence of adverse effects and laboratory testing for creatine kinase. Measures of concordance (Cohen’s kappa [κ]) and accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value) were calculated for the administrative database algorithms.
Half of the sample population was white, 52.9% were women, mean age was 60.6 years, and 35.7% were at high CV risk. SI was identified in 11.5% and 14.0%, absolute intolerance in 2.2% and 3.1%, and titration intolerance in 9.7% and 11.8% of the patients in the EMR and the administrative database, respectively. The algorithm identifying any SI had substantial concordance (κ = 0.66) and good sensitivity (78.1%), but modest PPV (64.0%). The titration intolerance algorithm performed better (κ = 0.74; sensitivity 85.4%; PPV 70.1%) than the absolute intolerance algorithm (κ = 0.40; sensitivity 50%; PPV 35.5%) and performed best in the high CV-risk group (n = 353), with robust concordance (κ = 0.73) and good sensitivity (80.9%) and PPV (75.3%).
Conservative but comprehensive algorithms are available to identify SI in administrative databases for application in real-world research. These are the first validated algorithms for use in administrative databases available to decision makers.
Diagnosis, Prevention, and Management of Statin Adverse Effects and Intolerance: Canadian Consensus Working Group Update (2016)
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However, underlying hypothyroidism is recognized as a potential contributing factor to statin intolerance, particularly muscle effects.299,300 A recent analysis of the Intermountain Healthcare electronic medical claims database compared statin users with and without statin intolerance.301 The OR for hypothyroidism in those with vs without statin intolerance was 1.49 (P < 0.0001), with women being particularly susceptible.
The Canadian Consensus Working Group has updated its evaluation of the literature pertaining to statin intolerance and adverse effects. This overview introduces a pragmatic definition of statin intolerance (goal-inhibiting statin intolerance) that emphasizes the effects of symptoms on achieving nationally vetted goals in patients fulfilling indications for lipid-lowering therapy and cardiovascular risk reduction. The Canadian Consensus Working Group provides a structured framework for avoiding, evaluating and managing goal-inhibiting statin intolerance. Particularly difficult practice situations are reviewed, including management in young and elderly individuals, and in athletes and labourers. Finally, targeted at specialty practitioners, more detailed analyses of specific but more unusual adverse effects ascribed to statins are updated including evidence regarding new-onset diabetes, cognitive dysfunction, cataracts, and the rare but important immune-mediated necrotizing myopathy.
Le Canadian Consensus Working Group a mis à jour son évaluation de la littérature concernant l’intolérance et les effets indésirables des statines. Cet aperçu présente une définition pragmatique de l’intolérance aux statines (intolérance aux statines GISI) qui souligne les effets des symptômes sur l’atteinte des objectifs approuvés à l’échelon national chez les patients qui remplissent les indications de traitement hypolipidémiant et de réduction du risque cardiovasculaire. Le Canadian Consensus Working Group offre un cadre structuré pour éviter, évaluer et prendre en charge l’intolérance aux statines GISI. Nous passons en revue des situations particulièrement difficiles dans la pratique, dont la prise en charge des individus jeunes et âgés, des athlètes et des ouvriers. Finalement, destinées aux praticiens spécialistes, des analyses plus détaillées sur les effets secondaires particuliers, mais plus inhabituels attribués aux statines sont mises à jour, y compris les données probantes concernant le diabète de novo, le dysfonctionnement cognitif, les cataractes, et la rare, mais importante, myopathie nécrosante immunomédiée.
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Analyzing current definitions for statin-associated muscle adverse events, a myalgia clinical index score was suggested by the National Lipid Association's Muscle Safety Expert Panel [24]. There might be many different causes and risk factors of statin intolerance, including genetic predisposition [25]. The confirmed genetic factors related to elevated statin muscle levels is a mitochondrial enzyme (GATM), the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), an influx transporter (SLCO1B1 – located on chromosome 12 is probably the most common genetic risk factor of statin intolerance) and the efflux transporters (ABCB1 and ABCG2) [26].
This paper is an effort to review all the most important studies and guidelines in the topics of lipid, blood pressure and kidney published in 2014. Irrespective of advances, the options for improving simultaneous hypercholesterolemia and hypertension management (as well as its complication – chronic kidney disease) remain a problem. Recommending hypolidemic, hypotensive and kidney disease drugs to obtain therapy targets in cardiovascular, diabetic, elderly and kidney disease (=high risk) patients might strengthen risk factor control, improve compliance and the therapy efficacy, and in the consequence reduce the risk of cardiovascular events and mortality rate. That is why the authors have decided to summary and discuss the recent scientific achievements in the field of lipid, blood pressure and kidney.

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View full text

Original ArticleHypothyroidism as a risk factor for statin intolerance

Highlights

Background

Objectives

Methods

Results

Conclusions

Section snippets

Methods

Results

Summary of study findings

Conclusions

Endocrinol Metab Clin North Am

Int J Cardiol

Endocrinol Metab Clin North Am

Int J Cardiol

Neuromuscul Disord

J Biol Chem

Arch Biochem Biophys

Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium

Circulation

The Colorado thyroid disease prevalence study

Arch Intern Med

Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study

Cardiovasc Drugs Ther

In vivo and in vitro effects of statins on lymphocytes in patients with Hashimoto’s thyroiditis

Eur J Endocrinol

Reduced thyroid volume and nodularity in dyslipidaemic patients on statin treatment

Clin Endocrinol (Oxf)

HMG-CoA reductase inhibitors (statins) might cause high elevations of creatine phosphokinase (CK) in patients with unnoticed hypothyroidism

Endocr J

Original Article
Hypothyroidism as a risk factor for statin intolerance