Am J Cardiovasc Drugs. 2008;8(6):373-418. doi: 10.2165/0129784-200808060-00004.
Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism.
Golomb BA, Evans MA.
Department of Medicine, University of California, San Diego, California 92093-0995, USA. email@example.com
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.
Statin therapy decreases myocardial function as evaluated via strain imaging.
Rubinstein J, Aloka F, Abela GS.
Cardiology Division, Department of Medicine, Michigan State University, East Lansing, MI 48824, USA.
The purpose of this study was to evaluate the effects of statin therapy on myocardial function as measured with echocardiography with tissue Doppler imaging (TDI) and strain imaging (SI) independent of its lipid-lowering effect.
Statin use is known to improve outcomes in the primary and secondary prevention of ischemic heart disease, but their use is also associated with myopathy, muscle weakness and in rare cases, rhabdomyolysis. We sought to evaluate whether TDI and SI is able to identify changes in myocardial function associated with statin use.
Myocardial function was evaluated in 28 patients via echocardiography with TDI and SI. We identified 12 patients (5 females) without overt cardiovascular disease (including hypertension, smoking, and diabetes) that were on statin therapy and compared their echocardiographic findings with 16 (12 females) age, sex, and cholesterol-profile-matched controls. Tissue Doppler imaging parameters of diastolic (E(')/A(') and E/E(')) and systolic (S') function were measured. Regional systolic function was obtained by SI in 4-chamber, 2-chamber, long axis, and average global views.
There was no significant difference in myocardial function as measured by Doppler and minor differences as measured via TDI among the 2 groups. There was significantly better function noted with SI in the control group vs the statin group in the 4-chamber (-19.05% +/- 2.45% vs -16.47% +/- 2.37% P = 0.009), 2-chamber (-20.30% +/- 2.66% vs -17.45% +/- 4.29% P = 0.03), long axis (-17.63% +/- 3.79% vs -13.83% +/- 3.74% P = 0.01), and average global (-19.0% +/- 2.07% vs -15.91% +/- 2.81% P = 0.004) views.
Statin therapy is associated with decreased myocardial function as evaluated with SI.
Nutr Metab Cardiovasc Dis. 2005 Feb;15(1):36-41.
Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease.
de Lorgeril M, Salen P, Guiraud A, Zeghichi S, Boucher F, de Leiris J.
Laboratoire Nutrition, Vieillissement et Maladies Cardiovasculaires (NVMCV), UFR de Médecine, Université Joseph Fourier, Grenoble, France. firstname.lastname@example.org
BACKGROUND AND AIM:
There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD).
METHODS AND RESULTS:
Male patients with CHD and high cholesterol levels (>6.2 mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5+/-1.7% of total fatty acids to 7.5+/-2.1, p<0.001 in S and from 6.2+/-1.4 to 6.8+/-1.4, p<0.005 in F) and a decrease in linoleate (from 26.9+/-3.9 to 24.2+/-3.6, p<0.001, and from 27.8+/-3.4 to 26.1+/-4.2, p<0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p<0.05), but only in F.
For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.
J Epidemiol Community Health. 2004 Dec;58(12):1047-51.
Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases.
Corrao G, Zambon A, Bertù L, Botteri E, Leoni O, Contiero P.
Dipartimento di Statistica, Università degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi 8, Edificio U7, 20126 Milan, Italy. email@example.com
Although lipid lowering drugs are effective in preventing morbidity and mortality from cardiovascular events, the extent of their adverse effects is not clear. This study explored the association between prescription of lipid lowering drugs and the risk of peripheral neuropathy.
A population based case-control study was carried out by linkage of several automated databases.
Resident population of a northern Italian Province aged 40 years or more.
Cases were patients discharged for peripheral neuropathy in 1998-1999. For each case up to 20 controls were randomly selected among those eligible. Altogether 2040 case patients and 36 041 controls were included in the study. Exposure ascertainment: Prescription drug database was used to assess exposure to lipid lowering drugs at any time in the one year period preceding the index date.Analysis: Conditional logistic regression model for matched data was used to estimate the risk of peripheral neuropathy associated with exposure to statins, fibrates, and other lipid lowering drugs.
Weak but significant effects of lipid lowering drugs as a whole (matched odds ratio: 1.27; 95% confidence intervals: 1.05 to 1.55), statins (1.19; 1.00 to 1.40), and fibrates (1.49; 1.03 to 2.17) were observed. Significant linear trends towards increased risk at increased exposure to both statins and fibrates were observed.
The use of both statins and fibrates was associated with the risk of peripheral neuropathy. The primary purpose of this exploratory study is signal generation. This requires further investigations to evaluate the causal role of lipid lowering drugs on the onset of peripheral neuropathy.
Br J Clin Pharmacol. 2004 Apr;57(4):525-8.
Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems.
Sinzinger H, O'Grady J.
Wilhelm Auerswald Atherosclerosis Research Group (ASF) Vienna, Institute for Diagnosis and Treatment of Atherosclerosis and Lipid Disorders (ATHOS), Vienna, Austria. firstname.lastname@example.org
Muscular problems are the major group of side-effects during statin treatment. They are known to occur much more frequently during and after exercise.
METHODS AND RESULTS:
For the last 8 years we have monitored 22 professional athletes in whom, because of familial hypercholesterolaemia, treatment with different statins was attempted. Only six out of the 22 finally tolerated at least one member of this family of drugs. In three of these six the first statin prescribed allowed training performance without any limitation. Changing the drug demonstrated that only two tolerated all the four or five statins examined (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin). Cerivastatin was not among the statins prescribed.
These findings indicate that in top sports performers only about 20% tolerate statin treatment without side-effects. Clinical decision making as to lipid lowering therapy thus becomes a critical issue in this small subgroup of patients.
Metabolism. 1997 Oct;46(10):1206-10.
Lovastatin increases exercise-induced skeletal muscle injury.
Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR.
Division of Cardiology, University of Pittsburgh, PA, USA.
This study tested the hypothesis that exercise in combination with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor produces greater creatine kinase (CK) elevations, an index of skeletal muscle injury, than exercise alone, using a double-blind, placebo-controlled design. Fifty-nine healthy men aged 18 to 65 years with low-density lipoprotein cholesterol (LDL-C) levels greater than 3.36 mmol/L (130 mg/dL) despite diet therapy were studied. Subjects were randomly assigned to receive lovastatin (40 mg/d) or placebo for 5 weeks. Subjects completed 45 minutes of downhill treadmill walking (-15% grade) at 65% of their predetermined maximum heart rate after 4 weeks of treatment. During the subsequent week, they completed four 10-repetition sets of one-arm biceps curl exercise using 50% of their maximum capacity. CK levels were measured before exercise and daily for 4 and 5 days after the treadmill and biceps exercises, respectively. Age, body weight, and blood lipid and lipoprotein levels were similar in lovastatin and placebo groups. Resting CK levels were 33% higher in the lovastatin group before treatment (P < .05), but were not significantly altered by lovastatin. CK levels were 62% and 77% higher (P < .05) in the lovastatin group 24 and 48 hours after treadmill exercise after adjusting for initial CK differences. There were no significant CK differences between lovastatin and placebo groups after biceps curl exercise. We conclude that HMG-CoA reductase inhibitors exacerbate exercise-induced skeletal muscle injury.
Cardiovasc Drugs Ther. 2003 Sep-Nov;17(5-6):459-65.
A comprehensive description of muscle symptoms associated with lipid-lowering drugs.
Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G.
Department of Endocrinology, Hôpital de La Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, 83 Bd de L'Hôpital, 75013 Paris, France. email@example.com
A spectrum of disease from myalgia to rhabdomyolysis exists as classic side-effect of lipid-lowering treatment (LLT). While myopathy has generated considerable interest, mild musculo-skeletal symptoms are poorly assessed.
To report on the muscular side-effects of LLT with a particular focus on the overlooked milder ones.
Hyperlipidemic patients under LLT and complaining of muscle symptoms were asked to complete a self administered questionnaire. Among the 815 adult hyperlipidemic patients under LLT and referred to the cardiovascular prevention unit of La Pitie Hospital, 165 patients answered that they experienced, or had experienced, muscle symptoms which they attributed to the LLT. One hundred and thirty three of these completed and returned a self-administered questionnaire.
A clear chronological link between symptoms and the LLT was revealed, either because they appeared soon after drug initiation or because of an improvement after drug withdrawal. While cramps and stiffness were the most frequent symptoms, tendonitis-associated pain was surprisingly common, reported in almost half the cases. Pain was often diffuse with a focus on a given location, mainly lower limbs. 39% of patients had used analgesics for pain relief. Unpredictably, a majority of patients reported pain during rest and the lying position. In a number of cases, a family history of pain under LLT was revealed.
The impact of these mild symptoms on daily activities might not be negligible in a subset of patients. The role and importance of a genetic background predisposing to low-grade myopathy deserves further investigation.
Arch Intern Med. 2005 Dec 12-26;165(22):26716.
Outcomes in 45 patients with statin-associated myopathy.
Hansen KE, Hildebrand JP, Ferguson EE, Stein JH.
Rheumatology Section, University of Wisconsin Medical School, H6/363 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA. firstname.lastname@example.org
Published studies regarding statin-associated myopathy may describe more dramatic patient presentations, potentially leading to inaccurate characterization of the condition. Furthermore, long-term outcomes and responses to statin rechallenge in patients with statin-associated myopathy are largely unknown.
The University of Wisconsin Hospital and Clinics Medical Informatics Department identified 437 patients with International Classification of Diseases, Ninth Revision codes potentially representing cases of statin-associated myopathy from more than 13 years of inpatient and outpatient data; 45 of these individuals were diagnosed as having statin-associated myopathy. Using a standardized form, 2 researchers abstracted all the case records to define the clinical course of statin-induced myopathy.
The mean (SD) duration of statin therapy before symptom onset was 6.3 (9.8) months. Resolution of muscle pain occurred a mean (SD) of 2.3 (3.0) months after discontinuation of statin therapy. Six patients (13%) were hospitalized for the management of rhabdomyolysis; 2 had reversible renal dysfunction, and 1 with preexisting renal insufficiency subsequently began lifelong dialysis. Hospitalized patients developed myopathy more quickly after initiating statin therapy (1.3 vs 7.1 months; P = .048) and were more likely to be taking concomitant medications known to increase the risk of statin-associated myopathy (P = .03). Thirty-seven patients received another statin after an episode of statin-associated myopathy; 21 (57%) reported recurrent muscle pain, whereas 16 (43%) tolerated other statins without recurrent symptoms.
Patients with statin-associated myopathy experienced full resolution of muscle pain on cessation of statin therapy. Although no deaths occurred, 13% of the patients required hospitalization for rhabdomyolysis. Recurrent muscle pain was common on statin rechallenge.
J Pathol. 2006 Sep;210(1):94-102.
Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia.
Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB.
Institute of Anatomy, Department of Cell Biology, University of Bern, Baltzerstrasse 2, 3012 Bern, Switzerland. email@example.com
Muscle pain and weakness are frequent complaints in patients receiving 3-hydroxymethylglutaryl coenzymeA (HMG CoA) reductase inhibitors (statins). Many patients with myalgia have creatine kinase levels that are either normal or only marginally elevated, and no obvious structural defects have been reported in patients with myalgia only. To investigate further the mechanism that mediates statin-induced skeletal muscle damage, skeletal muscle biopsies from statin-treated and non-statin-treated patients were examined using both electron microscopy and biochemical approaches. The present paper reports clear evidence of skeletal muscle damage in statin-treated patients, despite their being asymptomatic. Though the degree of overall damage is slight, it has a characteristic pattern that includes breakdown of the T-tubular system and subsarcolemmal rupture. These characteristic structural abnormalities observed in the statin-treated patients were reproduced by extraction of cholesterol from skeletal muscle fibres in vitro. These findings support the hypothesis that statin-induced cholesterol lowering per se contributes to myocyte damage and suggest further that it is the specific lipid/protein organization of the skeletal muscle cell itself that renders it particularly vulnerable.
Copyright (c) 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Fam Pract. 2002 Feb;19(1):95-8.
Do lipid-lowering drugs cause erectile dysfunction? A systematic review.
Rizvi K, Hampson JP, Harvey JN.
University of Wales College of Medicine, Wrexham Academic Unit, Wrexham, UK.
Erectile dysfunction (ED) is common although under-reported by patients. Along with the better known causes of ED, drug-induced impotence needs to be considered as a cause of this symptom. Lipid-lowering drugs have been prescribed increasingly. Their relationship to ED is controversial.
Our aim was to clarify the relationship between lipid-lowering therapy and ED. A secondary aim was to assess the value of the systematic review procedure in the area of adverse drug reactions.
A systematic review was carried out using computerized biomedical databases and Internet sources. Terms denoting ED were linked with terms referring to lipid-lowering drugs. Information was also sought from regulatory agencies.
A significant literature was identified, much from obscure sources, which included case reports, review articles, and information from clinical trials and from regulatory agencies. Information from all of these sources identified fibrates as a source of ED. A substantial number of cases of ED associated with statin usage have been reported to regulatory agencies. Case reports and clinical trial evidence supported the suggestion that statins can also cause ED. Some information on possible mechanisms was obtained, but the mechanism remains uncertain.
The systematic review procedure was applied successfully to collect evidence suggesting that both statins and fibrates may cause ED. More numerous reports to regulatory agencies complemented more detailed information from case reports to provide a new perspective on a common area of prescribing.
Drug Saf. 2006;29(12):1123-32.
Statins and pancreatitis: a systematic review of observational studies and spontaneous case reports.
Singh S, Loke YK.
Department of Internal Medicine, Section on General Internal Medicine, Wake Forest University Health Sciences, Winston Salem, North Carolina, USA. firstname.lastname@example.org
Many anecdotal reports have suggested that therapy with HMG-CoA reductase inhibitors ('statins') can cause acute pancreatitis. We aimed to quantify the association between statins and pancreatitis and to classify the adverse effect under the dose, time, susceptibility (DoTS) system. We searched for controlled observational studies that assessed the risk of pancreatitis in patients receiving statins. In order to identify case reports of statin-induced pancreatitis, we looked for reports published in scientific journals and manually reviewed reports within the Canadian Adverse Drug Event Monitoring System (CADRMP) database. Two observational studies were identified and the data pooled together in a meta-analysis. This yielded an odds ratio of 1.41 (95% CI 1.15, 1.74) for the risk of acute pancreatitis in patients with a past history of exposure to statins. We also identified 20 published case reports and 33 spontaneous reports from the CADRMP database. These data showed that pancreatitis can occur at both high and low doses, with 12 cases developing pancreatitis at less than the dose equivalent of simvastatin 20 mg daily. Statin-induced pancreatitis can occur at any time but seems to be very uncommon early on and more likely to occur after many months of therapy. There does not appear to be a cumulative dose effect and increasing age does not appear to be a major susceptibility factor. These finding should help clinicians to better manage and diagnose patients who are at risk of statin-induced pancreatitis.
CMAJ. 2007 Feb 27;176(5):649-54.
Does pravastatin promote cancer in elderly patients? A meta-analysis.
Bonovas S, Sitaras NM.
Department of Pharmacology, School of Medicine, University of Athens Athens, Greece. email@example.com
An increase in the incidence of cancer among elderly people assigned to pravastatin therapy has been reported in a randomized controlled trial; however, this finding has been attributed to chance. Our aim was to assess the effect of pravastatin therapy on cancer risk and to examine whether the effect varies according to age by performing a detailed meta-analysis and meta-regression analysis of randomized controlled trials.
We performed a comprehensive literature search for relevant studies published before February 2006. Before analysis, the selected studies were evaluated for publication bias and heterogeneity. Pooled relative risk estimates with 95% confidence intervals (CIs) were calculated using fixed-and random-effects models. Meta-regression analysis was performed to examine the impact of age on the study estimates of the relative risk of cancer due to pravastatin therapy.
Twelve trials that investigated the use of pravastatin therapy for cardiovascular outcomes were included in the analysis (n = 42 902). Although the overall association between pravastatin use and cancer was not statistically significant in the fixed-effects (risk ratio [RR] 1.06, 95% CI 0.99 - 1.13) or random-effects model (RR 1.06, 95% CI 0.97 - 1.14), the meta-regression analysis showed that the age of study participants significantly modified the effect of pravastatin therapy on cancer risk (p = 0.006). Specifically, this analysis showed that pravastatin therapy was associated with an increasing risk of cancer as age increased. This finding was remarkably robust in the sensitivity analysis.
Curr Opin Cardiol. 2011 Jul;26(4):342-7. doi: 10.1097/HCO.0b013e3283470359.
Are statins diabetogenic?
Sampson UK, Linton MF, Fazio S.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA. firstname.lastname@example.org
PURPOSE OF REVIEW:
Statins are widely utilized for low-density lipoprotein lowering and for prevention of atherosclerotic cardiovascular disease. Although these drugs have a good safety record, increased risk of developing diabetes during extended use has recently garnered attention. Here we review clinical trial evidence related to statin use and incident diabetes, and the potential mechanisms for this association.
The increased incidence of diabetes with rosuvastatin treatment in Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin (JUPITER) reignited attention on the link between statin therapy and diabetes. The JUPITER findings are supported by two recent meta-analyses of large-scale placebo-controlled and standard care-controlled trials, which, respectively, observed a 9% [odds ratio 1.09; 95% confidence interval (CI) 1.02-1.17] and 13% (risk ratio 1.13; 95% CI 1.03-1.23) increased risk for incident diabetes associated with statin therapy. However, the underlying mechanisms for this association remain unclear. Experimental evidence supports a paradigm implicating inhibition of β-cell glucose transporters, delayed ATP production, pro-inflammatory and oxidative β-cell effects of plasma-derived cholesterol, inhibition of calcium channel-dependent insulin secretion, and β-cell apoptosis.
The aggregate of large clinical trials supports the notion that statins modestly increase the risk of incident diabetes. Because diabetes is a risk equivalent condition for coronary and peripheral arterial diseases, these findings create a paradox whereby needed statin therapy may be withheld to avoid excess risk of diabetes while representing the strongest cardiovascular risk reduction tool in diabetics. We simply recommend regular glucose monitoring in patients taking statins.
Our findings suggest an association between pravastatin therapy and cancer in elderly patients. However, given the importance of this potential association, further verification is warranted.
The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials.
Schooling CM, Au Yeung SL, Freeman G, Cowling BJ.
CUNY School of Public Health at Hunter College, 2180 Third Avenue, New York, NY 10035, USA. email@example.com
Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.
A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.
Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).
Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.