Statin Rechallenge Research Articles

Plasma statin concentrations do not correlate with statin-induced myalgia

Abstract Aims Statins are essential in cardiovascular prevention. Although well-tolerated, patient adherence is often suboptimal due to experienced musculoskeletal symptoms ranging from mild myalgia to rare life-threatening rhabdomyolysis. This study aimed to investigate the relationship between plasma concentrations of statin metabolites in patients experiencing myalgia without rhabdomyolysis. Methods and results Plasma concentrations of statin metabolites were quantitatively assessed using mass spectrometry across three case-control cohorts evaluating statin-induced myalgia. The analysis included a total of 373 patients from the MILANO study (N=85 with self -reported myalgia), the MONTREAL study (N=248 with clinically verified myalgia) and the STOMP study (N=40 with rechallenge-verified statin-induced myalgia). STOMP found no significant difference in the plasma concentrations of statin metabolites between statin naïve patients with myalgia (N=12) taking atorvastatin 80 mg daily and asymptomatic controls (N=28), including upon subsequent statin rechallenge. Both the MILANO and MONTREAL studies showed lower plasma concentrations of statin metabolites in patients with myalgias compared to controls. MILANO showed a significant difference in rosuvastatin lactone concentration in patients with myalgias compared to asymptomatic controls (P = 0.025). Similarly, MONTREAL showed significantly lower mean atorvastatin metabolite concentrations in affected patients versus controls (P values ranging from 0.0073 to 0.037). Atorvastatin dosages in MONTREAL ranged from 5 to 80 mg daily, the most frequent regimens being 20 mg (27% in cases; 24% in controls) and 40 mg (33% in cases; 37% in controls). Creatine kinase levels were measured in all cohorts and were not different between cases and controls. Conclusion Development of myalgias in patients with normal creatine kinase levels is not associated with higher statin metabolite plasma concentrations. Myalgias during statin therapy are not caused by pharmacokinetic abnormalities.

Statin-associated muscle symptoms: A comprehensive exploration of epidemiology, pathophysiology, diagnosis, and clinical management strategies.

Statins are the first line of treatment for both primary and secondary prevention of atherosclerotic cardiovascular disease. Despite the positive effects of statins on cardiovascular events, not all patients can use them at an optimized dose. The reason for this is the skeletal muscle side effects, termed statin-associated muscle symptoms (SAMS). Despite extensive research, the precise pathophysiology of SAMS remains unclear and multiple mechanisms may contribute to this phenomenon. Various therapeutic options are available for the management of SAMS, ranging from rechallenging with the same or a different statin to utilizing non-statin therapeutic alternatives in patients intolerant to statins. However, the lack of consensus on the definition of SAMS, the absence of a definitive diagnostic test, and lack of a universally accepted management algorithm pose a great challenge in dealing with this entity. This review aims to explore the various pathophysiological mechanisms involved in SAMS and understand the difference between self-limited toxic myopathy and immune-mediated myopathy requiring immunomodulatory therapy. The conundrum of statin withdrawal, tapering, and rechallenge in SAMS will also be explored in detail along with the newer non-statin therapies that are available.

Overcoming patient reluctance to statin intolerance.

Statin therapy is a cornerstone in the management of dyslipidemia, both in primary and secondary prevention of cardiovascular events. Despite strong guidelines supporting statin use, concerns regarding side effects, particularly musculoskeletal symptoms, contribute to statin intolerance and patient reluctance. While statin intolerance is reported in 5% to 30% of patients, its true prevalence may be overestimated due to the influence of the nocebo effect. Factors associated with higher incidence of statin intolerance include older age, female sex, comorbidities such as diabetes and chronic kidney disease, and concurrent use of medications such as antiarrhythmic agents or calcium channel blockers. Clinical characterization of statin intolerance requires thorough evaluation and exclusion of alternative causes of musculoskeletal symptoms. Strategies to address statin intolerance include reassessing cardiovascular risk, engaging in shared decision-making, statin rechallenge after appropriate washout periods, dosage titration for tolerability, and consideration of alternative therapies when low-density lipoprotein goals cannot be achieved with statins. This review provides an overview of the spectrum of statin intolerance, its clinical assessment, and a systematic approach to caring for a patient with statin intolerance.

Intolerance upon statin rechallenge: A systematic review and meta-analysis of randomized controlled trials.

Although statins are often discontinued when myalgia arises, a causal relationship may not always exist. How well-tolerated statins are when rechallenge is blinded and controlled is unclear. We performed a systematic review and meta-analysis (PROSPERO CRD42023437648) to evaluate the success of statin rechallenge versus matched placebo in those who were previously statin intolerant. Our primary outcome was intolerance; our secondary outcome was the myalgia or global symptom score. Medline, Embase, CINAHL Plus, Scopus, and CENTRAL were searched from inception to May 1, 2023. Eligible trials were randomized controlled trials with parallel or crossover designs examining statin rechallenge in statin-intolerant adults. Two independent reviewers selected studies, extracted data, and assessed risk of bias (Cochrane Collaboration's risk-of-bias tool 1). Relative risk (RR) and mean difference (MD) were estimated using fixed effect Mantel-Haenszel statistics. Of 1,941 studies screened, 8 met our inclusion criteria (8 to 491 participants from Asia, Europe, North America, and Oceana). Compared to placebo, intolerance was more common in statin users [325/906 (36%) vs 233/911 (26%), RR 1.40, 95% CI, 1.23 to 1.60, I2 = 0%, 7 trials, number needed to harm 10] and there was no statistically significant difference in myalgia or global symptom score on a 100-point scale [MD 1.08, 95% CI, -1.51 to 3.67, I2 = 0%, 5 trials]. Limitations include only 1 trial asking participants about intolerable symptoms (vs inferring intolerance from discontinuation or trial withdrawal); the small number of trials; the possibility of attrition bias; and the potential for carryover effects in crossover/n-of-1 trial designs. Of those previously intolerant of statins who were rechallenged with a statin and compared to placebo recipients, medication intolerance was more common amongst statin recipients. However, there was no significant difference in mean myalgia or global symptom score between statin and placebo, and only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo.

Effect of statin treatment on metabolites, lipids and prostanoids in patients with Statin Associated Muscle Symptoms (SAMS).

Between 5-10% of patients discontinue statin therapy due to statin-associated adverse reactions, primarily statin associated muscle symptoms (SAMS). The absence of a clear clinical phenotype or of biomarkers poses a challenge for diagnosis and management of SAMS. Similarly, our incomplete understanding of the pathogenesis of SAMS hinders the identification of treatments for SAMS. Metabolomics, the profiling of metabolites in biofluids, cells and tissues is an important tool for biomarker discovery and provides important insight into the origins of symptomatology. In order to better understand the pathophysiology of this common disorder and to identify biomarkers, we undertook comprehensive metabolomic and lipidomic profiling of plasma samples from patients with SAMS who were undergoing statin rechallenge as part of their clinical care. We report our findings in 67 patients, 28 with SAMS (cases) and 39 statin-tolerant controls. SAMS patients were studied during statin rechallenge and statin tolerant controls were studied while on statin. Plasma samples were analyzed using untargeted LC-MS metabolomics and lipidomics to detect differences between cases and controls. Differences in lipid species in plasma were observed between cases and controls. These included higher levels of linoleic acid containing phospholipids and lower ether lipids and sphingolipids. Reduced levels of acylcarnitines and altered amino acid profile (tryptophan, tyrosine, proline, arginine, and taurine) were observed in cases relative to controls. Pathway analysis identified significant increase of urea cycle metabolites and arginine and proline metabolites among cases along with downregulation of pathways mediating oxidation of branched chain fatty acids, carnitine synthesis, and transfer of acetyl groups into mitochondria. The plasma metabolome of patients with SAMS exhibited reduced content of long chain fatty acids and increased levels of linoleic acid (18:2) in phospholipids, altered energy production pathways (β-oxidation, citric acid cycle and urea cycles) as well as reduced levels of carnitine, an essential mediator of mitochondrial energy production. Our findings support the hypothesis that alterations in pro-inflammatory lipids (arachidonic acid pathway) and impaired mitochondrial energy metabolism underlie the muscle symptoms of patients with statin associated muscle symptoms (SAMS).

Management of statin intolerance in a pharmacy led cardiology innovative medicines optimisation lipid clinic

Abstract Background Statins are cornerstone in the management of atherosclerotic cardiovascular disease. If a patient has experienced clinically significant adverse drug reactions (ADRs), representing an unacceptable risk or may result in adherence issues, we would consider them intolerant. The prevalence is lower in randomised trials than cohort observational studies, 5% vs. 17%. Purpose To assess how many people we reviewed in clinic were able to be re-challenged and successfully continued on a statin, free from side effects. Methods Over 6 months we reviewed all patients referred to our innovative clinic for lipid optimisation labelled as “statin intolerant”. Initially, as per our protocol, we adopted a person-centred approach and explored this label (actual vs. potential concerns, any previous issues, symptoms experienced and timings, statins tried (if any), and patient's feelings on re-challenge). A statin re-challenge was offered if not contraindicated. If agreed, based on shared-decision making, we offered patients a once weekly statin (usually rosuvastatin 5mg) with a clear self-management plan to up/down-titrate frequency and dose, until they identify a tolerated regimen. We measured LDL-C at baseline and every 3 months thereafter until satisfactory. Results Of 207 patients referred 152 (73%) were labelled as “statin intolerant”. Average age was 62 (±11), 51% females. 78% for secondary prevention and 37% had familial hypercholesterolaemia. The average baseline LDL-C was 4.4mmol/L. 108 (71%) qualified for PCSK9 inhibitors therapy (PCSK9i) as per UK NICE guidance. The top 3 reported ADRs were musculoskeletal side effects (48%), GI upsets (13%) and deranged LFTs (7%). 25 (58%) of those “intolerant” who did not qualify for PCSK9i attempted a re-challenge with statins vs. 44 (41%) among those who qualified. Of the 69 patients, who accepted a re-challenge, 43 (62%) were successfully restarted on a statin. At an average of 14 months post re-challenge, LDL-C (available for >80% of the sample) was reduced by an average of 31% in those not on PCSK9i, compared to a 62% reduction (sustained over an average of 40 months) in those on combination therapy with PCSK9i. The top 3 rosuvastatin regimens established were 5mg OD (29%), 5mg weekly (24%) and 10mg OD (15%). Approximately 80% of patients were on rosuvastatin, and the rest accepted atorvastatin, pravastatin or simvastatin. There was no attempt to re-challenge in 77 (51%) patients, mostly due to choice (45%) or statins re-challenged prior to referral (44%). We stopped statins in 6 cases due to intolerable ADRs. Conclusion(s) By using a person-centred approach, and a variety of strategies to tackle “statin intolerance” we have successfully re-established over 60% of patients with very high CVD risk on statins. While patients who qualified for PCSK9i therapy were less likely to consider re-challenge with statins (41% v 58%), combination lipid-lowering therapies produced better reduction in LDL-C. Funding Acknowledgement Type of funding sources: None.

Safety and Efficacy of Statin Rechallenge in Patients With Statin-Associated Muscular Symptoms: Long-Term Experience From a Speciality Lipid Clinic

Background: According to the most recent American College of Cardiology and American Heart Association guidelines for the reduction of atherosclerotic cardiovascular disease (ASCVD) risk, it is estimated that up to 48% of the United States population aged 40–75 years qualify for statin therapy, with an average absolute risk reduction of 5%. Despite statins being effective, cheap, and simple to use, uptake is limited in part by intolerance due to statin-associated muscular symptoms (SAMS). This study assessed the safety and efficacy of statin rechallenge for SAMS in a cohort of patients referred to the specialty lipid clinic.

Patients experiencing statin-induced myalgia exhibit a unique program of skeletal muscle gene expression following statin re-challenge.

Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of statin-treated patients experience myalgia symptoms, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels. Myalgia is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin myalgia are not clearly understood. To elucidate changes in gene expression associated with statin myalgia, we compared profiles of gene expression in skeletal muscle biopsies from patients with statin myalgia who were undergoing statin re-challenge (cases) versus those of statin-tolerant controls. A robust separation of case and control cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of patients with statin myalgia, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, cell senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals is genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario is further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myalgia and myositis were observed with increased frequency among patients with statin myalgia.

Statin-associated immune-mediated myopathy: biology and clinical implications.

In the last 6 years, our understanding of statin-associated myopathy expanded to include not only a toxic myopathy with limited and reversible side-effects but also an autoimmune variety in which statins likely induce an autoimmune myopathy that is both associated with a specific autoantibody and responsive to immunosuppression and immune modulation. This review widens the reader's understanding of statin myopathy to include an autoimmune process. Statin-associated immune-mediated myopathy provides an example of an environmental trigger (statins) directly implicated in an autoimmune disease associated with a genetic predisposition as well as potential risk factors including concomitant diseases and specific statins. Given a median exposure to statins of 38 months, providers should be aware that anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) myopathy may occur even after several years of statin exposure. It is important for the reader to understand the clinical presentation of statin-associated immune-mediated myopathy and the difference in its clinical presentation to that of statins as direct myotoxins. Prompt recognition of such an entity allows the clinician to immediately stop the offending agent if it has not already been discontinued as well as to recognize that statin rechallenge is not a likely option, and that prompt treatment with immunosuppression and/or immunomodulation is usually of enormous benefit to the patient in restoring muscle strength and physical function. VIDEO ABSTRACT.

Abstract P254: Willingness to Restart Statins: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study

Introduction: Many patients who discontinue statins due to side effects can restart treatment without the return of side effects. However, statin rechallenge is often met with resistance. Statins are associated with a larger absolute cardiovascular disease (CVD) risk reduction among high risk individuals, but it is unclear whether individuals with higher CVD risk are more willing to be rechallenged. Methods: Between 2014 and 2016, 12,604 participants in theREasons for Geographic and Racial Differences in Stroke study completed a study examination and a questionnaire about their experiences with statins. Of 6,947 participants who reported ever having taken a statin, this analysis included the 688 (9.9%) who reported having discontinued treatment due to side effects and who were not currently taking a statin. We asked participants whether they would be willing to restart a statin, and among those who answered no, we asked whether they were willing to restart at a lower dose or less frequently. Data from the study examination were used to define CVD risk factors and 10-year predicted CVD risk was calculated using the Pooled Cohort risk equations. Results: Participant mean age was 62.4 years, 29.6% were African American, and 66.4% were women. Overall, 26.0% (n=179) of participants were willing to be rechallenged with a statin (Table) . After adjustment for sociodemographic characteristics, older age, cigarette smoking, hypertension, diabetes, or history of CVD were not associated with an increased willingness to be rechallenged with a statin (Table) . Higher 10-year predicted CVD risk was also not associated with willingness to be rechallenged. Conclusions: Over a quarter of participants who discontinued statin treatment due to side effects were willing to be rechallenged. The presence of CVD risk factors and higher predicted CVD risk were not associated with increased willingness to be rechallenged with a statin.

Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.

Muscle-related statin intolerance is reported by 5% to 20% of patients. To identify patients with muscle symptoms confirmed by statin rechallenge and compare lipid-lowering efficacy for 2 nonstatin therapies, ezetimibe and evolocumab. Two-stage randomized clinical trial including 511 adult patients with uncontrolled low-density lipoprotein cholesterol (LDL-C) levels and history of intolerance to 2 or more statins enrolled in 2013 and 2014 globally. Phase A used a 24-week crossover procedure with atorvastatin or placebo to identify patients having symptoms only with atorvastatin but not placebo. In phase B, after a 2-week washout, patients were randomized to ezetimibe or evolocumab for 24 weeks. Phase A: atorvastatin (20 mg) vs placebo. Phase B: randomization 2:1 to subcutaneous evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Coprimary end points were the mean percent change in LDL-C level from baseline to the mean of weeks 22 and 24 levels and from baseline to week 24 levels. Of the 491 patients who entered phase A (mean age, 60.7 [SD, 10.2] years; 246 women [50.1%]; 170 with coronary heart disease [34.6%]; entry mean LDL-C level, 212.3 [SD, 67.9] mg/dL), muscle symptoms occurred in 209 of 491 (42.6%) while taking atorvastatin but not while taking placebo. Of these, 199 entered phase B, along with 19 who proceeded directly to phase B for elevated creatine kinase (N = 218, with 73 randomized to ezetimibe and 145 to evolocumab; entry mean LDL-C level, 219.9 [SD, 72] mg/dL). For the mean of weeks 22 and 24, LDL-C level with ezetimibe was 183.0 mg/dL; mean percent LDL-C change, -16.7% (95% CI, -20.5% to -12.9%), absolute change, -31.0 mg/dL and with evolocumab was 103.6 mg/dL; mean percent change, -54.5% (95% CI, -57.2% to -51.8%); absolute change, -106.8 mg/dL (P < .001). LDL-C level at week 24 with ezetimibe was 181.5 mg/dL; mean percent change, -16.7% (95% CI, -20.8% to -12.5%); absolute change, -31.2 mg/dL and with evolocumab was 104.1 mg/dL; mean percent change, -52.8% (95% CI, -55.8% to -49.8%); absolute change, -102.9 mg/dL (P < .001). For the mean of weeks 22 and 24, between-group difference in LDL-C was -37.8%; absolute difference, -75.8 mg/dL. For week 24, between-group difference in LDL-C was -36.1%; absolute difference, -71.7 mg/dL. Muscle symptoms were reported in 28.8% of ezetimibe-treated patients and 20.7% of evolocumab-treated patients (log-rank P = .17). Active study drug was stopped for muscle symptoms in 5 of 73 ezetimibe-treated patients (6.8%) and 1 of 145 evolocumab-treated patients (0.7%). Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks. Further studies are needed to assess long-term efficacy and safety. clinicaltrials.gov Identifier: NCT01984424.

Statin intolerance in a referral lipid clinic

Statins effectively prevent atherosclerotic cardiovascular disease, but rates of statin discontinuation after adverse events are high. Describe the range and relative frequencies of adverse events potentially attributable to statins in lipid referral practice and assess statin rechallenge outcomes. Retrospective cohort study of 642 patients with statin-associated adverse events evaluated in a referral lipid clinic between January 1, 2004 and January 27,2011. Patients experiencing adverse events by organ system included 92% with musculoskeletal, 8% central nervous system, 10% liver, 8% gastrointestinal, 5% peripheral nervous system, 5% skin, and 3% other events. Overlap of organ system involvement occurred in 22.5%. At least 1 follow-up visit was made by 557 patients, among whom overall median follow-up was 25months. Among patients treated with a statin in the clinic, 71% remained on a statin at the last follow-up visit. Patients with hepatic transaminase increases by history were numerically more likely than the overall group to resume or remain on statin treatment, whereas those reporting central nervous system or gastrointestinal symptoms trended lower for statin maintenance. Among patients who experienced an adverse event after statin rechallenge, the majority (64%) were being treated with intermittent, nondaily dosing at the time of the adverse event. Although musculoskeletal symptoms are reported by 90% of patients with statin intolerance, symptoms involving other organ systems may be more frequent than previously supposed. Understanding the range of symptoms, time course, and impact on daily activities informs counseling in patient-centered practice, but assessment of causation by statins remains challenging.

Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial

Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.

Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management.

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Statin Intolerance and Vitamin D Supplementation: Sunny, but a Few Clouds Remain….

Dear Editor, We read with interest the article by Khayznikov et al., regarding the resolution of statin intolerance with vitamin D repletion.[1] We too have tried this strategy among a similarly statin intolerant population (median – three previous statins) and believe vitamin D supplementation plays a role in treating certain individuals. Our results demonstrated that vitamin D repletion to >30 ng/ml, allowed 53% (18/34) of the intolerant patients to utilize some form of alternative or daily statin dosing or a higher dose among those receiving a statin but experiencing tolerable symptoms, for at least four months (mean follow up 8.5 + 4.4 months). Our findings are encouraging but well below the 88-95% statin tolerability rates reported in the present study. Directly comparing study populations and results is not feasible; however, one potential explanation for response differences may be the vitamin D level achieved. For instance, the vitamin D levels among those tolerating the statin rechallenge in our group was 44 ng/ml compared to 53-55 ng/ml in the current report, suggesting that perhaps our vitamin D repletion was incomplete, despite each group falling within the range suggested by the Endocrine Society.[2] Another factor that we believe played a prominent role in the resolution of myalgic symptoms in the current study was the predominant utilization of rosuvastatin. The authors recognize that rosuvastatin is less frequently associated with myotoxicity; however, this should not be minimized. In fact, the same research center performed a similar study, and determined that the vast majority of previously statin intolerant subjects reported no adverse effects when rechallenged with rosuvastatin 5-10 mg daily.[3] Lastly, we agree with the authors that an optimal study evaluating statin intolerance would be blinded and placebo-controlled, given the subjective nature of most myotoxicity. In fact, this design was recently utilized to assess various lipid-altering agents, including the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, among subjects unable to tolerate two or more different statins because of unexplained muscle-related symptoms.[4] After successful completion of a four-week single-blind placebo run-in period, subjects were randomized in a double-blind manner to a PCSK9 injection Q two weeks + oral placebo daily, ezetimibe 10 mg daily + placebo injection Q two weeks, or atorvastatin 20 mg daily + placebo injection Q two weeks, for 24 weeks. Such a study design provided novel, insightful, and revealing findings with regard to statin intolerance. For example, the trial demonstrated that 6.9% of subjects were excluded from randomization due to muscle-related adverse events during the placebo run-in period. Further, 75% of the previously intolerant patients tolerated the atorvastatin 20 mg daily for the duration of the 24-week study period. Such results strongly highlight the subjectivity of statin intolerance and the major influence of a placebo effect in many patients. Statin intolerance, especially among patients with previous sensitivity to multiple agents, is a complex and poorly understood issue that remains a clinical challenge. In the present study, vitamin D repletion likely improved muscle function and resolved symptoms in some patients. However, the vitamin D supplementation may have also provided a placebo effect, while the utilization of rosuvastatin further enhanced response. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Hypothyroidism as a risk factor for statin intolerance.

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. 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. 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. 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). 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.

N-of-1 (single-patient) trials for statin-related myalgia.

Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. Western University, London, Ontario, Canada.

Discontinuation of Statins in Routine Care Settings

LettersJuly 2, 2013Discontinuation of Statins in Routine Care SettingsDanijela Gnjidic, PhD, MPH, David G. Le Couteur, MBBS, PhD, and Sarah N. Hilmer, MBBS, PhDDanijela Gnjidic, PhD, MPHFrom University of Sydney, Sydney, New South Wales, Australia.Search for more papers by this author, David G. Le Couteur, MBBS, PhDFrom University of Sydney, Sydney, New South Wales, Australia.Search for more papers by this author, and Sarah N. Hilmer, MBBS, PhDFrom University of Sydney, Sydney, New South Wales, Australia.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-159-1-201307020-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read Zhang and colleagues’ article (1), which concludes that statin-related adverse events are tolerable and that patients should be rechallenged with statins, with great interest. Drawing such conclusions from observational studies may be limited, because the safety, efficacy, and effects of withdrawing statins were not considered in this setting.Although statin rechallenge may be justified for some patients, it may not be appropriate for those with limited evidence of statin efficacy and well-documented risk for harm, such as older patients (2). In persons older than 75 years, the role of statins in primary prevention of cardiovascular ...

Dyslipidemia: Treatment in Statin – Intolerant Patients

Statins are the mainstay of lipid-lowering therapy because of their well-established efficacy for reducing cardiovascular disease mortality and morbidity in various high risk populations. However, certain patients cannot avail themselves of these beneficial effects due to intolerance in these agents. Statin-induced myopathy is by far the most common side-effect. A less common side-effect of statin therapy is hepatic toxicity. Intolerance to statins is frequently encountered in clinical practice, mostly due to muscular symptoms and/or elevation of hepatic aminotransferases, which overall constitutes approximately two-thirds of reported adverse events during statin therapy. The first step in handling intolerant patients is to rule out any secondary causes of myopathy or liver toxicity. The second step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Another option is to restart with the same statin at a lower dosage or to switch to another statin with defferent pathways of metabolism. If the symptoms are recurrent, different approaches should be considered, such as unconventional dosing (every other-day or weekly administration) of statins with longer half-life. Another option in patients who cannot tolerate statins is the use of non-lipid lowering drugs, such as ezetimibe, bile acids sequestrants (colesevelam) and fibrates, alone or in combination. Concerning low-risk individuals the use of herbal supplements effective in reducing LDL cholesterol may be considered.

Statin Myopathy: A Lipid Clinic Experience on the Tolerability of Statin Rechallenge

Statin myopathy is a generally encountered side effect of statin usage. Both muscle symptoms and a raised serum creatine kinase (CK) are used in case definition, but these are common manifestations of other conditions, which may not be statin related. Statin rechallenge assuming no contraindication in selected cases is an option before considering a different class of lipid-lowering agent. We aim to characterize retrospectively the patients referred to our Lipid Clinic with a diagnosis of statin myopathy. The tolerability of different statins was assessed to determine a strategy for rechallenging statins in such patients in the future. Patients with statin myopathy constitute 10.2% of our Lipid Clinic workload. They are predominantly female (62.0%), Caucasian (63.9%), with a mean age of 58.3 years and mean body mass index (BMI) of 29.3 kg/m(2). The serum CK and erythrocyte sedimentation rate (ESR) were statistically higher compared to patients with statin intolerances with no muscular component or CK elevations. Secondary causes of statin myopathy were implicated in 2.7% of cases. Following statin myopathy to simvastatin we found no statistical difference between the tolerability rates between atorvastatin, rosuvastatin, pravastatin, and fluvastatin. Fibrates, cholestyramine, and ezetimibe were statistically better tolerated in these patients. Statin rechallenge is a real treatment option in patients with statin myopathy. Detailed history and examination is required to exclude muscle diseases unrelated to statin usage. In patients developing statin myopathy on simvastatin, we did not find any statistical difference between subsequent tolerability rates to rosuvastatin, pravastatin, and fluvastatin.