Statin-related Adverse Events Research Articles

Predicted deleterious variants in ABCA1, LPL, LPA and KIF6 are associated with statin response and adverse events in patients with familial hypercholesterolemia and disturb protein structure and stability.

This study explored the association of deleterious variants in pharmacodynamics (PD) genes with statin response and adverse effects in patients with familial hypercholesterolemia (FH) and analyzed their potential effects on protein structure and stability. Clinical and laboratory data were obtained from 144 adult FH patients treated with statins. A panel of 32 PD genes was analyzed by exon-targeted gene sequencing. Deleterious variants were identified using prediction algorithms and their structural effects were analyzed by molecular modeling studies. A total of 102 variants were predicted as deleterious (83 missense, 8 stop-gain, 4 frameshift, 1 indel, 6 splicing). The variants ABCA1 rs769705621 (indel), LPA rs41267807 (p.Tyr2023Cys) and KIF6 rs20455 (p.Trp719Arg) were associated with reduced low-density lipoprotein cholesterol (LDLc) response to statins, and the LPL rs1801177 (p.Asp36Asn) with increased LDLc response (P < 0.05). LPA rs3124784 (p.Arg2016Cys) was predicted to increase statin response (P = 0.022), and ABCA1 rs769705621 to increase the risk of statin-related adverse events (SRAE) (P = 0.027). LPA p.Arg2016Cys and LPL p.Asn36Asp maintained interactions with solvent, LPA p.Tyr2023Cys reduced intramolecular interaction with Gln1987, and KIF6 p.Trp719Arg did not affect intramolecular interactions. DDMut analysis showed that LPA p.Arg2016Cys and p.Tyr2023Cys and LPL p.Asp36Asn caused energetically favorable changes, and KIF6 p.Trp719Arg resulted in unfavorable energetic changes, affecting protein stability. Deleterious variants in ABCA1, LPA, LPL and KIF6 are associated with variability in LDLc response to statins, and ABCA1 rs769705621 is associated with SRAE risk in FH patients. Molecular modeling studies suggest that LPA p.Tyr2023Cys and KIF6 p.Trp719Arg disturb protein conformational structure and stability.

Modifiable Statin Characteristics Associated with Potential Statin-Related Prescribing Cascades.

Clinicians may prescribe new medications (marker drug) to treat statin-related (index drug) adverse events, constituting a prescribing cascade. We aimed to identify modifiable statin characteristics (intensity and individual statin agents) associated with lower risk of prescribing cascades to inform clinical decisions in the presence of statin-related adverse events. We conducted a secondary analysis based on our previous work, a high-throughput sequence symmetry analysis screening for potential statin-related prescribing cascades using MarketScan Commercial and Medicare Supplemental Insurance claims databases between 2005 and 2019. Among the previously identified 57 potential prescribing cascades, 42 statin-marker class dyad with a sample size of ≥ 500 were assessed in this study. Herein, we measured patients' baseline characteristics within -360 days of statin initiation and reported by modifiable statin characteristics. We also performed logistic regression and reported the adjusted odds ratios (aOR) with 95% confidence intervals (CIs) of modifiable statin characteristics after adjusting for baseline characteristics. We identified 1,307,867 statin initiators who met the study criteria (21% elderly, 52% female). Compared with patients initiating low-intensity statins, those initiating moderate- or high-intensity statins had significantly greater odds to develop 29 (69%) prescribing cascades, including antidiabetic drugs such as dipeptidyl peptidase 4 (DPP-4) inhibitors (aOR 1.22; 95% CI, 1.11-1.35) and glucagon-like peptide-1 (GLP-1) analogues (aOR 1.31; 95% CI, 1.16-1.47), and opioids (aOR 1.18; 95% CI, 1.13-1.23). Individual statin agent selection also had a differential effect on 34 (81%) of the prescribing cascades. For example, compared with simvastatin initiators, the probability of initiating osmotically-acting laxatives was significantly higher for lovastatin initiators (aOR 1.09; 95% CI, 1.03-1.15) and significantly lower in atorvastatin initiators (aOR 0.92; 95% CI, 0.89-0.94). Compared with low-intensity statins, high-intensity statins are associated with increased risk in many potential prescribing cascades, while the choice of individual statin agents affects the risk of prescribing cascades bidirectionally.

Drug safety signal detection in a regional healthcare database using the tree-based scan statistic and comparison to 3 other mining methods.

To evaluate and compare the relative performance of the tree-based scan statistic (TreeScan) with the crude cohort study, Bayesian confidence propagation neural network (BCPNN) and Gamma Poisson Shrinker (GPS) in detecting statin-related adverse events (AEs) in an electronic healthcare database. Data from a Chinese healthcare database from 2010 to 2016 were evaluated. We identified statin users based on prescription information in their out-/in-patient records, and AEs were defined according to the ICD-10 codes in patients' diagnosis records. TreeScan was applied to detect AE signals related to statin use and was compared with 3 other methods based on sensitivity, specificity, positive predictive value, negative predictive value, accuracy, the Youden index, area under the precision-recall curve and the area under the receiver operating characteristic curve. A total of 224 187 patients were enrolled and divided into 85 758 statin users and 138 429 nonusers. TreeScan generated 29 positive signals, of which 9 were known AEs. The sensitivities of TreeScan, BCPNN and GPS were all 69.2%, which was higher than that of the crude cohort study (46%). The specificity (82.3%), positive predictive value (31.0%), negative predictive value (95.9%), accuracy (81.0%), Youden index (51.5%) and area under the receiver operating characteristic curve (75.8%) of TreeScan were the highest among the 4 methods. TreeScan outperformed the crude cohort, BCPNN and GPS in detecting statin-related AEs in an electronic healthcare database. Therefore, it can be used as a complementary tool for other signal detection methods in drug safety surveillance.

High-throughput screening for prescribing cascades among real world statin initiators.

Statins are among the most prevalent medications prescribed and associated with adverse events that may prompt additional treatment (i.e., a prescribing cascade). No comprehensive assessment of statin-related prescribing cascades has been performed to our knowledge. We utilized sequence symmetry analysis to iteratively screen prescribing sequences of all therapeutic classes ("marker" classes) based on Level 4 Anatomical Therapeutic Chemical codes among adult statin initiators, using IBM Marketscan commercial and Medicare supplemental claims databases (2005-2019). Order of initiation and secular trend-adjusted sequence ratios were calculated for each statin-marker class dyad, among marker class initiators ±90 days of statin initiation. Among signals classified as prescribing cascades, we calculated naturalistic number needed to harm (NNTH) within 1 year as the inverse of the excess risk among exposed. We identified 2 265 519 statin initiators (mean ± SD age, 56.4 ± 12.0 years; 48.7% women; 7.5% with cardiovascular disease). Simvastatin (34.4% of statin initiators) and atorvastatin (33.9%) were the most commonly initiated statins. We identified 160 significant statin-marker class dyad signals, of which 35.6% (n=57) were classified as potential prescribing cascades. Of the top 25 strongest signals (lowest NNTH), 12 were classified as potential prescribing cascades, including osmotically acting laxatives (NNTH, 44, 95% CI 43-46), opioids + non-opioid combination analgesics (81, 95% CI 74-91), and first-generation cephalosporins (204, 95% CI 175-246). Using high-throughput sequence symmetry analysis screening, we identified previously known prescribing cascades as well as potentially new prescribing cascades based on known and unknown statin-related adverse events.

Incidence of Statin-Associated Adverse Events in Kidney Transplant Recipients.

Statins are the third most prescribed drug class in kidney transplant recipients as cardiovascular disease is the leading cause of death in this population. However, statins' safety profile remains unclear in kidney transplant recipients who are uniquely burdened by concomitant immunosuppression and comorbidities. We conducted a national study to characterize the association of statin use with adverse events in kidney transplant recipients. We studied adult (18 years or older) single-organ kidney transplant recipients in 2006-2016 with Medicare as primary payer ( n =57,699). We used prescription drug claims to capture statin use and International Classification of Diseases 9/10 diagnosis codes to capture statin-related adverse events (post-transplant diabetes mellitus, hemorrhagic stroke, cataract, liver injury, and rhabdomyolysis). We conducted multivariable Cox regression for each outcome with statin use as a time-varying exposure. Post-transplant diabetes mellitus was the most common outcome (5-year Kaplan-Meier incidence; 43% in statin users versus 35% in nonusers), followed by cataract (22% versus 12%), liver injury (2% versus 3%), hemorrhagic stroke (1.9% versus 1.4%), and rhabdomyolysis (1.5% versus 0.9%). In our multivariable analysis, statin use was associated with higher hazard of post-transplant diabetes mellitus (adjust hazard ratio [aHR], 1.12; 95% confidence interval [95% CI], 1.07 to 1.18), cataract (aHR, 1.22; 95% CI, 1.14 to 1.31), and rhabdomyolysis (aHR, 1.37; 95% CI, 1.10 to 1.71) but lower hazard of liver injury (aHR, 0.82; 95% CI, 0.71 to 0.95). Statin use was not associated with hemorrhagic stroke (aHR, 1.04; 95% CI, 0.86 to 1.26). Statins seem to be generally well tolerated in kidney transplant recipients. However, statin use might be associated with slightly higher risk of post-transplant diabetes mellitus, cataract, and rhabdomyolysis.

Statin-related adverse events in Latin America

Statin-related adverse events in Latin America

Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that arehighly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drugmetabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

Statin intensity and risk for cardiovascular events after heart transplantation.

AimsStatins improve survival and reduce rejection and cardiac allograft vasculopathy after heart transplantation (HT). The impact of different statin intensities on clinical outcomes has never been assessed. We set out to determine the impact of statin exposure on cardiovascular outcomes after HT.Methods and resultsWe performed a retrospective study of 346 adult patients who underwent HT from 2006 to 2018. Statin intensity was determined longitudinally after HT based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The primary outcome was the time to the first primary event defined as the composite of heart failure hospitalization, myocardial infarction, revascularization, and all‐cause mortality. Secondary outcomes included time to significant rejection and time to moderate–severe cardiac allograft vasculopathy. Adverse events were evaluated for subjects on high‐intensity statin therapy. A Cox proportional hazards model was used to evaluate the relationship between clinical variables, statin intensity, and outcomes. Most subjects were treated with low‐intensity statin therapy although this declined from 89.9% of the population at 1month after HT to 42.8% at 5years after HT. History of ischaemic cardiomyopathy, significant acute rejection, older donor age, and lesser statin intensity (p ≤ 0.001) were associated with reduced time to the primary outcome in a multivariable Cox model. Greater intensity of statin therapy was most beneficial early after HT. There were no statin‐related adverse events for the 14 subjects on high‐intensity statin therapy.ConclusionsGreater statin intensity was associated with a reduction in adverse cardiovascular outcomes after HT.

A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials.

Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This post hoc analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use. The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (n=1644) or placebo (n=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone. No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (e.g., musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%). Tolvaptan has been used safely in combination with statins in clinical trials. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.

Evolocumab in HIV-Infected Patients With Dyslipidemia: Primary Results of the Randomized, Double-Blind BEIJERINCK Study

BackgroundPeople living with human immunodeficiency virus (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and are prone to statin-related adverse events from drug–drug interactions with certain antiretroviral regimens. ObjectivesThis study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV. MethodsBEIJERINCK (EvolocumaB Effect on LDL-C Lowering in SubJEcts with Human Immunodeficiency VirRus and INcreased Cardiovascular RisK) is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C <70 mg/dl and percent change in other plasma lipid and lipoprotein levels. Treatment-emergent adverse events were also examined. ResultsA total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% confidence interval: 61.6% to 52.3%) from baseline to week 24 versus placebo. An LDL-C level of <70 mg/dl was achieved in 73.3% of patients in the evolocumab group versus 7.9% in the placebo group. Evolocumab also significantly reduced other atherogenic lipid levels, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (all p < 0.0001). Evolocumab was well tolerated, and treatment-emergent adverse events patient incidence was similar among evolocumab and placebo groups. ConclusionsEvolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk. (Safety, Tolerability & Efficacy on LDL-C of Evolocumab in Subjects With HIV & Hyperlipidemia/Mixed Dyslipidemia; NCT02833844)

Statin-associated muscle symptoms (SAMS) in primary prevention for cardiovascular disease in older adults: a protocol for a systematic review and meta-analysis of randomised controlled trials

IntroductionAlthough statins are commonly used for prevention of cardiovascular disease, there is limited evidence about statin-related adverse effects in older people. Statin-related adverse events (AEs), especially the statin-associated muscle symptoms...

Annals for Educators - 15 August 2017

Annals for Educators - 15 August 2017

Untreated Dyslipidemia in Lebanese Patients With Schizophrenia.

To investigate the prevalence of statin-untreated schizophrenic patients needing treatment according to the 2013 American College of Cardiology and the American Heart Association (ACC/AHA) guidelines and to compare the performance of these guidelines to the 2004 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP-III) recommendations. A cross-sectional study was conducted using medical charts, patient inverventions, and various anthropometric measures between April 2016 and July 2016 at the Psychiatric Hospital of the Cross enrolled 329 patients with schizophrenia (DSM-5 criteria) to determine dyslipidemia and risk for atherosclerotic cardiovascular disease (ASCVD). Of the patients, 81.25% (130 patients of 160) who need a statin therapy according to the ACC/AHA guidelines would not need a therapy according to the NCEP ATP-III, while only 9.1% of the total population met the criteria for both guidelines concomitantly. A significant difference in favor of the ACC/AHA guideline was found between the 2 guidelines (P < .001). Among the 130 patients who need a statin treatment, 124 (95.4%) had ASCVD ≥ 7.5%, 13 patients (10%) had diabetes, 1 patient (0.8%) had clinical cardiovascular disease (CVD), and none had low-density lipoprotein > 190 mg/dL. Although our results showed the superiority of the 2013 ACC/AHA guidelines over the 2004 NCEP guidelines for detecting undiagnosed dyslipidemia, the absolute benefit or risk of a statin therapy according to these guideline recommendations remains unclear in this population of schizophrenic patients because the actual occurrence of CVD or statin-related adverse events was not investigated in this study. Further studies are needed to evaluate the reduction in CVD by a statin treatment according to both guidelines and thus compare the actual benefit of statin assignment in schizophrenic patients.

Current treatment of dyslipidaemia: PCSK9 inhibitors and statin intolerance.

Statins are the cornerstone of the management of dyslipidaemias and prevention of cardiovascular disease. Although statins are, overall, safe and well tolerated, adverse events can occur and constitute an important barrier to maintaining long-term adherence to statin treatment. In patients who cannot tolerate statins, alternative treatments include switch to another statin, intermittent-dosage regimens and non-statin lipid-lowering medications. Nonetheless, a high proportion of statin-intolerant patients are unable to achieve recommended low-density lipoprotein (LDL) cholesterol goals, thereby resulting in substantial residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease implicated in LDL receptor degradation and plays a central role in cholesterol metabolism. In recent studies, PCSK9 inhibition by means of monoclonal antibodies achieved LDL cholesterol reductions of 50% to 70% across various patient populations and background lipid-lowering therapies, while maintaining a favourable safety profile. The efficacy and safety of the monoclonal antibodies alirocumab and evolocumab were confirmed in statin-intolerant patients, indicating that PCSK9 inhibitors represent an attractive treatment option in this challenging clinical setting. PCSK9 inhibitors recently received regulatory approval for clinical use and may be considered in properly selected patients according to current consensus documents, including patients with statin intolerance. In this review we summarise current evidence regarding diagnostic evaluation of statin-related adverse events, particularly statin-associated muscle symptoms, and we discuss current recommendations on the management of statin-intolerant patients. In view of emerging evidence of the efficacy and safety of PCSK9 inhibitors, we further discuss the role of monoclonal PCSK9 antibodies in the management of statin-intolerant hypercholesterolaemic patients.

The new lipid-lowering drugs: focus on monoclonal antibodies

The need for new lipid-lowering drugs is based on the clear-cut evidence that a considerable proportion of patients with dyslipidemia cannot reach the target of cardiovascular protection with the use of currently available drugs (statins, ezetimibe, fibrates). Among the new classes of drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (namely alirocumab and evolocumab) provide an effective solution for patients with familial hypercholesterolemia as well as for high-risk patients who do not achieve the target or complain statin-related adverse events. The use of PCSK9 inhibitors is associated with a huge reduction in LDL-cholesterol levels (up to 30-40 mg/dl) with 1-2 monthly administrations, and their effect is integrated with that of statins and ezetimibe. The improvement of lipid profile is in the range of that observed with other new drugs such as lopitamide and mipomersen, while the tolerability profile appears definitely better. A more effective characterization of patients with dyslipidemia is the trainer of new research in the field of lipid-lowering drugs and PCSK9 inhibitors appear the more reliable product of such a promising research.

Abstract 280: Defining Statin Intolerance Among High Cardiovascular Risk Patients: Do US Administrative Databases Lend Themselves to Identification Of Statin Intolerance?

Introduction: The clinical and economic impact of statin intolerance (SI) in high CV risk patients is unknown due, in part, to a lack of consensus in its definition. We sought to define and validate an SI algorithm for use in an administrative database (AD) among high-CV risk patients Methods: Adults with ≥1 qualifying change (See Table 1) in statin therapy and ≥1 prior diagnosis of hyperlipidemia, hypercholesterolemia, or mixed dyslipidemia were identified from the AD of the Health Alliance Plan at Henry Ford Health System (HFHS). A sample of 1000 patients was drawn from the pool of eligible adults and stratified by high CV risk based on presence of comorbid conditions including diabetes, coronary heart disease, and peripheral artery disease. Statin utilization and adverse events data were abstracted both from the AD and the HFHS electronic medical record (EMR). SI was defined using both a primary definition inclusive of all possible statin related adverse events and a secondary definition that included only musculoskeletal events. SI was categorized as absolute (AI) or titration (TI) intolerance. The performance of the AD algorithm was assessed using measures of concordance (Cohen’s kappa [κ]) and accuracy (sensitivity, specificity, positive predictive value [PPV]) with the EMR as reference. Results: A total of 353 patients (48% female, 44% Caucasian, mean (SD) age 63 (12) years) were identified as high CV risk with 33% having a history of CHD, 77% diabetes and 2% PAD. Forty-two percent of patients were on simvastatin, 35% atorvastatin, 11% lovastatin, 7% rosuvastatin and 6% pravastatin/fluvastatin. Table 1 characterizes the validation sample. SI was identified in 19.3% and 20.7%, AI in 3.1% and 2.8%, and TI in 16.7% and 18.7% of patients in the EMR and AD, respectively. The algorithm identifying any SI had robust concordance (κ=0.73), good sensitivity (80.9%) and PPV (75.3%). The TI algorithm performed better (κ=0.78, sensitivity=86.4%, PPV=77.3%) than the AI algorithm (κ=0.56, sensitivity=54.5%, PPV=60.0%). Specificity was high (&gt;94%) across all 3 algorithms. Conclusion: This study successfully defined SI among high-CV risk patients using an evidence-based validated algorithm. To our knowledge, this is the first such algorithm for use in AD to be made available to decision-makers.

Effect of atorvastatin withdrawal on circulating coenzyme Q10 concentration in patients with hypercholesterolemia

Statin therapy can reduce the biosynthesis of both cholesterol and coenzyme Q10 by blocking the common upstream mevalonate pathway. Coenzyme Q10 depletion has been speculated to play a potential role in statin-related adverse events, and withdrawal of statin is the choice in patients developing myotoxicity or liver toxicity. However, the effect of statin withdrawal on circulating levels of coenzyme Q10 remains unknown. Twenty-six patients with hypercholesterolemia received atorvastatin at 10 mg/day for 3 months. Serum lipid profiles and coenzyme Q10 were assessed before and immediately after 3 months and were also measured 2 and 3 days after the last day on the statin. After 3 months' atorvastatin therapy, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and coenzyme Q10 (0.43 +/- 0.23 to 0.16 +/- 0.10 microg/mL) were all significantly reduced (all p<0.001). On day 2 after the last atorvastatin, the coenzyme Q10 level was significantly elevated (0.37 +/- 0.16 microg/mL) and maintained the same levels on day 3 (0.39 +/- 0.18 microg/mL) compared with those on month 3 (both p< 0.001), while TC and LDL-C did not significantly change within the same 3 days. These results suggest that statin inhibition of coenzyme Q10 synthesis is less strict than inhibition of cholesterol biosynthesis.

Statin-related adverse events: A meta-analysis

Background: The absolute frequencies of adverseevents (AEs) between statins and placebo are very low in clinical trials, making clinical interpretation and application difficult. Objectives: This meta-analysis was intended to synthesize the collective AE data observed in prospective randomized clinical trials to facilitate clinical interpretation. Methods: Using the search terms atorvastatin, simvastatin,pravastatin, rosuvastatin, fluvastatin, lovastatin, prospective trial, and randomized trial, the MEDLINE/EMBASE and the Cochrane Collaboration databases were reviewed for prospective randomized primary and secondary prevention trials of statin monotherapy. Nonrandomized uncontrolled studies and those missing AE data were excluded. The Mantel-Haenszel test for fixed and random effects was used to calculate odds ratios (ORs) and log ORs. Results: Eighteen trials including 71,108 persons, and 301,374 person-years of follow-up were represented in this analysis. There were 36,062 persons receiving a statin and 35,046 receiving a placebo. Statin therapy increased the risk of any AE by 39% (OR = 1.4; 95% CI, 1.09–1.80; P = 0.008; NNH [number needed to harm] = 197) compared with placebo. Statins were associated with a 26% reduction in the risk of a clinical cardiovascular event (OR = 0.74; 95% CI, 0.69–0.80; P < 0.001; number needed to treat = 27). Treating 1000 patients with a statin would prevent 37 cardiovascular events, and 5 AEs would be observed. Serious events (creatine phosphokinase >10 times the upper limit of normal or rhabdomyolysis) are infrequent (NNH = 3400) and rhabdomyolysis, although serious, is rare (NNH = 7428). Atorvastatin was associated with the greatest risk of AEs and fluvastatin with the least risk. Simvastatin, pravastatin, and lovastatin had similar odds of AEs. Nonurgent AEs such as myalgia and liver function elevations were responsible for approximately two thirds of AEs reported in trials. Conclusions: Statin therapy was associated withgreater odds of AEs compared with placebo but with substantial clinical benefit. Similar rates of serious AEs were observed between statin and placebo.