Background Statins Research Articles

In the Era of the Universal Use of Statins Dyslipidemia's are Still Common in Heart Transplant Recipients: A Cross-Sectional Study

Background Statins are used in orthotopic heart transplant (OHT) recipients to avoid acute rejection episodes (ARE) during the first year after surgery and coronary vasculopathy (CAV) thereafter as established in prospective randomized trials, yielding the grounds for the universal use of this group of drugs. The aim of the study was to describe the occurrence of dyslipidemias among OHT recipients after introduction of guidelines suggesting the use of statins in all individuals able to tolerate this therapy. Methods Medical records of all OHT recipients undergoing routine clinical checkups between January and June 2010 were screened for the presence of dyslipidemia: total cholesterol > 5 mmol/L; low-density lipoprotein (LDL)-cholesterol > 3 mmol/L; triglycerides > 1.65 mmol/L; high-density lipoprotein (HDL) < 1 mmol/L in the serum. The study group consisted of 322 subjects including 265 males and 57 females of overall mean age of 53.6 ± 12 and 7 ± 4 years after OHT. There was coronary artery disease (CAD) before OHT in 113 (35%). The average number of ARE was 1.9 ± 1.9 and CAV was diagnosed in 77 (24%) patients. There were 247 (77%) patients on statins. We analyzed clinical, ultrasound, and biochemical evaluations to characterize subjects with dyslipidemias. Results At least one dyslipidemia was observed among 212 (66%) including hypercholesterolemia in 121 (38%), high LDL in 135 (42%), hypertriglyceridemia in 110 (34%), and low HDL in 48 (15%) patients. The subjects with dyslipidemia were prone to be older, to have CAD before OHT, and to be hypertensive, overweight, and obese, as well as display an higher HbA1C when diabetic. They were treated less frequently with tacrolimus but showed higher drug levels, and more often were prescribed everolimus. Conclusions Despite almost universal use of statins, dyslipidemias were present in 2/3 of OHT recipients. It was related to typical atherosclerotic risk factors; however, the influence of immunosuppressants seemed to also be significant.

Reducing vascular events risk in patients with dyslipidaemia: an update for clinicians.

Reducing the risk of vascular events in patients with dyslipidaemia requires cardiovascular disease risk stratification and lifestyle/pharmacological intervention on modifiable risk factors. Reduction of low-density lipoprotein cholesterol (LDL-C) with statins is highly effective in reducing cardiovascular disease in patients with and without diabetes, but leaves unaddressed a sizeable residual vascular risk (RvR), which is rarely quantified in routine clinical practice. Such RvR may relate to lack of strict target attainment for all atherogenic variables [LDL-C, non-high-density lipoprotein cholesterol (HDL-C) and/or apolipoprotein B(100)]. Another substantial lipid-related and modifiable RvR component is related to atherogenic dyslipidaemia, especially as global rates of obesity, type 2 diabetes and metabolic syndrome are increasing. Atherogenic dyslipidaemia is associated with insulin-stimulated very-low-density lipoprotein overproduction and reduced reverse cholesterol transport. The hallmark of atherogenic dyslipidaemia is the coexistence of low HDL-C and elevated triglycerides. Therapeutic lifestyle changes and combination lipid-lowering therapy with drugs targeting atherogenic dyslipidaemia (such as fibrates or innovative drugs targeting atherogenic dyslipidaemia and/or apolipoprotein B(100) metabolism) on top of background statins, have a potential to reduce RvR in high-risk groups, as shown in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, in which combination therapy with simvastatin plus fenofibrate decreased macrovascular risk in patients with diabetes and atherogenic dyslipidaemia, and retinopathy risk irrespective of baseline lipids.

Statin-Associated Rhabdomyolysis: Is There a Dose-Response Relationship?

Background Statins have a well-established role in prevention of vascular events but are associated with muscle-related adverse events. The dose relationship with these adverse events is unclear. We present an original analysis of Canadian and US case reports of statin-associated rhabdomyolysis with a focus on dose response. A typical clinical case is also summarized. Methods All cases of statin-associated rhabdomyolysis reported to Health Canada's Canadian Vigilance Program and to the US Food and Drug Administration's Adverse Event Reporting System from 2004-2008 were analyzed by severity and dose equivalence. Canadian national statin utilization data from 2002-2007 were used to estimate the dose-related incidence of rhabdomyolysis corrected for levels of utilization. Results The clinical case illustrates well the potential severity of statin-induced rhabdomyolysis. Combined Canadian/US data revealed an average of 812 cases of statin-induced rhabdomyolysis reported annually with a mean patient age of 64.4 years (35.5% female). The worst outcomes reported were renal dysfunction in 17.0%, acute renal failure in 19.8%, dialysis in 5.2%, and death in 7.6%. Using 10 mg atorvastatin per day as the reference dose, the odds ratios of rhabdomyolysis were 3.8 (95% CI 2.3-6.6) for 40 mg/day atorvastatin dose equivalent and 11.3 (95% CI 6.4-20.4) for 80 mg/day atorvastatin dose equivalent. Conclusions The results of our adverse drug analysis suggest a dose-response relationship. Given the widespread use of statins, the ability to predict which patients will experience serious muscle-related harm is a research priority.

Statin use and lipid levels in older adults: National Health and Nutrition Examination Survey, 2001 to 2006

Statins are the evidence-based drugs of choice for the prevention of cardiovascular disease (CVD). Statin use has increased in those ≥ 65 years, but patterns of use in subgroups of elderly are unknown. Weighted data from the 2001 through 2006 National Health and Nutrition Examination Surveys were combined for this analysis. Statin use increased in all sex, age, and risk categories between the 2001-2002 and 2005-2006 surveys, when the greatest use was by men 65 to 74 years of age with CVD (80%), followed by women with CVD who were 65-79 of age (64%-69%), women and men with diabetes who were 65-69 years of age (56% and 94%, respectively); statins were used by <42% of patients without CVD or diabetes. In adjusted logistic regression models, those with diabetes (odds ratio [OR] 2.1, 95% confidence intervals [95% CI] 1.8-2.6), CVD but no diabetes (OR 3.0, 95% CI 2.5-3.6), and CVD and diabetes (OR 5.2, 95% CI 3.9-7.1) were more likely to use statins than those without CVD or diabetes (P ≤ .001). A significant interaction between age and sex was found, where 75- to 79-year-old women were more likely to report statin use than men 65-69 years of age (OR 2.07, 95% CI 1.29-3.35). In general, those ages 65-69 years were more likely to use a statin than those ≥ 70 years (OR 0.57, 95% CI 0.39-1.08, P = .08). Nonwhite persons aged ≥ 70 years reported less statin use than whites aged 65-69 (OR 0.17, 95% CI 0.10-0.30). Mexican-American subjects were less likely to report statin use than whites. Although statin use has increased substantially over time, statins remain underused in both the primary and secondary prevention of CVD in the elderly, with some evidence of disparities by sex, advancing age, and race/ethnicity.

Preoperative Atorvastatin Treatment in CABG Patients Rapidly Improves Vein Graft Redox State by Inhibition of Rac1 and NADPH-Oxidase Activity

Statins improve clinical outcome of patients with atherosclerosis, but their perioperative role in patients undergoing coronary artery bypass grafting (CABG) is unclear. We hypothesized that short-term treatment with atorvastatin before CABG would improve the redox state in saphenous vein grafts (SVGs), independently of low-density lipoprotein cholesterol (LDL)-lowering. In a randomized, double-blind controlled trial, 42 statin-naïve patients undergoing elective CABG received atorvastatin 40 mg/d or placebo for 3 days before surgery. Circulating inflammatory markers and malondialdehyde (MDA) were measured before and after treatment. SVG segments were used to determine vascular superoxide (O(2)(*-)) and Rac1 activation. For ex vivo studies, SVG segments from 24 patients were incubated for 6 hours with atorvastatin 0, 5, or 50 μmol/L. Oral atorvastatin reduced vascular basal and NADPH-stimulated O(2)(*-) in SVGs (P<0.05 for all versus placebo) and reduced plasma MDA (P<0.05), independently of LDL-lowering and of changes in inflammatory markers. In SVGs exposed to atorvastatin ex vivo, without exposure to LDL, basal and NADPH-stimulated O(2)(·-) were significantly reduced (P<0.01 for both concentrations versus 0 μmol/L) in association with a striking reduction in Rac1 activation and 1 membrane-bound Rac1 and p67(phox) subunit. The antioxidant effects of atorvastatin were reversed by mevalonate, implying a dependence on vascular HMG-CoA reductase inhibition. Short-term treatment with atorvastatin 40 mg/d before CABG improves redox state in SVGs, by inhibiting vascular Rac1-mediated activation of NADPH-oxidase. These novel findings suggest that statin therapy should be maintained or initiated in patients undergoing CABG, independently of LDL levels. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.

Patients’ self-estimated likelihood of taking a statin as prescribed after different types of prognostic information

Background Statins are frequently used in cardiovascular prevention, however medication adherence is suboptimal. Aims To examine if different types of prognostic information associated with prescription of a statin by physicians, can influence the self-estimated likelihood of taking the drug as prescribed, and to investigate whether patients want this type of information. Methods A survey was performed in 313 patients diagnosed with CVD. Patients were presented to facts with relative risk reduction and absolute risk reduction figures associated with the use of a statin and the self-estimated likelihood of taking the drug as prescribed was registered after each given fact. Results Self-estimated likelihood of taking the statin as prescribed was highest when the cardiologist recommended the drug without presenting absolute and relative risk reduction figures. Presenting relative risk reduction figures for the patients gave significantly higher self-estimated likelihood to take the statin as prescribed compared to giving the patients absolute risk reduction figures ( p < 0.001). A vast majority of the patients (84%) wanted to achieve information about risk reduction associated with the statin treatment. Conclusion The patients wanted information about the CV risk reduction associated with the prescribed statin; however, the best self-estimated medication adherence was achieved when the cardiologist recommended the drug without presenting risk reduction figures.

A cluster randomised controlled trial of pharmacist led Statin Outreach Support (SOS) in primary care: Design and baseline characteristics

Background Statins reduce the risk of vascular events, however statin prescribing is often sub optimal and better evidence is needed to inform quality improvements. The Statin Outreach Support (SOS) trial was designed to test the efficacy of pharmacist led educational outreach directed at General Practices, aiming to improve statin prescribing for community dwelling patients with vascular disease. This paper describes the study rationale, design, methods and baseline characteristics of participants. Design The SOS trial was designed to investigate whether practices receiving SOS improve their statin prescribing and patients achieve reduced cholesterol levels. It was a prospective, single blind, cluster randomised controlled trial with a follow-up period of 5 months minimum post SOS intervention delivery. Results Thirty one practices were recruited from the UK's largest Health Board area. At randomisation, 16 practices were allocated to SOS and 15 to usual care with 4040 patients included at baseline. Participating practices showed few differences compared with non-participating practices; practices and patients randomised to each arm of the study had similar distributions with respect to age, complications, cholesterol levels and statin prescribing. Baseline data compared favourably with landmark, placebo-controlled statin trials. Conclusions Compared with existing implementation research, SOS trial has more participants, a detailed description of baseline characteristics and over 90% power (at 5% significance) to detect a difference of 12% in the proportion of patients with controlled cholesterol after SOS.

Statin Therapy Ameliorates Renal Allograft Function

Background Statins have proven ability as antilipidemic agents and benefit cardiovascular survival in transplant recipients. The pleiotropic effects of statins on renal function in renal allograft recipients are still undetermined. Methods Statin therapy was initiated according to guidelines for cardiovascular protection. Serum creatinine concentration and estimated glomerular filtration rate (eGFR) were analyzed before and after introduction of statins. The 73 patients who were retrospectively studied included those who were dialysis-dependent. Mean changes in eGFR and lipid profile were compared before and after commencing statins using χ 2 tests. Results Mean serum creatinine concentration 18 months before starting statin therapy was 160.13 μmol/L, and 24 months after starting statin therapy was 172.22 μmol/L. Mean eGFR was 53.40 mL/min 18 months before starting statin therapy, and decreased to 49.43 mL/min after starting statin therapy. This represented a decline in renal function of 0.22 mL/min/mo over 18 months. The eGFR at 12 months after beginning statin therapy was 52.67 mL/min, and at 24 months was 49.06 mL/min. The rate of decline of eGFR after starting statin therapy was significantly lower: 0.02 mL/min/mo over 24 months ( P < .001). Total cholesterol and low-density lipoprotein cholesterol concentrations were significantly decreased after starting statin therapy ( P < .001). Four of 73 patients developed graft failure within 24 months. Conclusion Statin therapy in our setting was associated with a lower rate of decline in renal function in renal allograft recipients within 2 years of starting treatment.

Structural and functional manifestations of human atherosclerosis: do they run in parallel?

Luscher and colleagues have presented the much-awaited results of the ENCORE II multicentre trial.1 Its intent was to determine whether long-acting nifedipine, given in addition to statins, reverses endothelial dysfunction and retards progression of coronary atherosclerosis over 18–24 months in patients with stable coronary artery disease (CAD). Considered broadly, this study investigated the relationship between functional and structural expression of atherosclerosis. Coronary endothelial function was assessed with acetylcholine, a measure of nitric oxide (NO) bioavailability (see Figure 1 ).2 In 214 patients, as compared with placebo, nifedipine significantly improved coronary endothelial function. ENCORE II reinforces the conclusions of ENCORE I which found improved coronary endothelial function after just 6 months of nifedipine treatment and in the absence of background statins.3 The consistency of these findings indicates that multicentre trials of coronary endothelial testing yield reproducible results when conducted by capable investigators. While confirming the ENCORE I results, ENCORE II also demonstrates that the nifedipine-induced improvement in endothelial function persists for 2 years. Furthermore, as study drugs were washed out in advance of the follow-up endothelial testing, nifedipine appears to have favourably altered the biology of human atherosclerosis. In ENCORE II, change in coronary plaque volume was assessed by intravascular ultrasound (IVUS). In 193 patients, nifedipine as compared with placebo failed to retard the increase in plaque volume (1.0 vs. 1.9% increase in plaque size, nifedipine vs. placebo, respectively, P = non-significant). Thus, while nifedipine improved coronary endothelial function, it did not alter the progression of atherosclerosis. As endothelial function and atherosclerosis progression are both viewed as ‘barometers of cardiovascular risk’,4,5 the apparent dissociation between endothelial function and structural atherosclerosis in ENCORE II may not seem at first glance very satisfying. However, this result suggests that endothelial function and measures of structural atherosclerotic progression provide … *Corresponding author. Tel: +1 415 206 3024, Fax: +1 415 206 5447, Email: ganzp{at}medsfgh.ucsf.edu

Ezetimibe and atorvastatin both immunoregulate CD4+ T cells from cardiac transplant recipients invitro

Background Statins are LDL lowering agents that reduce cardiac allograft vasculopathy (CAV) incidence after cardiac transplantation. Furthermore, ‘pleiotropic effects’ including immunomodulation have been demonstrated by statins following transplantation. It has also been previously suggested that ezetimibe may exert specific effects on the innate immune system in vitro. We compared the effects of ezetimibe and atorvastatin on T lymphocytes in vitro on the justification that these cells are implicated in the pathogenesis of atherosclerosis, allograft rejection and CAV. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 30 cardiac transplant recipients and co-cultured with the study drug (or placebo) over 48 h. In total, 150 cultures were performed (5 per patient). Drug concentrations were calculated to simulate 10 mg or 100 mg daily in a 70 kg adult. Flow cytometry was performed to analyse T lymphocyte counts and functional characteristics. Results Ezetimibe reduced the standard CD3+CD4+ T cell count and CD3+CD4+CD45ro T memory count by dose linear effect ( p < 0.001). Atorvastatin also reduced the CD3+CD4+ T cell count and CD3+CD4+CD45ro T memory count by dose linear effect ( p = 0.005). Neither drug affected CD3+CD8+ cytotoxic T cells. Discussion Both atorvastatin and ezetimibe may have selective immunomodulatory properties independent of their mechanisms of LDL lowering, given that both drugs affect CD4 T helper cells but have no effect on CD8 cytotoxic lymphocytes in vitro. Although speculative, both of these agents could potentially offer benefits to the transplant patient by modulating important components of the adaptive immune system. CD4+ cells in particular are implicated in both CAV and rejection processes.

Statin Cost-Effectiveness in the United States for People at Different Vascular Risk Levels

Statins reduce the rates of heart attacks, strokes, and revascularization procedures (ie, major vascular events) in a wide range of circumstances. Randomized controlled trial data from 20,536 adults have been used to estimate the cost-effectiveness of prescribing statin therapy in the United States for people at different levels of vascular disease risk and to explore whether wider use of generic statins beyond the populations currently recommended for treatment in clinical guidelines is indicated. Randomized controlled trial data, an internally validated vascular disease model, and US costs of statin therapy and other medical care were used to project lifetime risks of vascular events and evaluate the cost-effectiveness of 40 mg simvastatin daily. For an average of 5 years, allocation to simvastatin reduced the estimated US costs of hospitalizations for vascular events by approximately 20% (95% CI, 15 to 24) in the different subcategories of participants studied. At a daily cost of $1 for 40 mg generic simvastatin, the estimated costs of preventing a vascular death within the 5-year study period ranged from a net saving of $1300 (95% CI, $15,600 saving to $13,200 cost) among participants with a 42% 5-year major vascular event risk to a net cost of $216,500 ($123,700 to $460,000 cost) among those with a 12% 5-year risk. The costs per life year gained with lifetime simvastatin treatment ranged from $2500 (-$40 to $3820) in people aged 40 to 49 years with a 42% 5-year major vascular event risk to $10,990 ($9430 to $14,700) in people aged 70 years and older with a 12% 5-year risk. Treatment with generic simvastatin appears to be cost-effective for a much wider population in the United States than that recommended by current guidelines.

Comprehensive Whole-Genome and Candidate Gene Analysis for Response to Statin Therapy in the Treating to New Targets (TNT) Cohort

Statins are effective at lowering low-density lipoprotein cholesterol and reducing risk of cardiovascular disease, but variability in response is not well understood. To address this, 5745 individuals from the Treating to New Targets (TNT) trial were genotyped in a combination of a whole-genome and candidate gene approach to identify associations with response to atorvastatin treatment. A total of 291 988 single-nucleotide polymorphisms (SNPs) from 1984 individuals were analyzed for association with statin response, followed by genotyping top hits in 3761 additional individuals. None was significant at the whole-genome level in either the initial or follow-up test sets for association with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride response. In addition to the whole-genome platform, 23 candidate genes previously associated with statin response were analyzed in these 5745 individuals. Three SNPs in apoE were most highly associated with low-density lipoprotein cholesterol response, followed by 1 in PCSK9 with a similar effect size. At the candidate gene level, SNPs in HMGCR were also significant though the effect was less than with those in apoE and PCSK9. rs7412/apoE had the most significant association (P=6x10(-30)), and its high significance in the whole-genome study (P=4x10(-9)) confirmed the suitability of this population for detecting effects. Age and gender were found to influence low-density lipoprotein cholesterol response to a similar extent as the most pronounced genetic effects. Among SNPs tested with an allele frequency of at least 5%, only SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR were also revealed.

The in vitro effects of cigarette smoke on fatty acid metabolism are partially counteracted by simvastatin

Background Statins enhance the synthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) from their precursors both in vitro and in vivo. In particular, an increased conversion of linoleic acid (LA) and of alpha-linolenic acid to their derivatives is observed in cultured cells. On the contrary, cigarette smoke (CS) negatively and dose-dependently affects the LC-PUFA production. Aim To evaluate the effects of CS alone or with simvastatin, on [1- 14C] LA metabolism in THP-1 cells. Results CS inhibits LA conversion; after co-incubation, simvastatin nullifies the effects of CS, maintaining LA conversion comparable to controls. However, at the highest CS concentration, simvastatin is unable to counteract the effects of CS. Changes of LA conversion reflect the modulation of desaturase activities by simvastatin and CS. Conclusion CS decreases PUFA conversion and its effects are modulated by the opposite effect of statins. It can be speculated that statin treatments in smoking patients may provide some beneficial effects on PUFA metabolism in addition to lowering cholesterol levels.

Impact of Statin Therapy on Central Aortic Pressures and Hemodynamics

Statins reduce the risk of cardiovascular events in people with hypertension. This benefit could arise from a beneficial effect of statins on central aortic pressures and hemodynamics. The Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) study, an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, investigated this hypothesis in a prospective placebo-controlled study of treated patients with hypertension. CAFE-LLA recruited 891 patients randomized to atorvastatin 10 mg/d or placebo from 5 centers in the United Kingdom and Ireland. Radial artery applanation tonometry and pulse-wave analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits over 3.5 years of follow-up. Atorvastatin lowered low-density lipoprotein cholesterol by 32.4 mg/dL (95% confidence interval [CI], 28.6 to 36.3) and total cholesterol by 35.1 mg/dL (95% confidence interval, 30.9 to 39.4) relative to placebo. Time-averaged brachial blood pressure was similar in CAFE-LLA patients randomized to atorvastatin or placebo (change in brachial systolic blood pressure, -0.1 mm Hg [95% CI, -1.8 to 1.6], P=0.9; change in brachial pulse pressure, -0.02 mm Hg [95% CI, -1.6 to 1.6], P=0.9). Atorvastatin did not influence central aortic pressures (change in aortic systolic blood pressure, -0.5 mm Hg [95% CI, -2.3 to 1.2], P=0.5; change in aortic pulse pressure, -0.4 mm Hg [95% CI, -1.9 to 1.0], P=0.6) and had no influence on augmentation index (change in augmentation index, -0.4%; 95% CI, -1.7 to 0.8; P=0.5) or heart rate (change in heart rate, 0.25 bpm; 95% CI, -1.3 to 1.8; P=0.7) compared with placebo. The effect of statin or placebo therapy was not modified by the blood pressure-lowering treatment strategy in the factorial design. Statin therapy sufficient to significantly reduce cardiovascular events in treated hypertensive patients in ASCOT did not influence central aortic blood pressure or hemodynamics in a large representative cohort of ASCOT patients in CAFE-LLA.

Prior Statin Use Is Associated with Improved Outcomes in Community-acquired Pneumonia

Background Statins have potent anti-inflammatory effects in laboratory studies of pulmonary inflammation. We investigated whether statin users had improved outcome when admitted with community-acquired pneumonia. Methods We carried out a prospective observational study of patients admitted to the hospital with community-acquired pneumonia between January 2005 and November 2007. The use of statins, angiotensin-converting enzyme inhibitors, beta-blockers, and aspirin were recorded. The outcomes of interest were 30-day mortality, need for mechanical ventilation or inotropic support, and the development of complicated pneumonia. Results On multivariate logistic regression, statin use was associated with significantly lower 30-day mortality (adjusted odds ratio [AOR] 0.46, 95% confidence interval [CI], 0.25-0.85, P = .01) and development of complicated pneumonia (AOR 0.44, 95% CI, 0.25-0.79, P = .006). There was no effect on requirement of mechanical ventilation or inotropic support (AOR 0.93, 95% CI, 0.49-1.76, P = .8). Patients prescribed statins had more severe pneumonia (median Pneumonia Severity Index 4, interquartile range [IQR] 3-4) compared with patients not prescribed cardiovascular drugs (median Pneumonia Severity Index 3, IQR 2-4, P < .0001). Despite this, C-reactive protein levels on admission were significantly lower in patients prescribed statins (median 119 mg/L, IQR 46-215) compared with patients prescribed no cardiovascular drugs (182 mg/L, IQR 66-326, P < .0001). On multivariate logistic regression, statin use was independently protective against a C-reactive protein that failed to fall by 50% or more at day 4 (AOR 0.50, 95% CI 0.27-0.92, P = .02). Conclusions Statin use is associated with reduced markers of systemic inflammation and improved outcomes in patients admitted with community-acquired pneumonia.

Interpretation of creatine kinase and aldolase for statin-induced myopathy: Reliance on serial testing based on biological variation

Background Statins are widely used drugs to reduce LDL cholesterol and risk for cardiovascular disease. Varying degrees of myopathies occur with statin use, ranging from mild myalgic symptoms alone to documented muscle damage and rhabdomyolysis. The activity of creatine kinase (CK) above a population-based reference range has been used to differentiate myalgias from documented myositic injury due to statins. However, because normal ranges for CK depend on gender, exercise, and ethnicity and are necessarily broad, it is possible for a patient to have myositic injury with a result that is within the reference range. Therefore, serial testing relative to baseline levels may be more effective in detecting mild increases in CK. Methods To properly interpret results of serial testing, we determined the biologic variation of CK and aldolase, another enzyme released from muscle, from biweekly blood collections for 8 weeks from 17 healthy subjects. Results Using log transformation, we calculated a reference change value of about + 140% and − 60% for both CK and aldolase. Conclusions The use of calculated RCV could help to improve the detection of those statin side effects promoting variation in CK values, which must be determined in clinical studies. The clinical significance of detecting more cases of statin-induced myopathy must also be examined.

Influence of statins treatment on survival in patients with amyotrophic lateral sclerosis

Background Statins are increasingly recognized as causing muscle damage and, more rarely, peripheral neuropathy. A preliminary report that there are more cases of amyotrophic lateral sclerosis (ALS) among people treated with statins caused considerable concern. We considered the possibility that statins could affect survival in patients already diagnosed as having amyotropic lateral sclerosis who were taking statins for dyslipidemia. Methods We reviewed the clinical charts of 459 patients with ALS followed-up in our clinic between 1997 and 2007. Retrieved data included age, all administered medications, form of ALS at onset and survival. We compared the survival rates of patients taking any statins with that of patients not taking statins, while adjusting for other factors which influence disease progression, such as age, gender and ALS form at onset. Results 72 patients were on statins for dyslipidemia at disease onset. The doses ranged from 10–60 mg daily and varied throughout the disease course. As expected, the patients on statins were older than the non-treated ones (65.7 ± 9 versus 57.5 ± 13 years, respectively). After correcting for age, gender and disease form, there was no significant difference in survival between the groups. Conclusion Our findings indicate that statins treatment for dyslipidemia in patients with ALS does not carry any survival risks.

Atorvastatin Attenuates Cardiomyocyte Loss in Adult Rats From Protein-Restricted Dams

Background Statins are cholesterol-lowering drugs that have been proved to prevent cardiac events. Their direct effects on cardiac remodeling, when administered in programmed protein restricted animals, still are unknown. Methods and Results Wistar male 6-month-old offspring from dams fed normal protein (NP, 19% of protein) or low-protein (LP, 5% of protein) during pregnancy and first 10 days after birth were studied. After weaning, male pups were allocated to untreated or treated groups with atorvastatin (low and high doses, 5 or 30 mg·kg·day) in two different periods (from 21 days old to 3 months old and from 3 to 6 months old). The blood pressure (BP) was 30% greater in untreated LP offspring than in treated offspring (from 165 ± 6 mm Hg to 127 ± 3 mm Hg, P < .01). After 1 month of treatment, only untreated LP offspring continued with high BP. Compared with untreated LP offspring, atorvastatin reduced blood glucose (less 30%, P < .05) and cardiomyocyte size (less 24%, P < .05), whereas untreated LP offspring had greater interstitial fibrosis (plus 74%, P < .01), reduction of myocardial vascularization (less 25%, P < .01) and major reduction of cardiomyocyte number (less 38%, P < .01) than treated LP offspring. Conclusion Atorvastatin from 3 to 6 months olds in both low and high doses (but not from 0 to 3 months) has beneficial effects improving myocardial vascularization by diminishing fibrosis and cardiomyocyte loss.

Early Improvements in insulin sensitivity and inflammatory markers are induced by pravastatin in nondiabetic subjects with hypercholesterolemia

Background Statins may improve lipid profiles and inflammation-associated biomarkers, but the effect on insulin sensitivity is controversial. We investigated the effects of 2 doses of pravastatin (40 and 10 mg/day) on insulin sensitivity and serum inflammatory markers in nondiabetic hypercholesterolemic patients. Methods This was a randomized, parallel, comparative design study. A total of 40 nondiabetic subjects with elevated low-density lipoprotein (LDL) cholesterol were randomized to either the 40 mg pravastatin/day group ( n = 21) or the 10 mg pravastatin/day group ( n = 19) for 8 weeks. The fasting serum lipid profile, homeostasis model assessment (HOMA), glucose and insulin response of the two-hour glucose tolerance test (2 h-OGTT), and several inflammatory markers were determined. Results Eight weeks of pravastatin treatment in both dose groups led to a significant reduction in serum LDL cholesterol, total cholesterol, triglycerides, and total cholesterol/ high-density lipoprotein (HDL) cholesterol ratios (all p < 0.01 in 40 mg group and all p < 0.05 in 10 mg group), though the 40 mg group had greater effects. Although the fasting HOMA insulin resistance did not change significantly in either group, glucose and insulin areas under the curve of 2 h-OGTT were significantly decreased, suggesting improvement in insulin sensitivity post glucose challenge. Serum CD-40 ligand concentration was significantly reduced in the 40 mg pravastatin/day group and soluble P-selectin significantly reduced in both groups. Conclusions Pravastatin treatment, at 10 mg or 40 mg daily for 8 weeks, reduced serum lipids and some inflammatory markers in nondiabetic hypercholesterolemic subjects. Furthermore, insulin resistance was improved even in short-term treatment by pravastatin.

Statins Benefit Outcomes of Renal Transplant Recipients on a Sirolimus-Cyclosporine Regimen

Background Statins offer a strategy to address dyslipidemia commonly experienced by immunosuppressed transplant recipients. Methods This single-center, retrospective study of 325 recipients (mean posttransplant follow-up of over 6 years; 75.0 ± 26.0 months) correlated four adverse outcomes—biopsy-confirmed acute rejection episodes, biopsy-confirmed chronic rejection/allograft nephropathy, graft loss, or death—with demographic and posttreatment variables. Patients were treated with a combination of sirolimus (SRL), cyclosporine (CsA), and various durations of steroids. Statins were prescribed for 259/325 (79%) recipients whose serum cholesterol exceeded 240 mg/dL and discontinued when the creatine phosphokinase increased fivefold (3.4%) or the liver function, threefold (3.0%) above normal. Results Upon univariate (hazard ratio [HR] 0.16; P < .001) and multivariate analysis (HR 0.38; P = .02), statins were markedly protective against acute rejection episodes. They reduced occurrence of chronic nephropathy/chronic rejection (HR 0.60; P = .03 and HR 0.52; P = .01, respectively). Incidences of graft loss were diminished (HR 0.26; P < .001 and HR 0.49; P = .01, respectively). Finally, the mortality rate was decreased (HR 0.21, P = .001 and HR 0.26, P = .01, respectively). Upon multivariate analysis, a reduced incidence of acute rejection was correlated with greater exposure to SRL (HR 0.78, P = .016) and CsA (HR 0.39; P = .006). Conclusions This study demonstrated compelling effects of statins against all adverse outcomes among patients treated with SRL-based, CsA-containing regimens. The profoundly dyslipidemic properties of SRL may explain these unique findings compared with previous studies on patients treated with CsA-based regimens.