High-dose Statin Therapy Research Articles

TNT and Recurrent Cardiovascular Events: High-Dose Statin Therapy Offers a Lot of Bang for the Buck

The Treating to New Targets trial compared the clinical efficacy of two doses of the same statin in 10,001 patients with stable coronary heart disease (CHD) [1]. Patients were treated with either 10 mg or 80 mg of atorvastatin, with mean attained LDL-C levels of 101 and 77 mg/dL. The primary composite end point evaluated first major cardiovascular events, including cardiovascular mortality, nonfatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal/nonfatal stroke. The primary end point was reduced 22% more by the higher atorvastatin dose. In addition, secondary end point reductions included nonfatal MI (22%), fatal and nonfatal stroke (25%), need for revascularization (28%), angina pectoris (12%), and hospitalization for congestive heart failure (26%). The primary end point consisted of reductions in first events. Aims

Cost/effectiveness analysis of atorvastatin in patients with acute coronary syndromes

Introduction: recent clinical trials found that high-dose statin therapy, compared with conventional-dose statin therapy, reduces the risk of cardiovascular events in patients with acute coronary syndromes (ACS) and stable coronary artery disease (CAD). With the introduction of simvastatin and pravastatin generics and the next patent expiration of atorvastatin, projected for 2011 in Italy, it is natural to ask: what is the most cost-effective treatment for a rational use of resources?Aim: the aim of this study was to estimate the cost-effectiveness of high-dose atorvastatin versus conventional standard-dose statins based on the scenario of atovastatin price evolution.Methods: a cost-effectiveness analysis was conducted in the perspective of the Italian National Health Service over the 4.9 years time horizon. Clinical data were obtained from a pooled analyses of the 3 clinical trials that directly compared high-dose atorvastatin with conventional standard-dose statins in patients with either ACS or CAD. Hospitalizations were quantified based on the Italian National Health Service tariffs and drug costs according to the Italian National Therapeutic Formulary (2009). Assuming the cost of atorvastatin reduces in line with that observed for simvastatin when the patent expires, 3 scenarios were constructed: atorvastatin current price (scenario 1); 55% price discount (scenario 2); 65% price discount (scenario 3). Effects were measured in terms of primary composite endpoint (coronary death or any adverse cardiovascular event). All costs were discounted at 3% per annum. Sensitivity analyses were performed to assess the robustness of findings. Results: intensive therapy with atorvastatin provided a hospitalization cost saving of 245,519.36 € per 1,000 patients. Under the assumptions established for scenario 1 and scenario 2, the incremental cost-effectiveness of treatment with atorvastatin 80 mg was estimated to be 20,289.72 € and 917.05 € for patient free from event, respectively; it was cost-saving for the scenario 3. Conclusions: high-dose atorvastatin represented a cost-effective use of healthcare resources in Italy. If the cost of atorvastatin reduces by 65% when the patent expires, for every million patient with SCA or CAD stable, treated for 5 years, the high-dose atorvastatin strategy potentially yields a cost-saving of ~2,4 billion € for the NHS.

High Dose Statin Therapy Reduces Muscle Oxidative Capacity In Healthy Adults

Statins are one of the most commonly prescribed medications used to lower cholesterol as well as reduce cardiovascular disease risk. This has led to widespread use of statins and more aggressive statin therapy. This class of medication has widespread effects that include potential effects on skeletal muscle metabolism. Although the majority of the effects of statin therapy are positive, statins may interfere with the mitochondria respiratory chain and reduce skeletal muscle aerobic capacity. PURPOSE: The purpose of this study was to determine if statins reduce muscle aerobic capacity. METHODS: Thirteen adults (6 females, 45±9 yrs old, BMI=27±3, mean±SD) were tested before and after 4 weeks of 80mg Lipitor®. 31P magnetic resonance spectroscopy (GE 3T Signa® HDx MR scanner) was used to acquire phosphorus spectra from the quadriceps muscle during and following knee extension. Three 90-s cycles of dynamic exercise (2 contractions per 3 s) followed by 300-s recovery were averaged and PCr resynthesis was measured using a mono-exponential model to estimate the time constant (tau, t) of PCr recovery. Paired t-tests were used to evaluate changes. RESULTS: Following 4 weeks of 80-mg Lipitor, total cholesterol decreased from 218±48 to 126±22 mg/dL (mean±SD). PCr resynthesis was ∼11% slower following statin therapy (prestatin t = 44.7±2.9 s, poststatin t = 49.5±3.6 s, mean±SE, p<0.05). Minimum pH following exercise was not different (p>0.05, 6.977±0.015 pre vs. 6.948 ± 0.070 post, mean±SE). Force during exercise was also not different pre vs. post statin (p>0.05). CONCLUSION: Statin use prolonged PCr resynthesis rate after short-term high dose in middle-aged adults. These results suggest that statins may compromise skeletal muscle mitochondrial function. Funded by NIH R21 AR054117

Meta‐analysis of the role of high‐dose statins administered prior to percutaneous coronary intervention in reducing major adverse cardiac events in patients with coronary artery disease

1. There is considerable evidence regarding the efficacy of statins for the primary and secondary prevention of coronary artery disease (CAD). However, due to lack of sufficient evidence, there is still doubt whether high-dose statin therapy prior to percutaneous coronary intervention (PCI) is beneficial. In the present study, we performed a meta-analysis to evaluate the effect of preoperative high-dose statin therapy on the incidence of major adverse cardiac events (MACE) after successful PCI. 2. Trials were retrieved through Medline (1980-2009) and the reference files limited to English-language articles. Data were abstracted using a standardized protocol and a meta-analysis was performed. 3. Five studies of a total 1789 patients with CAD qualified for analysis. Administration of high-dose statins in CAD patients before PCI was associated with a significant reduction in MACE 30 days after the procedure. The incidence of MACE in the high-dose statin group (6.98%) was significantly lower than that in the placebo group (14.77%), with an odds ratio (OR) of 0.43 (95% confidence interval (CI) 0.31-0.59; P < 0.00001). The incidence of post-PCI increases in creatine kinase MB in the high-dose statin and placebo groups was 9.20%vs 18.83%, respectively (OR 0.43; 95% CI 0.33-0.58; P < 0.00001), whereas the incidence of increases in troponin I was 30.13%vs 44.53%, respectively (OR 0.53; 95% CI 0.43-0.67; P < 0.00001), respectively. 4. In conclusion, high-dose statin therapy before PCI provides a significant benefit over placebo in preventing post-PCI MACE. Findings from the present analysis strongly support a strategy of routine loading of high-dose statins before interventional therapy.

Atorvastatin in stroke: a review of SPARCL and subgroup analysis.

Statin therapy in patients with cardiovascular disease is associated with reduced incidence of stroke. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) trial showed daily treatment with 80 mg of atorvastatin in patients with a recent stroke or transient ischemic attack (TIA) reduced the incidence of fatal or nonfatal stroke by 16%. Several post hoc analyses of different subgroups followed the SPARCL study. They have not revealed any significant differences when patients were sorted by age, sex, presence of carotid disease or type of stroke, with the exception of intracranial hemorrhage as the entry event. Lower low-density lipoprotein cholesterol levels in addition to possible neuroprotective mechanisms due to atorvastatin treatment correlate with improved risk reduction. Although not predefined subgroups and subject to an insufficient power, these post hoc studies have generated new clinical questions. However, clinicians should avoid denying therapy based on such subgroup analysis. At this point, the best evidence powerfully demonstrates stroke and TIA patients should be prescribed high dose statin therapy for secondary stroke prevention.

Cost Effectiveness of Intensive Lipid-Lowering Treatment for Patients with Congestive Heart Failure and Coronary Heart Disease in the US

A recent study found fewer hospitalizations for congestive heart failure (CHF) patients receiving high-dose versus low-dose statin therapy. To examine the cost effectiveness of high-dose versus low-dose statin therapy in CHF patients. Two scenarios (literature-based [base-case scenario] vs trial-based post-event mortality [alternative scenario]) assessed the cost effectiveness of atorvastatin 80 mg/day (A80) versus atorvastatin 10 mg/day (A10) in patients with both CHF and coronary heart disease (CHD) [CHF/CHD], using a lifetime Markov model. The model predicts treatment-specific probabilities of major and minor cardiovascular events and death, based on clinical trial data. The quality of life and costs were literature based. Measures included costs per life-year saved (LYS) and QALY gained. Health consequences and costs were discounted at 3.0% annually. Analyses were conducted from the payer perspective and valued in $US, year 2006-7 values. Literature-based mortality estimates (base case) increased life-years and QALYs for A80 compared with A10 (incremental cost-effectiveness ratios [ICERs]: $US9600 per LYS; $US13 600 per QALY). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 80% of simulations. A10 dominated A80 when using trial-based mortality estimates (alternative scenario). At a willingness to pay of $US100 000 per QALY, A80 was cost effective in 48% of simulations. Intensive A80 treatment may be cost effective versus A10 in cardiovascular prevention in CHF/CHD patients in the US, due to projected gains in life expectancy and health-related quality of life. However, the results are highly sensitive to assumptions about the mortality rate in the model. When using the mortality rate observed in the trial, A10 dominates A80.

Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia.

High-dose potent statin therapy in combination with ezetimibe is now standard practice for the treatment of adult patients with heterozygous familial hypercholesterolemia (heFH), as the result of numerous studies in patients with primary hypercholesterolemia or heFH. These studies have shown the combination to be both effective and safe in the short to medium term. Recently, short-term ezetimibe therapy has also been shown to be effective and safe in combination with statin therapy for children and adolescents with heFH. Effective statin–ezetimibe combination therapy is capable of achieving near-normal lipid profiles in heFH patients, with expected improvement in risk for cardiovascular disease (CVD) and improved life expectancy resulting predominantly from reduction in levels of low-density lipoprotein cholesterol. There are few data to support a pleiotropic action of ezetimibe with regard to CVD benefit, unlike therapy with statins. No serious and unexpected clinical adverse effects of combination statin–ezetimibe therapy have emerged till date, although data are limited in children and adolescents, for whom longer-term studies are required. Recent data suggesting possible proatherogenic effects of ezetimibe require confirmation. One large long-term randomized controlled clinical outcomes trial is in progress in non-FH patients to determine the efficacy and safety of ezetimibe therapy; it is unlikely that such a trial will ever be performed in patients with FH.

Bedeutung der Lipidtherapie bei Diabetes

LDL cholesterol plays a central role in atherogenesis and LDL lowering statin therapy significantly reduces cardiovascular risk in patients with diabetes. Therefore, LDL cholesterol in current guidelines is the primary target of lipid intervention. All patients with type 2 diabetes should reach an LDL cholesterol of <100 mg/dl, the very-high risk patients with both diabetes and coronary artery disease an LDL cholesterol <70 mg/dl. Given the overwhelming body of evidence for the efficacy of statin therapy with respect to cardiovascular event prevention, LDL cholesterol should primarily be lowered by statins. Many very-high risk patients will require high-dose statin therapy to meet the stringent treatment goal of LDL cholesterol <70 mg/dl. Importantly, patients with type 2 diabetes typically exhibit a pattern of dyslipidemia with high triglycerides, low HDL cholesterol, and small, atherogenic LDL particles, which is a strong predictor of vascular events in patients with diabetes. Despite the currently limited evidence from large clinical endpoint-trials additional treatment of this diabetic dyslipidemia with niacin or fibrates therefore appears a promising option at least in the very-high risk patients with the combination of diabetes and coronary artery disease.

Meta-analysis of Comparative Efficacy of Increasing Dose of Atorvastatin Versus Rosuvastatin Versus Simvastatin on Lowering Levels of Atherogenic Lipids (from VOYAGER)

Statins are the most commonly prescribed agents for lowering levels of low-density lipoprotein (LDL) cholesterol. Although dose-dependent reductions in levels of atherogenic lipids are observed with all statins, the impact of increasing dose has not been fully elucidated. An individual patient data pooled analysis was performed of 32,258 patients in studies comparing the efficacy of rosuvastatin with that of atorvastatin or simvastatin. The impact of increasing dose on lowering LDL cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B was investigated. Doubling the dose of each statin was accompanied by a 4% to 7% greater degree of lowering of all atherogenic lipids. A stronger correlation was observed between changes in LDL cholesterol and non-HDL cholesterol (r = 0.92, p <0.001) or apolipoprotein B (r = 0.76, p <0.001) than triglycerides (r = 0.14, p <0.001). On multivariate analysis, baseline lipid level (p <0.0001) and increasing statin dose (p <0.0001) were strong predictors of achieving treatment goals in high-risk patients. Increasing age was a strong independent predictor of achieving goal for all atherogenic lipids (p <0.0001). Achieving LDL cholesterol goals was also more likely in women (p <0.0001), patients with diabetes (p <0.0001), and patients without atherosclerotic disease (p = 0.0002). In contrast, normal triglyceride levels were more often observed in men (p <0.0001) and patients without diabetes mellitus (p = 0.03). In conclusion, doubling statin dose was associated with greater lowering of LDL cholesterol by 4% to 6% and non-HDL cholesterol by 3% to 6%. Greater lipid goal achievement with increasing dose supports the use of high-dose statin therapy for more effective cardiovascular prevention.

Effect of Intensive Statin Therapy on Clinical Outcomes Among Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndrome: PCI-PROVE IT: A PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) Substudy

The goal of this analysis was to determine whether intensive statin therapy, compared with moderate-dose statin therapy, leads to a reduction in major adverse cardiovascular events (MACE) among patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). When compared with moderate-dose statins, intensive statin therapy reduces MACE among patients with ACS. The role of intensive statin therapy specifically among patients who undergo PCI for ACS is unknown. Outcomes were compared in 2,868 patients who underwent PCI for ACS just prior to enrollment in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial, which randomized patients to either atorvastatin 80 mg or pravastatin 40 mg daily. The incidence of the primary composite end point of all-cause mortality, myocardial infarction, unstable angina leading to hospitalization, and revascularization after 30 days and stroke was evaluated, as was the incidence of target vessel revascularization (TVR) and non-TVR during follow-up. Treatment with 80 mg atorvastatin reduced the incidence of the composite end point (21.5% vs. 26.5%, hazard ratio: 0.78, 95% confidence interval: 0.67 to 0.91, p=0.002) and lowered the incidence of both TVR (11.4% vs. 15.4%, p=0.001) and non-TVR (8.0% vs. 10.5%, p=0.017) compared with 40 mg pravastatin. After adjusting for on-treatment serum low-density lipoprotein cholesterol and C-reactive protein concentrations, the odds of TVR with high-dose statin therapy remained significant (odds ratio: 0.74, p=0.015) while the odds of non-TVR did not (odds ratio: 0.92, p=0.55). Among patients with ACS who undergo PCI, intensive statin therapy reduces MACE compared with moderate-dose statin therapy. The reduction in the incidence of TVR was independent of low-density lipoprotein cholesterol and C-reactive protein lowering and may therefore be due, at least in part, to a pleiotropic effect of high-dose statin therapy. (PROVE IT-TIMI 22; NCT00382460).

Total Cardiovascular Disease Burden: Comparing Intensive With Moderate Statin Therapy: Insights From the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) Trial

This post-hoc analysis of the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial was designed to assess the comparative treatment efficacy of high-dose atorvastatin and usual-dose simvastatin for the prevention of events subsequent to the first event, using the Wei, Lin, and Weissfeld method. Time-to-first-event analysis of data is frequently utilized to provide efficacy outcome information in coronary heart disease prevention trials. However, during the course of such long-term trials, a large number of events occur subsequent to the first event, the analysis of which will be precluded by this approach. The Wei, Lin, and Weissfeld method allows the analysis of repeated occurrence of events of the same type or of entirely different natures. It regards the recurrence times as multivariate event (failure) times, and models the marginal (individual) distribution for each event with the Cox proportional hazards model. In the IDEAL trial, compared with patients taking simvastatin 20 to 40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first cardiovascular event reduced by 17% (p < 0.0001), of a second by 24% (p < 0.0001), of a third by 19% (p = 0.035), of a fourth by 24% (p = 0.058), and of a fifth by 28% (p = 0.117). Our results indicate that intensive statin therapy continues to be more effective than standard statin therapy, even beyond the first event, and suggest that clinicians should not hesitate to prescribe high-dose statin therapy for patients experiencing multiple recurrent cardiovascular events.

Statin Therapy with Ezetimibe or Niacin in High-Risk Patients

The use of statin therapy to reduce levels of low-density lipoprotein (LDL) cholesterol in patients who are at high risk for vascular events results in a 30 to 40% reduction in the rate of clinical events.1 However, many patients continue to be at risk. This residual risk has resulted in the search for additional therapeutic approaches. One approach is the further reduction of the LDL cholesterol level through treatment with higher doses of statins or through the addition of the cholesterol-absorption inhibitor ezetimibe. However, to date, only high-dose statin therapy has shown a clear clinical benefit beyond a moderate reduction . . .

Secondary Prevention in Concurrent Coronary Artery, Cerebrovascular, and Chronic Kidney Disease: Focus on Pharmacological Therapy

Patients with coronary artery disease (CAD) commonly have varying degrees of coexisting cerebrovascular disease (CVD) and chronic kidney disease (CKD), and proper management is complicated partly because of a lack of unifying guidelines. The aim of this article is to review the current literature and propose the optimal treatment regimen in patients with all three disease states. Angiotensin-converting enzyme inhibitors (ACE-I) should be universally administered. High-dose statin therapy to reach a target low-density lipoprotein (LDL) of 70-100 mg/dL is advocated, although patients with a history of cerebral bleeding must be carefully monitored for possible recurrence. Beta-blockers are appropriate after a recent coronary event, and amlodipine or thiazide diuretics should be used after a recent stroke (within 6 months). Patients with a history of stroke (with or without coexisting CAD and CKD) should receive aspirin (75-150 mg/day) indefinitely. Clopidogrel or aspirin plus extended-release dipyridamole (ER-DP) may be prescribed in patients allergic or resistant to aspirin. If stroke is attributable to cardiogenic embolism, anticoagulation is indicated. In patients with acute coronary syndromes (ACS) (excluding ST-elevated myocardial infarct) who undergo percutaneous coronary intervention (PCI), aspirin plus clopidogrel is indicated for secondary prevention for up to 12 months. There are no data supporting the use of aspirin plus clopidogrel in patients with CKD who develop ACS. Aspirin plus clopidogrel is contraindicated for stroke prevention.

Narrative Review: Statin-Related Myopathy

Statin-related myopathy is a clinically important cause of statin intolerance and discontinuation. The spectrum of statin-related myopathy ranges from common but clinically benign myalgia to rare but life-threatening rhabdomyolysis. Observational studies suggest that myalgia can occur in up to 10% of persons prescribed statins, whereas rhabdomyolysis continues to be rare. The mechanisms of statin-related myopathy are unclear. Options for managing statin myopathy include statin switching, particularly to fluvastatin or low-dose rosuvastatin; nondaily dosing regimens; nonstatin alternatives, such as ezetimibe and bile acid-binding resins; and coenzyme Q10 supplementation. Few of these strategies have high-quality evidence supporting them. Because statin-related myopathy will probably become more common with greater numbers of persons starting high-dose statin therapy and the increasing stringency of low-density lipoprotein cholesterol level targets, research to better identify patients at risk for statin myopathy and to evaluate management strategies for statin-related myopathy is warranted.

Hypobetalipoproteinaemia secondary to chronic hepatitis C virus infection in a patient with familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is a common genetic disorder characterized by high plasma low-density lipoprotein (LDL)-cholesterol and premature coronary artery disease. Many factors, such as illness, high-dose statin therapy or a strict vegan diet can cause hypobetalipoproteinaemia (HBL). The more common secondary causes of HBL in the hospital setting include cachexia, intestinal malabsorption, malnutrition, severe liver disease and hyperthyroidism. We report a case of HBL in a 43-year-old man with previously demonstrated marked hypercholesterolaemia who attended a lipid disorders clinic for FH cascade screening. Surprisingly, a lipid profile taken at that time showed low plasma LDL-cholesterol and apolipoprotein B concentrations of 1.6 mmol/L and 0.61 g/L, respectively. He was not on lipid-lowering therapy. DNA sequencing showed that he was heterozygous for the LDLR gene mutation (C677R) present in other affected family members. Of interest, his serum transaminases were increased by approximately 3-fold and hepatitis serology and genotyping confirmed a diagnosis of hepatitis C virus (HCV) infection. In summary, we describe a case of HBL secondary to chronic HCV infection in a patient with FH, confirmed by mutational analysis.

Impact of High‐Dose Atorvastatin in Coronary Heart Disease Patients Age 65 to 78 Years

High-dose statin therapy may be underutilized in aged patients due to doubts about efficacy and safety. To investigate outcomes and safety in patients aged 65-78 years compared with patients aged < 65 years in the ALLIANCE study. A total of 2,442 stable coronary heart disease (CHD) patients with dyslipidemia were randomized to either aggressive treatment (low-density lipoprotein cholesterol titration goal of < 80 mg/dL or maximum 80 mg/d of atorvastatin) or usual care (continuation of baseline lipid-lowering therapy, with changes and laboratory analyses directed by treating physicians). A total of 1,001 patients aged 65-78 years were followed for a median period of 53.9 mo. Older, aggressively treated atorvastatin patients experienced a 27% relative risk reduction for the primary composite endpoint of adverse cardiovascular outcomes (hazard ratio [HR]: 0.73; 95% confidence intervals [CI]: 0.57-0.94; p = 0.016). In addition, significant risk reductions were observed for nonfatal myocardial infarction (MI; HR: 0.43; 95% CI: 0.23-0.79; p = 0.006), cardiac revascularization (HR: 0.67; 95% CI: 0.48-0.93; p = 0.017), and the combined endpoint of cardiac death and nonfatal MI (HR: 0.48; 95% CI: 0.32-0.72; p = 0.001). The rate of significant liver transaminase elevations in atorvastatin patients was low and not age related. There were no cases of rhabdomyolysis. The rate of study discontinuations due to serious adverse events was higher in patients aged 65-78 years than in those younger than 65 years, but was similar between the treatment groups. Our data support the efficacy and safety of aggressive lipid management with atorvastatin in older CHD patients.

Maximal initiative dose of simvastatin causing acute renal failure through rhabdomyolysis: Risk factors, pathomechanism and therapy related to a case

Abstract Rhabdomyolysis (RML) is a rare and severe adverse effect of simvastatin (SIM). Several risk factors were described to play a role in its pathogenesis, namely age > 65, diabetes mellitus, renal disease, high dose statin therapy, chemicals metabolized by cytochrome P450 3A4 or idiosyncrasia. Case summary A 66-year-old man with diabetes, ischaemic heart disease and hypertension, on medication of CYP3A4 substrates amlodipine and alprazolam, maximal daily dose of SIM started for unknown cholesterol level. On the second day dark-brown urine, paraparesis, bile-like vomiting, on the fourth day of treatment total tetraparesis and oliguria characterized RML with acute renal failure. During his hospitalization of one-hundred-six days he underwent fourty-nine dialysis treatments. At the follow-up sixteen months after exmission from hospital, his walking improved to using one stick. His cholesterol level is in the physiological range with no statin therapy. Conclusions On account of risk factors listed above this case should have been administered low initial dose of SIM. On developing myalgia or weakness in muscles, treatment must be stopped. In a case of predisposition to RML statin therapy and dosage can only be performed under continuous supervision.

Intensive Statin Therapy in Coronary Artery Disease: Is Lower Cholesterol Better and Safe?

Primary- and secondary-prevention trials involving subjects with or at risk for coronary artery disease have previously demonstrated a beneficial effect of conventional-dose statin therapy. Recent trials of high-dose statin therapy in subjects with stable coronary disease or acute coronary syndromes have yielded conflicting results. The aim of this narrative article is to provide a critical and up-to-date summary of the findings of clinical trials of intensive statin therapy, including a brief overview of the safety and efficacy of such treatments.

Muscle Microvascular Dysfunction in Central Obesity Is Related to Muscle Insulin Insensitivity but Is Not Reversed by High-Dose Statin Treatment

OBJECTIVETo test the hypotheses that decreased insulin-mediated glucose disposal in muscle is associated with a reduced muscle microvascular exchange capacity (Kf) and that 6 months of high-dose statin therapy would improve microvascular function in people with central obesity.RESEARCH DESIGN AND METHODSWe assessed skeletal muscle microvascular function, visceral fat mass, physical activity levels, fitness, and insulin sensitivity in skeletal muscle in 22 female and 17 male volunteers with central obesity whose age (mean ± SD) was 51 ± 9 years. We tested the effect of atorvastatin (40 mg daily) on muscle microvascular function in a randomized, double-blind, placebo-controlled trial lasting 6 months.RESULTSKf was negatively associated with a measure of glycemia (A1C; r = −0.44, P = 0.006) and positively associated with insulin sensitivity (the ratio of insulin-stimulated glucose effectiveness, or M value, to the mean insulin concentration, or I value; r = 0.39, P = 0.02). In regression modeling, A1C, visceral fat mass, and M:I explained 38% of the variance in Kf (in a linear regression model with Kf as the outcome [R2 = 0.38, P = 0.005]). M:I was associated with Kf independently of visceral fat mass (B coefficient 3.13 [95% CI 0.22–6.02], P = 0.036). Although 6 months' treatment with atorvastatin decreased LDL cholesterol by 51% (P < 0.001) and plasma high-sensitivity C-reactive protein by 75% (P = 0.02), microvascular function was unchanged.CONCLUSIONSDecreased insulin-mediated glucose uptake in skeletal muscle is associated with impaired muscle microvascular exchange capacity (Kf), independently of visceral fat mass. Muscle microvascular function is not improved by 6 months of high-dose statin treatment, despite marked statin-mediated improvements in lipid metabolism and decreased inflammation.

Maximal initiative dose of simvastatin causing acute renal failure through rhabdomyolysis: risk factors, pathomechanism and therapy related to a case

Rhabdomyolysis (RML) is a rare and severe adverse effect of simvastatin (SIM). Several risk factors have been described which play a role in its pathogenesis, namely age >65, diabetes mellitus, renal disease, high-dose statin therapy, chemicals metabolized by cytochrome P450 3A4 or idiosyncrasy. A 66-year-old man with diabetes, ischaemic heart disease and hypertension, on medication of CYP3A4 substrates amlodipine and alprazolam, maximal daily dose of SIM has been started for unknown cholesterol level. On the second day dark-brown urine, paraparesis, bile-like vomiting, on his fourth day of treatment total tetraparesis and oliguria characterized RML with acute renal failure. During his hospitalization of one-hundred-six days he underwent fourty-nine dialysis treatments. Sixteen months follow-up after discharge from hospital, his walking improved up to using one stick now. His cholesterol level is in physiological range with no statin therapy. On account of risk factors listed above this case should have been administered to low initial dose of SIM. Developing myalgia or weakness in muscles, treatment must be stopped. In a case of predisposition to RML statin therapy and dosage can only be performed under continuous supervision.