Charles R. Harper

The broad spectrum of statin myopathy: from myalgia to rhabdomyolysis.

Purpose of review The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the cornerstone of therapy for dyslipidemia. A significant portion of patients are not adherent to statin therapy, due to either intolerance from muscle symptoms or fears of myopathy reported in the media. The diagnosis and management of patients with statin-induced myopathy will be reviewed. Recent findings Based on a review of healthy clinical-trial participants, the placebo-corrected incidences of minor muscle pain, myopathy (with significant elevations in creatinine kinase), and rhabdomyolysis are 190, 5, and 1.6 per 100 000 patient years, respectively. More recent prospective observational data yield better, real-world estimates of muscle complaints (>10%) in patients started on high-dose statins. Current data suggest that important patient characteristics, statin–drug pharmacokinetics, and statin–drug interactions play a role in myopathy. Myopathy is more related to statin dose and blood levels than to LDL reductions. Evidence for managing myopathic patients with coenzyme Q10 is not conclusive. Summary It is important to maintain perspective by looking at the impact of statin myopathy relative to the impact of preventing atherosclerotic complications. The potential benefits of therapy must outweigh the risks. In the case of statin therapy the benefit/risk ratio is overwhelmingly positive.

Managing dyslipidemia in chronic kidney disease.

The incidence of chronic kidney disease (CKD) in the U.S. continues to increase, and now over 10% of the U.S. population has some form of CKD. Although some patients with CKD will ultimately develop renal failure, most patients with CKD will die of cardiovascular disease before dialysis becomes necessary. Patients with CKD have major proatherogenic lipid abnormalities that are treatable with readily available therapies. The severe derangements seen in lipoprotein metabolism in patients with CKD typically results in high triglycerides and low high-density lipoprotein (HDL) cholesterol. Because of the prevalence of triglyceride disorders in patients with CKD, after treating patients to a low-density lipoprotein goal, non-HDL should be calculated and used as the secondary goal of treatment. A review of the evidence from subgroup analysis of several landmark lipid-lowering trials supports treating dyslipidemia in mild to moderate CKD patients with HMG-CoA reductase inhibitors. The evidence to support treating dyslipidemia in hemodialysis patients, however, has been mixed, with several outcome trials pending. Patients with CKD frequently have mixed dyslipidemia and often require treatment with multiple lipid-lowering drugs. Although statins are the cornerstone of therapy for most patients with CKD, differences in their pharmacokinetic properties give some statins a safety advantage in patients with advanced CKD. Although most other lipid-lowering agents can be used safely with statins in combination therapy in patients with CKD, the fibrates are renally metabolized and require both adjustments in dose and very careful monitoring due to the increased risk of rhabdomyolysis. After reviewing the safety and dose alterations required in managing dyslipidemia in patients with CKD, a practical treatment algorithm is proposed.

Evidence-Based Management of Statin Myopathy

Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for statin myopathy, including higher statin doses, statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1. Coenzyme Q10 and vitamin D have been used to prevent and treat statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose statins, alternate-day dosing, or using twice-weekly dosing with longer half-life statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.

Using apolipoprotein B to manage dyslipidemic patients: time for a change?

Low-density lipoprotein cholesterol (LDL-C) concentration has been established as an independent risk factor for the development of atherosclerosis; consequently, multiple practice guidelines recognize LDL-C as the primary target of therapy.1,2 For decades, considerable effort has been committed to educating physicians and the general public about the importance of lowering LDL-C levels. Despite the extensive data relating LDL-C to atherosclerosis, some have suggested that focusing only on LDL-C may not be an optimal strategy.3 Several limitations exist for an approach that focuses only on LDL-C: (1) evidence is increasing that triglyceride-rich lipoproteins, including very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL) (Figure 1)4 are also atherogenic5,6; and (2) a substantial percentage of patients with atherosclerotic vascular disease have LDL-C in the optimal range.7 Furthermore, many patients who receive treatment and achieve recommended LDL-C goals even lower than 70 mg/dL (to convert to mmol/L, multiply by 0.0259) still develop the complications of atherosclerotic vascular disease, which is referred to as residual risk.8 One explanation for these discrepancies is the mismatch that has been described in many patients between the LDL-C concentration reported on a basic lipid panel and the number of atherogenic lipid particles, which is often expressed as low-density lipoprotein (LDL) particle number or the number of apolipoprotein B (apo B)–containing lipoproteins.9 The reason for this mismatch is that LDL particles are extremely heterogeneous with respect to the amount of cholesterol contained in the LDL particle core.10 Patients with a predominance of cholesterol-depleted LDL particles (also called small dense LDL-C) may have a low LDL “cholesterol” concentration as reported on the standard lipid panel but still have a large number of circulating atherogenic LDL particles.11 For example, 2 patients with the same LDL-C concentration on a basic lipid panel may have markedly different LDL particle numbers and different cardiovascular risk (Figure 2).12 Extrapolating information concerning the number of atherogenic LDL particles from the LDL-C content is an unreliable strategy. FIGURE 1. Lipoprotein subclasses and apolipoprotein (apo) B–containing lipoproteins. HDL = high-density lipoprotein; iDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very low-density lipoprotein. FIGURE 2. Same low-density lipoprotein cholesterol (LDL-C) levels, different cardiovascular risk. apo = apolipoprotein. SI conversion factors: To convert LDL-C value to mmol/L, multiply by 0.0259. Recently, some expert panels and national organizations have proposed using apo B in conjunction with standard lipid testing to address the aforementioned limitations.13 Apo B is a key structural component of all the atherogenic lipoprotein particles, including LDL, VLDL, and IDL. Each of these atherogenic particles carries only one apo B molecule; thus, the total apo B level represents the total number of circulating atherogenic lipoprotein particles and provides the clinician a more accurate picture of a patients risk of cardiovascular events.13 Other advantages to the measurement of apo B include the fact that it does not require a fasting specimen, its relative low cost, and the existence of a World Health Organization–approved standard. Alternatively, some experts advocate calculating and using non–high-density lipoprotein cholesterol (non–HDL-C) instead of LDL-C to improve risk prediction in certain groups of patients, particularly in those with elevated triglyceride values.1 The National Cholesterol Education Program (NCEP)/Adult Treatment Panel (ATP) III guidelines recommend that, in patients with triglyceride levels of 200 mg/dL or higher, non–HDL-C should be calculated and the goal set at 30 mg/dL higher than the LDL-C goal (Table1).1 Substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction. Non–HDL-C is calculated by subtracting the HDL-C from the total cholesterol, and it represents the cholesterol concentration of all atherogenic lipoproteins.14,15 Although non–HDL-C is a good surrogate measure of apo B, it does not measure the same thing. Non–HDL-C measures the “cholesterol” content of all atherogenic lipoproteins (LDL, IDL, and VLDL), whereas apo B represents the total number of circulating atherogenic particles. Although substantial evidence supports the idea that non–HDL-C is clearly superior to LDL-C for cardiovascular disease risk prediction, strong evidence shows that apo B may be superior to both LDL-C and non–HDL-C for both risk stratification and determination of goal attainment during therapy. TABLE 1. ATP III LDL-C Goals and Cutpoints for Drug Therapya In this commentary, we propose how apo B might be used by clinicians involved in the primary and secondary prevention of coronary heart disease. First, we briefly discuss the evidence that suggests the superiority of apo B as a risk predictor compared to non–HDL-C and LDL-C. Then, we suggest certain patient populations in whom clinicians may wish to target apo B because of demonstrated superiority to LDL-C, including those with diabetes and those receiving statin therapy. Finally, we discuss current recommendations for apo B goals of therapy and the evidence for these goals.

Clinical characterization and molecular mechanisms of statin myopathy

Myopathy has been reported in a small percentage of statin-treated patients for the past 30 years, but the etiologic mechanisms for inducing muscle injury have not yet been fully characterized. Statin-induced myopathy is now understood to be a heterogeneous condition that may be due to: mechanisms of the drug itself; interactions with other drugs; or genetic, metabolic and immunological vulnerabilities in individual patients. In some cases, statins may unmask latent conditions (e.g., asymptomatic baseline myopathy) that predispose patients to muscle toxicity. The definitions, epidemiology, clinical features, risk factors and proposed mechanisms of statin-induced myopathy are reviewed. Muscle metabolism can be adversely impacted by statin therapy, including changes in fatty acid oxidation, possibly reduced coenzyme Q10 biosynthesis, and increased myocyte protein degradation via the activity of atrogin-1 and the ubiquitin–proteasome pathway. Statin therapy may also activate a variety of autoimmune phenomena that potentiate myocellular injury. Improving our understanding of statin-induced myopathy is a high clinical priority given the large number of patients eligible for statin therapy and the fact that the development of myalgia and myopathy are leading reasons cited by patients for statin discontinuation.

Effects of a global risk educational tool on primary coronary prevention: the Atherosclerosis Assessment Via Total Risk (AVIATOR) study.

ABSTRACT Objective: The use of Framingham equations to determine 10-year absolute coronary risk (“global risk”) represents an accepted strategy to target coronary prevention measures and enhance clinical outcomes. The aim of this study was to determine the effects of providing global risk scores to physicians on the prescription of lipid-lowering therapy for patients at increased coronary risk. Research design and methods: This prospective, randomized controlled trial enrolled 368 primary-care patients without a history of coronary heart disease and not on therapy with a hydroxymethylglutaryl coenzyme A reductase inhibitor (i.e. statin). The study was conducted in the general medical clinics of an academic US teaching hospital. In the intervention group ( n = 186) patients’ charts were reviewed, 10‐year absolute coronary risk computed, and this information conveyed via a simple educational tool appended to charts. In the control group ( n = 182), charts were accompanied by a form with general information on coronary prevention goals and strategies. Main outcome measure: The primary endpoint was the proportion of high-risk patients receiving a new statin prescription. Secondary and tertiary endpoints included (1) the proportion of moderate-risk patients receiving a statin prescription; and (2) the proportion of patients in the whole cohort who had other coronary prevention measures recommended. Results: There was no significant difference in statin prescription to high-risk individuals in the intervention group (40.0%) compared with the control group (37.9%; p = 0.86). Moderate-risk individuals who were not eligible for treatment according to the National Cholesterol Education Program Adult Treatment Panel II guidelines were more likely to receive a statin prescription in the intervention group versus the control group (28.8% vs. 12.5%. p = 0.036) Conclusions: Although a simple global risk educational tool did not improve the targeting of statin therapy to patients at high absolute coronary risk, it may be of benefit in targeting moderate-risk individuals who do not have markedly elevated low-density lipoprotein cholesterol (LDL‐C) levels. Future research should evaluate the effects of physicians performing their own Framingham risk calculations on statin prescribing and on cholesterol goal attainment.

Avoiding statin myopathy: understanding key drug interactions

Abstract Statin interaction with other drugs may play an important role in statin myopathy. Clinician familiarity with statin metabolism, pharmacokinetics and drugs that commonly interact with statins may reduce the incidence of muscle.related side effects. The dose of a statin is frequently related to statin myopathy. Many drugs including simvastatin, lovastatin and atorvastatin are metabolized by the CYP3A4 isoenzyme system. This article reviews commonly prescribed drugs that are potent inhibitors of the CYP3A4 system. We also review statin cell membrane drug transporters including OATP and MDR1 that have also been shown to play a key role in statin metabolism and drug interactions. There is now a growing list of drugs known to inhibit the activity of these transporters. In this review, we highlight three key populations at an increased risk for statin drug interactions including patients receiving treatment for mixed dyslipidemia, HIV and chronic kidney disease. We discuss treatment strategies for use in these high-risk populations. An understanding of statin pharmacokinetics, metabolism by the CYP450 system, and uptake or elimination by cell membrane transporters, helps explain many of the drug interactions that lead to statin myopathy.

Effect of baseline plasma fatty acids on eicosapentaenoic acid levels in individuals supplemented with α-linolenic acid

We previously reported a >50% increase in mean plasma eicosapentaenoic acid levels in a general medicine clinic population after supplementation with α-linolenic acid. In the current analysis, we evaluate the variability of changes in eicosapentaenoic acid levels among individuals supplemented with α-linolenic acid and evaluated the impact of baseline plasma fatty acids levels on changes in eicosapentaenoic acid levels in these individuals. Changes in eicosapentaenoic acid levels among individuals supplemented with α-linolenic acid ranged from a 55% decrease to a 967% increase. Baseline plasma fatty acids had no statistically significant effect on changes in eicosapentaenoic levels acid after α-linolenic acid supplementation. Changes in eicosapentaenoic acid levels varied considerably in a general internal medicine clinic population supplemented with α-linolenic acid. Factors that may impact changes in plasma eicosapentaenoic acid levels after α-linolenic acid supplementation warrant further study.

Treating isolated low high-density lipoprotein cholesterol: prescient or premature?

Coronary heart disease (CHD) and its sequela are the leading cause of morbidity and mortality in the world. Defining those individuals at highest risk of developing CHD and targeting them for more aggressive prevention is an important clinical and public health issue. A low serum high-density lipoprotein (HDL) cholesterol is a potent predictor of premature CHD, whereas elevated levels of HDL cholesterol are thought to be cardioprotective.1 To date, most lifestyle and pharmacologic interventions have been directed at lowering low-density lipoprotein (LDL) cholesterol, the main target lipoprotein in the second report of the Adult Treatment Panel of the National Cholesterol Education Program (NCEP).2 Isolated low HDL (ILHDL) has been defined as patients with HDL cholesterol #35 mg/dl (0.91 mm/ L), LDL cholesterol ,160 mg/dl (4.14 mm/L), and triglycerides ,250 mg/dl (2.83 mm/L).3 Targeted therapy for low levels of HDL cholesterol has been controversial for several reasons including (1) lack of randomized controlled trials designed to study the effect of raising HDL cholesterol, (2) uncertainty about the mechanism whereby HDL imparts its cardioprotective effect, and (3) the absence of an easyto-use risk prediction tool that allows the busy clinician to risk stratify patients with ILHDL. Recent advances in our knowledge of HDL and cholesterol transport at the cellular and physiologic level, along with new data from human randomized controlled trials, suggest that aggressive treatment of patients with ILHDL should be reconsidered. The prevalence of ILHDL (#35 mg/dl) in the US population is quite significant. The National Health and Nutrition Examination Survey III (NHANES III), a population-based survey on noninstitutionalized US adults revealed that 11% of US men and 3% of US women have ILHDL.4 The Quebec Cardiovascular Study measured lipoprotein levels in .2,000 Canadian men free of CHD and found a similar prevalence, with 13% having ILHDL.5 The prevalence of ILHDL cholesterol in patients with CHD has been found also to be quite substantial, ranging from 17% to 36%.6,7