Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). ...Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.
n-3 Fatty acids (FAs) when used in doses of 3-4 g/d eicosapentaenoic acid and docosahexaenoic acid have profound effects on triacylglycerol (TG) concentrations. The mechanism for their TG reduction ...relates to their favorable effects on reducing hepatic production and secretion of VLDL and VLDL apolipoprotein B particles, along with favorable effects on plasma lipolytic activity through lipoprotein lipase-mediated clearance, as well as stimulation of β-oxidation of other FAs in the liver. Their hypotriglyceridemic properties are related to both the dose of n-3 FAs used and the baseline TG concentrations of the population. In patients with TG concentrations >500 mg/dL, 4 g n-3 FAs have been shown to reduce TGs by 45%, VLDL by 42%, and non-HDL by 10.2%. A recent pooled meta-analysis with multiple doses of n-3 FAs ranging from 0.8 to 5.4 g revealed changes in TGs of -27 mg/dL (95% CI: -33, -20), in HDL of +1.6 mg/dL (95% CI: + 0.8, +2.3), and in LDL cholesterol of +6 mg/dL (95% CI: + 3, +8). The clinical uses of n-3 FAs include treatment of severe and moderate hypertriglyceridemia, use in statin-treated patients with elevated TG concentrations or non-HDL cholesterol (mixed hyperlipidemia), and use in the secondary and primary prevention of cardiovascular disease. Existing large-scale clinical trials such as the GISSI-Prevenzione Study and JELIS with low doses of n-3 FAs (1-2 g) show clinical benefit in reducing coronary heart disease without substantial changes in concentrations of TGs or other lipids. Future clinical trials need to determine whether the TG-lowering doses of n-3 FAs (3-4 g/d) result in additional risk reduction.
Lipoprotein(a) Lp(a) is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational ...and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease–related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention.
•Causal association between high lipoprotein(a) Lp(a) and atherosclerotic cardiovascular disease–related events and mortality.•Laboratory methods and population-based considerations for Lp(a) cut points.•When to measure Lp(a) in adults and youth.•Treatment implications in primary and secondary prevention.
Abstract Elevated lipoprotein(a) (Lpa) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in ...high-risk patients, an English-language search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening.
Omega-3 fatty acid supplements containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce triglycerides but also increase low-density lipoprotein (LDL). ...Whether EPA or DHA given as monotherapy has differential effects on serum lipoproteins has not been systematically evaluated. We performed a meta-analysis of randomized placebo-controlled trials of monotherapy with EPA (
n
= 10), DHA (
n
= 17), or EPA versus DHA (
n
= 6). Compared with placebo, DHA raised LDL 7.23 mg/dL (95% CI, 3.98–10.5) whereas EPA non-significantly reduced LDL. In direct comparison studies, DHA raised LDL 4.63 mg/dL (95% CI, 2.15–7.10) more than EPA. Both EPA and DHA reduced triglycerides, with a greater reduction by DHA in direct comparison studies. DHA also raised high-density lipoprotein (4.49 mg/dL; 95% CI, 3.50–5.48) compared with placebo, whereas EPA did not. Although EPA and DHA both reduce triglycerides, they have divergent effects on LDL and high-density lipoprotein. Further research is needed to elucidate the mechanisms and significance of these differences.
Abstract The leadership of the National Lipid Association convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. ...An Executive Summary of those recommendations was previously published. This document provides support for the recommendations outlined in the Executive Summary. The major conclusions include (1) an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins (non–high-density lipoprotein cholesterol and low-density lipoprotein cholesterol LDL-C, termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascular disease (ASCVD) events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk; (6) nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus; and (7) the measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.
Objectives To determine the relationship between non–high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. ...Background Non–HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Methods Randomized placebo or active-controlled trials were evaluated. The effect of mean non–HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Results Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non–HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non–HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Conclusions Non–HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an ≈1:1 relationship between percent non–HDL-C lowering and CHD reduction.
Background Statins substantially reduce the risk of cardiovascular disease and are generally well-tolerated. Despite this, many patients discontinue therapy. A better understanding of the ...characteristics of current and former statin users may be helpful for formulating strategies to improve long-term adherence. Objective The Understanding Statin Use in America and Gaps in Education (USAGE) survey assessed the attitudes, beliefs, practices, and behavior of current and former statin users. Methods Individuals 18 years or older who reported a history of high cholesterol and current or former statin use were identified within a registered consumer panel cohort in the United States and invited to participate in an Internet survey. Results Of the 10,138 respondents, 8918 (88%) were current statin users and 1220 (12%) were former users. Participants (mean age 61 years) were predominantly white (92%), female (61%), of middle income (median $44,504/yr), and had health insurance (93%). Among current users, 95% took a statin alone, and 70% had not missed a dose in the past month. Although ∼70% reported that their physicians had explained the importance of cholesterol levels for their heart health former users were less satisfied with the discussions (65% vs. 83%, P < .05). Muscle-related side effects were reported by 60% and 25% of former and current users, respectively ( P < .05). Nearly half of all respondents switched statins at least once. The primary reason for switching by current users was cost (32%) and the primary reason for discontinuation was side effects (62%). Conclusions This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs.
This study evaluated the relation between apolipoprotein B (apoB) decrease and coronary heart disease, stroke, and cardiovascular disease risk. Bayesian random-effects meta-analysis was used to ...evaluate the association of mean absolute apoB decrease (milligrams per deciliter) with relative risk of coronary heart disease (nonfatal myocardial infarction and coronary heart disease death), stroke (nonfatal stroke and fatal stroke), or cardiovascular disease (coronary heart disease, stroke, and coronary revascularization). Analysis included 25 trials (n = 131,134): 12 on statin, 4 on fibrate, 5 on niacin, 2 on simvastatin–ezetimibe, 1 on ileal bypass surgery, and 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol and blood pressure targets. Combining the 25 trials, each 10-mg/dl decrease in apoB was associated with a 9% decrease in coronary heart disease, no decrease in stroke, and a 6% decrease in major cardiovascular disease risk. Non-high-density lipoprotein (non-HDL) cholesterol decrease modestly outperformed apoB decrease for prediction of coronary heart disease (Bayes factor BF 1.45) and cardiovascular disease (BF 2.07) risk decrease; apoB decrease added to non-HDL cholesterol plus LDL cholesterol decrease slightly improved cardiovascular disease risk prediction (1.13) but did not improve coronary heart disease risk prediction (BF 1.03) and worsened stroke risk prediction (BF 0.83). In the 12 statin trials, apoB and non-HDL cholesterol decreases similarly predicted cardiovascular disease risk; apoB improved coronary heart disease prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 3.33) but did not improve stroke risk prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 1.06). In conclusion, across all drug classes, apoB decreases did not consistently improve risk prediction over LDL cholesterol and non-HDL cholesterol decreases. For statins, apoB decreases added information to LDL cholesterol and non-HDL cholesterol decreases for predicting coronary heart disease but not stroke or overall cardiovascular disease risk decrease.
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