Hypercholesterolemia: Schwartz LM

Woloshin S, Schwartz LM, Kerin K, Welch HG. · VA Outcomes Group, White River Junction, VT, USA. · J Gen Intern Med. · Pubmed #17356986 links to  free full text

Abstract: BACKGROUND: There is growing interest in using C-reactive protein (CRP) levels to help select patients for lipid lowering therapy--although this practice is not yet supported by evidence of benefit in a randomized trial. OBJECTIVE: To estimate the number of Americans potentially affected if a CRP criteria were adopted as an additional indication for lipid lowering therapy. To provide context, we also determined how well current lipid lowering guidelines are being implemented. METHODS: We analyzed nationally representative data to determine how many Americans age 35 and older meet current National Cholesterol Education Program (NCEP) treatment criteria (a combination of risk factors and their Framingham risk score). We then determined how many of the remaining individuals would meet criteria for treatment using 2 different CRP-based strategies: (1) narrow: treat individuals at intermediate risk (i.e., 2 or more risk factors and an estimated 10-20% risk of coronary artery disease over the next 10 years) with CRP > 3 mg/L and (2) broad: treat all individuals with CRP > 3 mg/L. DATA SOURCE: Analyses are based on the 2,778 individuals participating in the 1999-2002 National Health and Nutrition Examination Survey with complete data on cardiac risk factors, fasting lipid levels, CRP, and use of lipid lowering agents. MAIN MEASURES: The estimated number and proportion of American adults meeting NCEP criteria who take lipid-lowering drugs, and the additional number who would be eligible based on CRP testing. RESULTS: About 53 of the 153 million Americans aged 35 and older meet current NCEP criteria (that do not involve CRP) for lipid-lowering treatment. Sixty-five percent, however, are not currently being treated, even among those at highest risk (i.e., patients with established heart disease or its risk equivalent)-62% are untreated. Adopting the narrow and broad CRP strategies would make an additional 2.1 and 25.3 million Americans eligible for treatment, respectively. The latter strategy would make over half the adults age 35 and older eligible for lipid-lowering therapy, with most of the additionally eligible (57%) coming from the lowest NCEP heart risk category (i.e., 0-1 risk factors). CONCLUSION: There is substantial underuse of lipid lowering therapy for American adults at high risk for coronary disease. Rather than adopting CRP-based strategies, which would make millions more lower risk patients eligible for treatment (and for whom treatment benefit has not yet been demonstrated in a randomized trial), we should ensure the treatment of currently defined high-risk patients for whom the benefit of therapy is established.

Yu JG, Sewright K, Hubal MJ, Liu JX, Schwartz LM, Hoffman EP, Clarkson PM. · Department of Surgical and Perioperative Science, Sports Medicine Unite, Umeå University, Umeå, Sweden. · J Atheroscler Thromb. · Pubmed #19262002 links to  free full text

Abstract: AIM: The 3-hydroxy-3methylgutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective prescribed drugs for lowering serum cholesterol; however, although statins are extremely safe medications and have brought significant benefits to patients with hypercholesterolemia, they have been shown to produce myalgia, cramps, exercise intolerance and fatigue. The aim of the study was to investigate the molecular mechanisms that may mediate statin myopathy. METHODS: We used DNA microarray analysis to examine the changes in gene expression profiles induced by 1 hour and 6 hours of statin treatment on differentiated C(2)C(12) myotubes. Four genes were selected for analysis at the protein level using Western blot analysis on myotubes treated with statin with or without additional mechanical stretching. RESULTS: Eighty-five genes exhibited more than a 2-fold up- or down-regulation in expression, of which 46 have known biological functions related primarily to transmembrane transport, signal transduction, cell growth/maintenance, protein metabolism, or apoptosis. At protein level, three of the four proteins were induced (Adrb1, Socs4 and Cflar) and one was repressed (Birc4). Changes in protein expression largely mirrored the changes in their corresponding transcripts, although the fold-change was less dramatic. The addition of imposed muscle fiber stretching did not exacerbate the expression of these genes at the protein level with the exception of Cflar, a pro-apoptotic protein. CONCLUSION: These data suggested that alterations in the expressions of some statin-regulated genes could be causative factors for statin toxicity in muscle. Repression of the anti-apoptosis gene (Birc4) and activation of the pro-apoptosis gene (Cflar) indicated that cell death may play an important role in statin-induced myopathy.

Schwartz LM, Woloshin S. · Veterans Affairs Career Development Program, White River Junction, Vt., USA. · Eff Clin Pract. · Pubmed #10538480 links to  free full text

Abstract: CONTEXT: In the hope of extending treatment benefits to patients with early disease, various professional societies have recommended changing several common disease definitions by lowering the threshold value for diagnosis. COUNT: Number of Americans labeled "diseased" under new definitions for diabetes, hypertension, hypercholesterolemia, and being overweight. CALCULATION: [symbol: see text] DATA SOURCE: Adult participants (age > 17 years) in the Third National Health and Nutrition Examination Survey (1988-1994). RESULTS: Adopting the new definitions would dramatically inflate disease prevalence. Changing the threshold for diabetes from a fasting glucose level of > or = 140 mg/dL to > or = 126 mg/dL would result in 1.7 million new cases. Redefining hypertension as systolic blood pressure > or = 140 mm Hg instead of > or = 160 mm Hg or diastolic blood pressure > or = 90 mm Hg instead of > or = 100 mm Hg would create 13 million new hypertensive patients. For hypercholesterolemia (a cholesterol level of > or = 200 mg/dL instead of > or = 240 mg/dL) and being overweight (body mass index > or = 25 kg/m2 instead of > or = 27 kg/m2), the number of new cases would be 42 million and 29 million, respectively. The new definitions ultimately label 75% of the adult U.S. population as diseased. CONCLUSIONS: If these modest changes in disease definition were adopted, great numbers of people would be considered diseased. The extent to which new "patients" would ultimately benefit from early detection and treatment of these conditions is unknown. Whether they would experience important physical or psychological harm is an open question.