Gordon Schectman

Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol

BACKGROUND Although it is generally accepted that lowering elevated serum levels of low-density lipoprotein (LDL) cholesterol in patients with coronary heart disease is beneficial, there are few data to guide decisions about therapy for patients whose primary lipid abnormality is a low level of high-density lipoprotein (HDL) cholesterol. METHODS We conducted a double-blind trial comparing gemfibrozil (1200 mg per day) with placebo in 2531 men with coronary heart disease, an HDL cholesterol level of 40 mg per deciliter (1.0 mmol per liter) or less, and an LDL cholesterol level of 140 mg per deciliter (3.6 mmol per liter) or less. The primary study outcome was nonfatal myocardial infarction or death from coronary causes. RESULTS The median follow-up was 5.1 years. At one year, the mean HDL cholesterol level was 6 percent higher, the mean triglyceride level was 31 percent lower, and the mean total cholesterol level was 4 percent lower in the gemfibrozil group than in the placebo group. LDL cholesterol levels did not differ significantly between the groups. A primary event occurred in 275 of the 1267 patients assigned to placebo (21.7 percent) and in 219 of the 1264 patients assigned to gemfibrozil (17.3 percent). The overall reduction in the risk of an event was 4.4 percentage points, and the reduction in relative risk was 22 percent (95 percent confidence interval, 7 to 35 percent; P=0.006). We observed a 24 percent reduction in the combined outcome of death from coronary heart disease, nonfatal myocardial infarction, and stroke (P< 0.001). There were no significant differences in the rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer. CONCLUSIONS Gemfibrozil therapy resulted in a significant reduction in the risk of major cardiovascular events in patients with coronary disease whose primary lipid abnormality was a low HDL cholesterol level. The findings suggest that the rate of coronary events is reduced by raising HDL cholesterol levels and lowering levels of triglycerides without lowering LDL cholesterol levels.

Drug therapy for hypercholesterolemia in patients with cardiovascular disease : Factors limiting achievement of lipid goals

PURPOSE To determine the extent that goal lipid levels derived from the National Cholesterol Education Program (NCEP) are achievable in clinical practice, and to identify factors associated with the achievement of these goals. PATIENTS AND METHODS We conducted a retrospective cohort study consisting of a consecutive sample of 244 patients with either coronary artery disease or peripheral vascular disease treated for hypercholesterolemia at a large Veterans Affairs medical center. Primary outcomes, recorded prospectively, were lipid levels and lipoprotein cholesterol response, and tolerance and compliance to drug therapy. Goal lipid levels were defined as low-density lipoprotein cholesterol (LDL-C) < or = 130 mg/dL and triglyceride (TG) < or = 200 mg/dL. RESULTS Lipid-lowering drug therapy reduced LDL-C from 25% to 42% below baseline in patients with hypercholesterolemia varying from mild (130 to 160 mg/dL) to severe ( > 220 mg/dL), respectively. Approximately 75% of patients with LDL-C < or = 160 mg/dL ultimately achieved their lipid goal with drug therapy; however, less than half of patients with baseline LDL-C > 160 mg/dL achieved target lipid values. Multivariate analysis indicated that lower baseline LDL-C and triglycerides, use of combinations of drug therapy rather than monotherapy, and patient adherence to treatment predicted the achievement of goal lipid levels. CONCLUSIONS Successful implementation of NCEP guidelines, frequently requires combination drug therapies, and is limited by poor patient tolerance and acceptance of niacin and the sequestrants.

Effect of Fish Oil Concentrate on Lipoprotein Composition in NIDDM

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with elevated very-low-density lipoprotein (VLDL) triglyceride concentrations and abnormalities of low-density lipoprotein (LDL) composition. Because fish oil supplementation may favorably affect lipid and lipoprotein concentrations in nondiabetic subjects, we determined the effect of fish oil concentrate on plasma lipids and lipoprotein composition in patients with NIDDM. Dietary-supplementation 1-mo periods of 4.0 and 7.5 g of omega-3 fatty acids in fish oil were compared with a placebo of 12 g safflower oil by use of a single-blind crossover design. Medications, including antidiabetic therapy, were continued through the study. Compared with safflower oil treatment, fish oil supplementation resulted in a significant reduction of total plasma triglycerides of 24% at the 4-g doseand a larger reduction of 39% at the 7.5-g dose. These decreases were due to similar reductions in VLDL triglycerides. LDL cholesterol levels were mildly elevated, but a larger 20% increase in LDL apolipoprotein B (apoB) concentration was observed. During supplementation with the fish oil concentrate, the LDL cholesterol-to-apoB ratio was significantly reduced when compared with pretreatment values, but not when compared with safflower oil treatment. Highdensity lipoprotein (HDL) cholesterol and plasma apoA1 levels were not significantly changed during fish oil treatment. At the 7.5-g dose, fasting glucose and glycohemoglobin levels increased by 20 and 12%, respectively, but were unchanged at the lower level of supplementation. Thus, in NIDDM patients, dietary supplementation with omega-3 fatty acids induces a reduction in total plasma and VLDL triglyceride levels. However, the observed increase in LDL apoB levels, and the deterioration in glycemic control, indicate thatfurther study will be required to establish whether fish oil has a role in the treatment of NIDDM.

Dose-Response Characteristics of Cholesterol-Lowering Drug Therapies: Implications for Treatment

In patients with coronary heart disease, aggressively lowering cholesterol levels slows the progression of disease [1] and decreases overall morbidity and mortality rates [2, 3]. In patients who have hypercholesterolemia and are at high risk for clinical coronary heart disease, reducing the cholesterol level also reduces the incidence of coronary heart disease [4-6] and the total mortality rate [6]. For patients with coronary heart disease who have a low-density lipoprotein (LDL) cholesterol level greater than 3.36 mmol/L (130 mg/dL) despite dietary therapy, practice guidelines established by the National Cholesterol Education Program (NCEP) now recommend drug therapy to reduce the LDL cholesterol level to less than 2.59 mmol/L (100 mg/dL). In persons at high risk for clinical coronary heart disease (that is, persons with two or more risk factors for this condition) who have an LDL cholesterol level greater than 4.14 mmol/L (160 mg/dL) after a trial of dietary therapy, pharmacologic therapy is recommended to reduce the LDL cholesterol level to less than 3.36 mmol/L (130 mg/dL). The recommendations suggest that patients at lower risk (that is, those that have one or no risk factors for coronary heart disease) receive drug therapy if their level of LDL cholesterol remains greater than 4.91 mmol/L (190 mg/dL) after dietary therapy. The goal is to reduce the LDL cholesterol level to less than 4.14 mmol/L (160 mg/dL) [7, 8]. Establishment of these treatment guidelines has important implications for the use of cholesterol-lowering drugs. First, many patients who have a suboptimal response to dietary therapy will require lipid-lowering drugs; effective drug management strategies therefore need to be devised for large numbers of patients. For example, 59% of men with coronary heart disease have an LDL cholesterol level greater than 3.36 mmol/L (130 mg/dL) and are likely to require drug therapy [9]. It has been estimated that more than 5% of persons who do not have heart disease may benefit from drug therapy [10]. Second, NCEP guidelines recognize that more complex drug treatment strategies are frequently needed to achieve recommended goals. More than 25% of men with coronary heart disease have an LDL cholesterol level greater than 4.14 mmol/L (160 mg/dL) [9] and require a reduction of approximately 40% to achieve the target level. This degree of cholesterol lowering is difficult to achieve routinely with monotherapy [11]. To develop optimal treatment strategies for hypercholesterolemia that use the LDL cholesterol-lowering agents that are currently available, we review the relation between dose, response, and toxicity of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants (sequestrants), and niacin. We also evaluate the efficacy of these agents as combination therapy and suggest a treatment strategy for hypercholesterolemia that is designed to optimize effectiveness and improve tolerance of drug therapy. Methods To evaluate the effectiveness and toxicity of lipid-lowering agents at various doses, a MEDLINE search was done for the period of January 1975 through November 1995. Articles were evaluated if they combined subject headings of hyperlipidemia or hypercholesterolemia and one of the following cholesterol-lowering agents: statins (lovastatin, pravastatin, simvastatin, and fluvastatin), bile acid sequestrants (including cholestyramine and colestipol), or niacin. Abstracts were reviewed and received further consideration if a clinical trial that used a cholesterol-lowering drug as monotherapy at two or more doses for hypercholesterolemia was described (Table 1, Table 2, and Table 3). Further inclusion criteria were 1) the clinical trial included at least 10 adult patients per treatment group, 2) the treatment period was at least 1 month in duration, 3) the drug dose did not depend on whether target lipid levels were achieved, and 4) the study design was adequately described. Patients were generally excluded from these trials if their triglyceride levels were greater than 2.8 to 4.5 mmol/L (250 to 400 mg/dL) at baseline and their mean triglyceride levels at study entry were less than 2.5 mmol/L (220 mg/dL). Table 1. Statin Dose-Response Relation for Reduction in Low-Density Lipoprotein Cholesterol Level* Table 2. Sequestrant Dose-Response Relation for Reduction in Low-Density Lipoprotein Cholesterol Level* Table 3. Niacin Dose-Response Relation for Change in Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Levels To evaluate the effectiveness of drug combinations for the reduction of LDL cholesterol levels, we did a MEDLINE search for clinical trials that included at least two of the following classes of lipid-lowering drugs: statins, sequestrants, and niacin. In addition to the criteria stated above, responses in LDL cholesterol levels had to be reported when the two drugs were used separately and in combination (Table 4). Studies reporting the effect of low-dose combination therapy on LDL cholesterol levels were considered separately (Table 5). Table 4. Response of Low-Density Lipoprotein Cholesterol Level to Cholesterol-Lowering Drugs Used as Monotherapy and Combination Therapy Table 5. Responses of Low-Density Lipoprotein Cholesterol Level to Low-Dose Combination Therapy Compared with Higher-Dose Monotherapy* We evaluated controlled clinical trials that used combination therapy to lower cholesterol levels to determine whether the reduction is consistent with an additive and independent effect for each drug [45]. To estimate the additive effects of two agents (drug A and drug B), assuming that both act independently, we used the following two-step formula: 1. (initial LDL cholesterol level) x (1-x) = (LDL cholesterol level with monotherapy), where x is the percentage of reduction in the LDL cholesterol level after use of drug A, divided by 100. 2. (LDL cholesterol level with monotherapy) x (1-y) = (LDL cholesterol level with combination therapy), where y is the percentage of reduction in the LDL cholesterol level after use of drug B, divided by 100. For example, if drug A reduced the LDL cholesterol level by 25%, drug B reduced the LDL cholesterol level by 30%, and the LDL cholesterol level at baseline was 5 mmol/L (193 mg/dL), then the percentage of reduction of these two agents together can be calculated as follows: 1. (5.0) x (1 0.25) = 3.75 2. (3.75) x (1 0.30) = 2.63 The expected reduction from these two drugs combined would be 47.4%, a reduction of 2.37 mmol/L from a baseline value of 5.0 mmol/L. Role of Dietary Therapy The importance of dietary therapy in the management of hypercholesterolemia has recently been reviewed [46]. Modest reductions of 3% to 10% in the LDL cholesterol level are frequently achieved by persons in the United States who adopt the step I cholesterol-lowering diet devised by NCEP [46-49]. Somewhat greater reductions may be achieved by persons who can adhere to the step II diet, which allows less dietary intake of saturated fat and cholesterol [50]. The ability of an overweight patient to lose weight may be an important predictor of LDL cholesterol response among patients with hypercholesterolemia who follow the step I diet [47, 48]. Because reductions of more than 10% to 15% are uncommon with dietary therapy, patients with moderate to severe hypercholesterolemia are unlikely to achieve the target level with dietary therapy alone. For example, among patients with moderate hypercholesterolemia who received an aggressive dietary intervention program, only 7% achieved the target level and thus avoided therapy with cholesterol-lowering drugs [51]. However, the individual patients response to diet varies and is not easily predicted; therefore, dietary intervention should be attempted for most patients before drug therapy is considered [8]. Although implementation of the NCEP step I diet will obviate the need for drug therapy in few patients, close adherence may allow the reduction of drug doses or may avoid the need to use several cholesterol-lowering agents together to achieve the target LDL cholesterol level. Dose-Response Characteristics of Cholesterol-Lowering Drugs Statins Fluvastatin, lovastatin, pravastatin, and simvastatin are the most effective agents for lowering levels of LDL cholesterol. These drugs are well tolerated; fluvastatin, pravastatin, and simvastatin can be taken once daily at bedtime, and lovastatin can be taken twice daily with meals, particularly when the dose exceeds 20 mg. The initial recommended doses are 10 mg for simvastatin and 20 mg for the other statins. Hepatotoxicity and myopathy, the major adverse effects associated with these agents, are unusual and only rarely require cessation of therapy. Rash, heartburn, and sleep disturbance have occasionally been noted but are uncommon. Statins have much smaller effects on triglyceride and high-density lipoprotein (HDL) cholesterol levels. In patients who do not have hypertriglyceridemia, statins reduce triglyceride levels by approximately 10% to 25%. Statin therapy increases HDL cholesterol levels by 5% to 10%, but responses vary. Studies that evaluate dose-response relations for the statins are reviewed in Table 1 and show that increasing the dose of each statin to more than 20 mg produces only small incremental reductions in the LDL cholesterol level. The expanded clinical evaluation of lovastatin (EXCEL) trial [12], which is the largest dose-response study of a statin, randomly assigned 8245 patients to receive 20 mg, 40 mg, or 80 mg of lovastatin for 48 weeks. The 20-mg dose achieved 60% of the maximum LDL cholesterol-lowering effect that was seen with the 80-mg dose. Tuomilehto and colleagues [24] found little increase in efficacy when they increased the dose of simvastatin from 10 mg (which reduced LDL cholesterol levels by 30%) to 40 mg (which reduced LDL cholesterol levels by 40%). Another trial [15] found that pravastatin reduced LDL cholesterol lev

Estimating Ascorbic Acid Requirements for Cigarette Smokers

This analysis of a large, population based, cross-sectional survey demonstrates that the association of smoking with decreased serum ascorbic acid (AA) levels is independent of the reduced AA intake found in smokers. Smokers have a threefold higher incidence of low serum AA levels (< or = 11 mumol/L) which could place them at increased risk for the clinical manifestations of AA deficiency. Smokers not taking vitamin supplements who consumed less than 15 servings weekly of fruits and vegetables were especially prone to have serum AA levels less than 11 mumol/L. An AA intake of > or = 200 mg was necessary to provide smokers with equivalent protection from hypovitaminosis AA as had nonsmokers whose AA intake exceeded the recommended dietary allowance (RDA [60 mg]). This level of dietary AA intake is considerably higher than the newly increased RDA for smokers of 100 mg. Although the simplest and most direct method to increase the low serum vitamin C levels found in many smokers would be to stop smoking, markedly increasing dietary AA consumption is appropriate when this is unsuccessful. However, if dietary modification fails to sufficiently increase AA intake, then vitamin supplementation may be necessary to significantly reduce the high prevalence of hypovitaminosis AA present in smokers.

Can the Hypotriglyceridemic Effect of Fish Oil Concentrate Be Sustained

STUDY OBJECTIVE To determine whether high doses of fish oil concentrate followed by low-dose maintenance therapy can sustain the initial plasma triglyceride reductions. DESIGN Before-and-after trial with 3-month treatment periods. SETTING Outpatient lipid clinic at a university medical center. PATIENTS Sixteen patients with hypertriglyceridemia recruited from the General Internal Medicine Clinics. Five had concomitant hypercholesterolemia (type IIb). INTERVENTION Fish oil supplementation at two doses. After basal measurements, 9.8 g/d omega-3 fatty acids were provided for study months 1 to 3, and 3.9 g/d were provided for study months 4 to 6. MEASUREMENTS AND MAIN RESULTS Blood was drawn monthly and plasma was analyzed for levels of triglycerides, low-density-lipoprotein (LDL) cholesterol and apolipoprotein B, high-density-lipoprotein (HDL) cholesterol and apolipoprotein A1, and glucose and glycohemoglobin. During therapy with the higher dose, mean plasma triglyceride levels were reduced from 3.65 +/- 0.35 mmol/L at baseline to 1.85 +/- 0.20 mmol/L at 1 month, but increased by 30% to 2.40 +/- 0.30 mmol/L by the third month of therapy (P less than 0.05): this increase could not be explained by changes in body weight or compliance. Plasma triglyceride levels continued to increase with low-dose therapy and remained only 11% below baseline values by the sixth month of therapy (P = not significant). Although fish oil therapy increased HDL cholesterol levels (+18% at high dose; 99% CI, 5% to 31%), favorable changes were not seen in LDL cholesterol, apolipoprotein B, or apolipoprotein A1 levels. CONCLUSIONS Fish oil concentrate at high doses followed by low-dose maintenance therapy cannot sustain the initial large plasma triglyceride reductions. Moreover, the efficacy of the higher dose becomes less pronounced after the first month of therapy. This reduced efficacy during prolonged therapy, and the lack of beneficial effect on apolipoprotein and LDL cholesterol levels, may limit the practical benefit of fish oil in the treatment of hypertriglyceridemia.

Telephone Contacts Do Not Improve Adherence to Niacin or Bile Acid Sequestrant Therapy

OBJECTIVE: Noxious adverse effects frequently limit patient acceptance of niacin and bile acid sequestrants (BAS), first-line agents in the management of hypercholesterolemia. The purpose of this study was to determine whether telephone contacts from a healthcare professional could improve drug adherence and tolerance in patients prescribed these medications. PATIENTS AND METHODS: This was a randomized, single-blind trial of telephone contacts vs. no intervention in patients with hyperlipidemia who were prescribed either niacin or BAS in a large, Veterans Affairs, lipid clinic. Patients randomized to telephone contact (n=81) received weekly calls from a trained healthcare professional during the first month of drug therapy. Counseling regarding adverse effects, and prescriptions to overcome minor adverse effects, were provided as needed to patients during the telephone contact. RESULTS: Significant differences were not observed between groups in the drug discontinuance rate, adherence assessed by two independent methods, or in the final dosage of medication ingested. CONCLUSIONS: Telephone contacts do not improve either adherence or tolerance to niacin or BAS. Alternative approaches to enhance acceptance of these medications requires further evaluation.

The effect of interferon on the metabolism of LDLs.

Interferons have been shown to lower low density lipoprotein (LDL) cholesterol concentrations by 20-50%. To evaluate the effect of interferons on LDL metabolic behavior in individuals with normal and mildly elevated LDL cholesterol levels, autologous LDL labeled with 125I was administered to subjects at baseline and during interferon treatment. Interferon beta serine (IFN-beta serine) was administered intravenously at 4.5 x 10(6) units daily for at least 3 weeks before the start of kinetic study and continued for an additional 2 weeks. Results were analyzed by using a multicompartmental model that allows for two intravascular LDL compartments. In normal subjects, IFN-beta serine reduced LDL cholesterol and apolipoprotein (apo) B levels by 25% and 27%, respectively (p less than 0.05); LDL apo B synthesis was decreased by 59% (p less than 0.05). In hypercholesterolemic subjects, IFN-beta serine reduced LDL cholesterol levels by 38% (p less than 0.05); however, apo B concentrations and production rates were not significantly decreased. Clearance of LDL from the first intravascular apo B pool was markedly reduced in these subjects, resulting in a shift in the distribution of LDL apo B from the second to the first intravascular LDL apo B pool. We conclude that interferons actions on LDL metabolism differ in normocholesterolemic and hypercholesterolemic subjects. In normal subjects, interferon decreased LDL cholesterol and apo B levels through a reduction in the LDL apo B production rate. However, in hypercholesterolemic subjects, interferon reduced LDL cholesterol by altering the distribution of apo B mass between LDL subspecies.

Physician extenders for cost-effective management of hypercholesterolemia

OBJECTIVE: Treatment of elevated cholesterol levels reduces morbidity and mortality from coronary heart disease in high-risk patients, but can be costly. The purpose of this study was to determine whether physician extenders emphasizing diet modification and, when necessary, effective and inexpensive drug algorithms can provide more cost-effective therapy than conventional care.DESIGN: Randomized controlled trial.SETTING: A Department of Veterans Affairs Medical Center.PATIENTS: Two hundred forty-seven veterans with type IIa hypercholesterolemia.INTERVENTIONS: Patients assigned to either a cholesterol treatment program (CTP) or usual health care provided by general internists (UHC). CTP included intensive dietary therapy administered by a registered dietitian utilizing individual and group counseling and drug therapy initiated by physician extenders for those failing to achieve goal low-density lipo-protein (LDL) levels with diet alone. A drug selection algorithm for CTP subjects utilized niacin as initial therapy followed by bile acid sequestrants and lovastatin. Subjects were followed prospectively for 2 years.MEASUREMENTS: Primary outcome measurements were effectiveness of therapy defined as reductions in LDL cholesterol (LDL-C), and whether goal LDL-C levels were achieved; costs of therapy; and cost-effectiveness defined as the cost per unit reduction in the LDL-C.MAIN RESULTS: Total program costs were higher for CTP patients than for UHC patients (

9 Hormones and lipoprotein metabolism

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