Mean Reductions In Total Cholesterol Research Articles

A six-month, multicenter, open-label, noncomparative, prospective, observational study of the efficacy and tolerability of atorvastatin in the primary care setting(estudio del control de las hiperlipidemiasen atención primaria): the cheap study

Background: A close relationship exists between high levels of total cholesterol (TC) (particularly low-density lipoprotein cholesterol [LDL-C]) and low levels of high-density lipoprotein cholesterol (HDL-C), which is associated with an increased risk for arteriosclerosis and cardiovascular disease (CVD). Evidence shows that atorvastatin produces significantly greater reductions in LDL-C and TC than other hydroxymethylglutaryl-coenzyme A reductase inhibitors. However, the results achieved in clinical studies could be different from those found in general clinical practice, where patient follow-up is less thorough and poorer compliance may reduce the effectiveness of the lipid-lowering therapy. Objective: The aim of this study was to assess the effectiveness of atorvastatin in achieving the LDL-C levels recommended by several Spanish scientific societies, as well as its tolerability in standard clinical use. Methods: This 6-month, open-label, noncomparative, prospective, observational study was conducted in 1351 primary care centers in Spain. All patients were aged 18 to 80 years and had primary hypercholesterolemia (TC >200 mg/dL and triglycerides [TG] <200 mg/dL) or combined hyperlipidemia (TC >200 mg/dL and fasting TG 200–400 mg/dL). All patients also had LDL-C levels higher than those established by the Spanish Society of Arteriosclerosis ( Sociedad Española de Arteriosclerosis [SEA]) according to baseline cardiovascular risk and previous use of lipid-lowering therapy (for patients with low, moderate, or high cardiovascular risk, the recommended LDL-C goals are ≤175 mg/dL, ≤155 mg/dL, and ≤135 mg/dL, respectively; for patients with CVD, the LDL-C goal is ≤100 mg/dL). None of the patients had creatine kinase activity ≥540 U/L or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥60 U/L. Study visits occurred at months 0, 2, and 6 of treatment. Patients received atorvastatin calcium 10 mg/d for 2 months. The dosage was then doubled to 20 mg/d in patients who did not achieve the SEA LDL-C goal and also in those patients whose primary care physicians (PCPs) deemed this higher dosage necessary; this dosage was continued for at least 4 additional months, to complete at least a 6-month course of treatment. The percentage of patients who achieved their goals was used to measure atorvastatin effectiveness. Percentages of change in LDL-C, TC, TG, and HDL-C from baseline to the final study visit also were used as measures of effectiveness. The incidence of adverse events (AEs) per 10,000 patient-months was used for the primary tolerability analysis. A secondary tolerability analysis was performed in all patients treated with atorvastatin who had some recorded follow-up, regardless of whether the patient met inclusion criteria. Information was obtained from data recorded in the case-report forms. Results: A total of 5317 outpatients (2715 women, 2598 men, 4 sex unknown; mean [SD] age, 58.7 [10.5] years) were enrolled. Among patients receiving known dosages of atorvastatin, 1580 of 4033 (39.2%) and 2378 of 3585 (66.3%) patients met the SEA LDL-C goal after 2 and 6 months of therapy, respectively ( P<0.001 for 2 months vs 6 months). Among the patients with low and moderate cardiovascular risk, 85.8% achieved the SEA LDL-C goal compared with 64.4% of high-risk patients ( P<0.001). Mean LDL-C decreased by 36.2%. Mean reductions in TC and TG levels were 26.9% and 19.2%, respectively. Mean HDL-C increased 17.0%. One hundred forty-eight patients (2.9%) experienced at least 1 AE and 25 (0.5%) had serious AEs. Eighty-nine patients had 134 AEs considered treatment related. Two of the serious AEs (phlebitis and a severe increase in ALT and AST activity) were considered treatment related. A total of 98.5% and 97.2% of PCPs and patients, respectively, reported excellent or good tolerability with atorvastatin. Conclusions: In this study population, the use of atorvastatin in the primary care setting was associated with high achievement rates of the SEA LDL-C goals and with a substantial decrease in TG levels. In addition, a considerable increase in HDL-C levels occurred. Tolerability with atorvastatin was reported to be excellent or good by most of the patients and PCPs. The incidence of serious AEs was minimal, as reported by both patients and PCPs.

Evaluation of the effects of exercise and a mild hypocaloric diet on cardiovascular risk factors in obese subjects.

A weight reduction program to improve cardiovascular risk factors was implemented in obese subjects. The program consisted of exercise training corresponding to the anaerobic threshold (AT) and a mild hypocaloric diet for 12 weeks. In this program, we evaluated the effects of a combination of exercise training and a diet on cardiovascular risk factors such as obesity, dyslipidemia, and poor exercise performance in obese subjects. In addition, we also evaluated the independent effects of exercise training and dietary modification. For this purpose, we adopted a relative training time and a diet score. A relative training time was calculated as the number of times that the subject performed exercises divided by all of the training sessions scheduled, and the diet score was calculated from information which each subject provided on a self-assessment questionnaire. Twenty three obese subjects (Age: 24-54 years old, 19 men and 4 women, body mass index (BMI) > 26 kg/m2) participated in this study. After the 12-week intervention, the mean reductions in body weight, body mass index and body fat were 4.7 kg, 1.7 kg/m2 and 2.9%, respectively (P < 0.0001). The % change in body weight was significantly associated with the diet score and with the relative training time. The mean reductions in total cholesterol, triglyceride and low density lipoprotein cholesterol were 21 mg/dl (P < 0.002), 34 mg/dl (P < 0.01) and 15.9 mg/dl (P < 0.01), respectively, and the % change in triglyceride was significantly associated with the diet score (P = 0.0056) and tended to correlate with the relative training time (P = 0.0596). Oxygen uptake at AT and at peak exercise were increased from 14.1 +/- 1.6 to 16.0 +/- 3.1 ml/min/kg (P < 0.005) and from 26.3 +/- 4.8 to 28.4 +/- 4.9 ml/min/kg (P < 0.002), respectively. A combination of aerobic exercise and a mild hypocaloric diet significantly contributed not only to weight loss but also to the improvement of dyslipidemia and exercise performance, but either hypocaloric diet or mild exercise independently did less. The diet score and the relative training time were useful for evaluating separately dietary modification and the quantity of exercise.

Attaining United States and European Guideline LDL-cholesterol Levels with Simvastatin in Patients with Coronary Heart Disease (the GOALLS Study)

SummaryThe effectiveness and safety of simvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to target levels in patients with coronary heart disease (CHD) were evaluated in the GOALLS (Getting to Appropriate LDL-C Levels with Simvastatin) study. This multinational, multicentre, prospective, open-label, study consisted of a six-week diet washout period followed by a 14-week titrate-to-goal treatment period with simvastatin. One hundred and ninety-eight men and women with documented CHD and a fasting LDL-C level between 115 mg/dl (3.0 mmol/l) and 180 mg/dl (4.7 mmol/l) and triglycerides (TGs) ≤ 400 mg/dl (4.5 mmol/l) were enrolled. The patients were started on 20 mg simvastatin with dose titration up to 80 mg if the LDL-C remained above 100 mg/dl at weeks 6 and 10. The key efficacy parameters were the percentage of patients achieving US and European LDL-C goals [≤ 100 mg/dl (2.6 mmol/l) and ≤ 115 mg/dl(3.0 mmol/l), respectively]. Safety was evaluated by monitoring laboratory tests and recording adverse events.After 14 weeks of simvastatin (20–80 mg) treatment, approximately 90% of the patients achieved LDL-C goals according to US (87%) and European (94%) guidelines. Most patients (72–93%) achieved target LDL-C levels on 20 mg simvastatin. An estimated 14% of the patients required titration to the 80 mg dose. Treatment with simvastatin (20–80 mg) produced statistically significant improvements in all measured lipid variables by the end of the study. The mean reductions in total cholesterol and LDL-C, and the median reduction in TG, were 28%, 41% and 16%, respectively. The increase in high-density lipoprotein cholesterol and apolipoprotein A-1 were 5% and 4%, respectively. Simvastatin was well tolerated across the dosage range.In conclusion, simvastatin, 20–80 mg/day, was safe and highly effective at reducing LDL-C levels. The recommended US and European LDL-C treatment goals were achieved in approximately 90% of the patients. These goals were similarly achieved for a variety of high-risk sub-groups (hypertensives, diabetics and elderly patients).

Lipid risk profile and weight stability after gastric restrictive operations for morbid obesity

There are no longitudinal data that address weight loss stability and lipid levels in bariatric surgical patients. The goal of this study was to determine whether weight regain adversely affected reduction in lipid levels after gastric bariatric operations. Of 651 consecutive patients undergoing gastric restrictive surgery for morbid obesity, 227 (35%) had increased serum levels of total cholesterol (TC), triglycerides, or both preoperatively. High-density lipoprotein cholesterol (HDL-C) levels were subnormal (≤35 mg/dl) in 45 (20%) of the hyperlipidemic patients. Fasting lipid profiles were determined at 6-month intervals postoperatively. This series included the following three operations: gastroplasty (GP; N = 13), standard Roux-en-Y gastric bypass (RYGB; N = 205), and distal Roux-en-Y gastric bypass (DRY; N = 9). By 6 months postoperatively, patients had a ≥15% mean reduction in TC and a ≥50% mean reduction in triglycerides, both of which were significant in comparison with preoperative levels ( P ≤0.05). Mean HDL-C levels had increased significantly vs. preoperative levels by 12 months postoperatively ( P <0.05) and continued to increase through 5 years. By 18 months both HDL-C and TC were significantly lower after DRY than after GP or RYGB. In 91 patients who were followed for 2 years or longer (mean 48 ± 25 months), mean excess weight loss was 55% with mean body mass index reduced from 48 to 33 kg/m 2. This group was divided into patients whose weight remained stable (N = 54) and patients who regained ≥15% of their lost weight or lost less than 50% of excess weight (N = 37). Although mean excess weight loss and body mass index were significantly different between the two groups ( P <0.0001) at 2 years, there was no difference in the lipid profile (TC/HDL) between the two groups at any interval through 5 years. These results show that abnormal lipid profiles can be permanently improved after gastric bariatric surgery and are not adversely affected by mediocre weight loss or regaining ≥15% of lost weight. DRY appears to be a superior operation for TC reduction in comparison with GP and RYGB.

Attaining United States and European Guideline LDL-cholesterol Levels with Simvastatin in Patients with Coronary Heart Disease (the GOALLS Study)

SummaryThe effectiveness and safety of simvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to target levels in patients with coronary heart disease (CHD) were evaluated in the GOALLS (Getting to Appropriate LDL-C Levels with Simvastatin) study. This multinational, multicentre, prospective, open-label, study consisted of a six-week diet washout period followed by a 14-week titrate-to-goal treatment period with simvastatin. One hundred and ninety-eight men and women with documented CHD and a fasting LDL-C level between 115 mg/dl (3.0 mmol/l) and 180 mg/dl (4.7 mmol/l) and triglycerides (TGs) ≤ 400 mg/dl (4.5 mmol/l) were enrolled. The patients were started on 20 mg simvastatin with dose titration up to 80 mg if the LDL-C remained above 100 mg/dl at weeks 6 and 10. The key efficacy parameters were the percentage of patients achieving US and European LDL-C goals [≤ 100 mg/dl (2.6 mmol/l) and ≤ 115 mg/dl(3.0 mmol/l), respectively]. Safety was evaluated by monitoring laboratory tests and recording adverse events.After 14 weeks of simvastatin (20–80 mg) treatment, approximately 90% of the patients achieved LDL-C goals according to US (87%) and European (94%) guidelines. Most patients (72–93%) achieved target LDL-C levels on 20 mg simvastatin. An estimated 14% of the patients required titration to the 80 mg dose. Treatment with simvastatin (20–80 mg) produced statistically significant improvements in all measured lipid variables by the end of the study. The mean reductions in total cholesterol and LDL-C, and the median reduction in TG, were 28%, 41% and 16%, respectively. The increase in high-density lipoprotein cholesterol and apolipoprotein A-1 were 5% and 4%, respectively. Simvastatin was well tolerated across the dosage range.In conclusion, simvastatin, 20–80 mg/day, was safe and highly effective at reducing LDL-C levels. The recommended US and European LDL-C treatment goals were achieved in approximately 90% of the patients. These goals were similarly achieved for a variety of high-risk sub-groups (hypertensives, diabetics and elderly patients).

Can Computerized Risk Profiles Help Patients Improve Their Coronary Risk? The Results of The Coronary Health Assessment Study (CHAS)

Background.The Coronary Health Assessment Study (CHAS) was developed to determine the feasibility of using patient-specific, multifactorial computerized coronary risk profiles as a clinical decision aid to support primary prevention of CHD.Methods.Study participants included 253 community based physicians, randomized into profile and control groups, and 958 of their patients. The profile group physicians received coronary risk profiles for their patients within 10 working days after the baseline patient assessment providing early feedback. The control group received their profiles only if the patient was clinically reevaluated during a 3-month follow-up visit. Patients' coronary risk factors were evaluated at baseline and at follow-up.Results.The profile group had a significantly higher (P< 0.05) ratio of high-risk/low-risk patients who returned for a follow-up visit compared to the control group (1.23 vs 0.77). The patients in the profile group also had significantly (P< 0.05) greater mean reductions in total cholesterol (−0.5 vs −0.1 mmol/L), LDL cholesterol (−0.4 vs 0.0 mmol/L), the total cholesterol/ HDL ratio (−0.6 vs −0.2), and the predicted 8-year coronary risk (−1.8 vs −0.3%).Conclusions.Computer-generated coronary risk profiles can be effective in assisting physicians to identify high-risk patients. Their use is also associated with significantly greater improvements in the serum lipid profiles and the overall coronary risk of these patients.

Therapeutic efficiency of lipoprotein(a) reduction by low-density lipoprotein immunoapheresis

This study was performed to investigate the effect of low-density lipoprotein (LDL) immunoapheresis on lipoprotein(a) [Lp(a)] reduction in patients with heterozygous and homozygous familial hyperlipidemia (N = 16) and insufficient response to lipid-lowering agents. By desorption of approximately 5,700 ± 500 mL of plasma, a mean reduction in total cholesterol of 62% ( P < .001) and in LDL-cholesterol of 70% ( P < .001) was achieved. Lp(a), which was elevated at study entry in seven of these patients (82.1 ± 34.3 mg/dL; range, 48 to 148 mg/dL), was reduced during the initial LDL-apheresis procedure by 74.8% ± 14.1% ( P < .001). Long-term apheresis treatment performed at weekly intervals resulted in an mean reduction in Lp(a) pretreatment values to 39.1 ± 28.5 mg/dL (−54%; P < .001). Desorbed Lp(a) was measured at the waste of the columns for 31 apheresis treatments. LP(a) concentration of the column waste was higher in patients with elevated serum Lp(a) pretreatment values as compared with those with Lp(a) serum values within the normal range (elevated Lp(a), 1.420 ± 380 mg; without elevated Lp(a), 235 ± 190 mg; P < .001). The rate of return of Lp(a) following apheresis treatment scheduled at weekly intervals was comparable to that of LDL-cholesterol.

Changes in total and high-density lipoprotein cholesterol over 10- and 20-year periods (the Honolulu Heart Program)

Limited data are available on patterns of change in lipids and lipoproteins as persons age. The purpose of this report is to describe the 10-year change in total and high-density lipoprotein (HDL) cholesterol according to suspected determinants in 898 Japanese-American men enrolled in the Honolulu Heart Program. Data are based on examinations that occurred from 1970 to 1972 and at repeat examinations received 10 and 20 years later. At the last examination, men were aged 71 to 93 years. Mean reductions in total cholesterol in the second 10 years of follow-up (24 mg/dl) were more than double the reductions observed in the first 10 years (9 mg/dl). Levels of total cholesterol declined and levels of HDL cholesterol increased regardless of beginning levels of systolic blood pressure, body mass index, physical activity, cigarette smoking status, or the use of treatment for hypertension or elevated total cholesterol. Men with prevalent coronary heart disease experienced greater reductions (p <0.05) in total cholesterol during the second 10 years of follow-up (32 mg/dl) versus men without coronary heart disease (22 mg/dl). Adjustment for baseline covariates failed to alter these findings appreciably. We conclude that alterations in total and HDL cholesterol with advancing age may be expected to occur regardless of risk factor status, disease prevalence, or pharmacologic intervention. In the presence of such effects, evaluation of treatment programs to alter levels of total and HDL cholesterol in older persons should consider the possibility that even in the absence of intervention, changes could also occur due to aging alone.

Cholesterol reduction and clinical benefit. Are there limits to our expectations?

Encouraging intervention trials drive our expectations toward more aggressive cholesterol-lowering therapies, lower target levels, and less severe hypercholesterolemia. Available studies may predict which patients, degrees of total cholesterol (TC) reduction, and baseline and target levels of TC provide the most clinical benefit. Data were pooled from seven primary and nine secondary controlled trials with major coronary heart disease (CHD) events as primary endpoints. The analysis showed that we can expect large reductions in CHD from TC reduction in primary and secondary prevention. However, the reduction is much larger in subjects with high TC and/or previous CHD events. The percent reduction in CHD increased exponentially with increasing percent TC reductions, which predicted > 70% of the change in CHD. Consequently, we cannot expect cost-effective clinical benefits from mean reductions in TC > 15 (LDL cholesterol > 20%). The TC level at the study endpoint correlated with CHD incidence irrespective of the study group and explained almost 45% of CHD incidence. The relationship was progressive and leveled off at a TC level below about 150 mgdL (3.9 mmol/L) (LDL cholesterol approximately equal to 110 mg/dl [approximately equal to 2.8 mmol/L]). Little extra clinical benefit can be expected from further reductions. We can expect an average 2% reduction in CHD events per percent reduction in TC. We can also expect a 2-fold greater clinical benefit among subjects with high initial TC levels than among those with low levels. Finally, we can expect that the cholesterol-attributable risk is reset to that predicted by the TC level achieved within 4 to 6 years.

Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene.

The 10-kb deletion ("French Canadian mutation") of the low-density lipoprotein (LDL) receptor gene is the most common mutation causing familial hypercholesterolemia among subjects of French Canadian descent. In affected subjects, it results in a null allele of the LDL receptor gene and provides a unique opportunity to examine single-allele regulation of this gene in humans. We sought to ascertain the response of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in subjects with the French Canadian mutation of the LDL receptor gene and to correlate this response with biochemical variables and the haplotype of the nondeletion LDL receptor allele. The prevalence of non-responders to high doses of HMG CoA reductase inhibitors (defined as < 15% decrease in LDL cholesterol [LDL-C] from baseline values after dietary intervention) was ascertained in 105 patients heterozygous for the 10-kb deletion after excluding first-degree relatives and those on combined lipid-lowering therapy or other lipid-lowering agents. Lipoprotein cholesterol levels were examined after a diet period (30% calories as fat) and after receiving HMG CoA reductase inhibitors as mono-therapy for a minimum of 3 months. The mean reduction in total cholesterol was 45 +/- 23%, in LDL-C 33 +/- 15%, and in triglycerides 32 +/- 49% (all P < .005). There was a slight increase in high-density lipoprotein cholesterol of 8.5 +/- 18% (P > .05).(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter comparison of lovastatin and probucol for treatment of severe primary hypercholesterolemia

A multicenter study was undertaken to compare the effects of lovastatin (given in 4 different dosage regimens) and probucol in patients with severe primary hypercholesterolemia. The subjects were 290 patients taking lipid-lowering diets who were randomly assigned to 1 of the following treatment regimens for 14 weeks: lovastatin, 40 mg once a day with the morning meal (qam); lovastatin, 40 mg once a day with the evening meal (qpm); lovastatin 80 mg qpm; lovastatin, 40 mg twice daily, or probucol, 500 mg twice daily. One-third of the patients received probucol, and the other two-thirds were equally divided between the 4 lovastatin treatment groups. The mean reductions in total cholesterol in the 5 groups were, respectively, 20, 25, 30, 33 and 10%. The corresponding values for low-density lipoprotein cholesterol were 25, 32, 37, 40 and 8%. High-density lipoprotein cholesterol increased by 9 to 12% in all the lovastatin groups, but decreased by 23% in the probucol group. Triglycerides were reduced by 17 to 25% in all the lovastatin groups, but did not change significantly in the probucol group. Both drugs were well tolerated; no serious adverse events could be attributed to either agent. It is concluded that lovastatin is a considerably more effective lipid-lowering agent than probucol. In addition, lovastatin is almost as effective when given in a single daily dose as when given in a divided dose. When a once-a-day regimen is used, lovastatin is more effective if taken in the evening rather than the morning.

Effects of simvastatin and cholestyramine in familial and nonfamilial hypercholesterolemia. Multicenter Group I

Simvastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was compared with cholestyramine resin in a randomized open-label 12-week multicenter study of 251 high-risk patients with familial or nonfamilial hypercholesterolemia. Simvastatin, 20 mg and 40 mg daily, produced mean reductions in total cholesterol of 26% and 33%, respectively, and reductions in low-density lipoprotein cholesterol level of 32% and 40%. Cholestyramine resin, 4 to 12 g twice daily, reduced total cholesterol and low-density lipoprotein cholesterol levels 15% and 21%, respectively. High-density lipoprotein cholesterol levels were increased 8% to 10% by all treatments. Plasma triglyceride levels were moderately decreased by simvastatin treatment, while triglyceride levels increased with cholestyramine treatment. Simvastatin was better tolerated than cholestyramine, which had numerous gastrointestinal tract side effects. No patient had a serious drug-related adverse event.

Effects of Simvastatin and Cholestyramine in Familial and Nonfamilial Hypercholesterolemia

• Simvastatin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was compared with cholestyramine resin in a randomized open-label 12-week multicenter study of 251 high-risk patients with familial or nonfamilial hypercholesterolemia. Simvastatin, 20 mg and 40 mg daily, produced mean reductions in total cholesterol of 26% and 33%, respectively, and reductions in low-density lipoprotein cholesterol level of 32% and 40%. Cholestyramine resin, 4 to 12 g twice daily, reduced total cholesterol and low-density lipoprotein cholesterol levels 15% and 21%, respectively. High-density lipoprotein cholesterol levels were increased 8% to 10% by all treatments. Plasma triglyceride levels were moderately decreased by simvastatin treatment, while triglyceride levels increased with cholestyramine treatment. Simvastatin was better tolerated than cholestyramine, which had numerous gastrointestinal tract side effects. No patient had a serious drug-related adverse event. (<i>Arch Intern Med.</i>1990;150:341-345)