Combination treatment with cholestyramine and bezafibrate for heterozygous familial hypercholesterolaemia.

Cholestyramine and bezafibrate were compared individually and in combination in the treatment of 18 patients with heterozygous familial hypercholesterolaemia. The study used a double blind, placebo controlled block design with a placebo run in period of two months followed by three phases of active treatment, each of two months'' duration. Patients were randomly allocated to one of the six possible sequences of medication so that three patients would be treated with each sequence. Two patients withdrew from the study before completion. The median concentration of total cholesterol decreased from 9.65 mmol/l (interquartile range 8.62 to 8.72) to 7.24 mmol/l (6.70 to 7.52) with cholestyramine, to 8.09 mmol/l (7.18 to 8.68) with bezafibrate, and to 6.31 mmol/l (5.84 to 7.27) with the combination. This fall was due almost entirely to a decrease in the low density lipoprotein cholesterol concentration, and the combination was significantly more effective than either drug alone. The 98% confidence intervals for the median differences between the combination and cholestyramine and the combination and bezafibrate were 0.04 to 1.49 mmol/l and 0.51 to 2.18 mmol/l respectively. These results suggest that this combination is an effective and useful treatment in heterozygous familial hypercholesterolaemia.     

Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease,and stroke: systematic review and meta-analysis

Objectives To determine by how much statins reduce serum concentrations of low density lipoprotein (LDL) cholesterol and incidence of ischaemic heart disease (IHD) events and stroke, according to drug, dose, and duration of treatment.Design Three meta-analyses: 164 short term randomised placebo controlled trials of six statins and LDL cholesterol reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies and the same 58 trials on stoke.Main outcome measures Reductions in LDL cholesterol according to statin and dose; reduction in IHD events and stroke for a specified reduction in LDL cholesterol.Results Reductions in LDL cholesterol (in the 164 trials) were 2.8 mmol/l (60%) with rosuvastatin 80 mg/day, 2.6 mmol/l (55%) with atorvastatin 80 mg/day, 1.8 mmol/l (40%) with atorvastatin 10 mg/day, lovastatin 40 mg/day, simvastatin 40 mg/day, or rosuvastatin 5 mg/day, all from pretreatment concentrations of 4.8 mmol/l. Pravastatin and fluvastatin achieved smaller reductions. In the 58 trials, for an LDL cholesterol reduction of 1.0 mmol/l the risk of IHD events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in years three to five, and by 36% thereafter (P < 0.001 for trend). IHD events were reduced by 20%, 31%, and 51% in trials grouped by LDL cholesterol reduction (means 0.5 mmol/l, 1.0 mmol/l, and 1.6 mmol/l) after results from first two years of treatment were excluded (P < 0.001 for trend). After several years a reduction of 1.8 mmol/l would reduce IHD events by an estimated 61%. Results from the same 58 trials, corroborated by results from the nine cohort studies, show that lowering LDL cholesterol decreases all stroke by 10% for a 1 mmol/l reduction and 17% for a 1.8 mmol/l reduction. Estimates allow for the fact that trials tended to recruit people with vascular disease, among whom the effect of LDL cholesterol reduction on stroke is greater because of their higher risk of thromboembolic stroke (rather than haemorrhagic stroke) compared with people in the general population.Conclusions Statins can lower LDL cholesterol concentration by an average of 1.8 mmol/l which reduces the risk of IHD events by about 60% and stroke by 17%.     

Cardiovascular outcomes among participants with diabetes in the recent large statin trials

PURPOSE OF REVIEW: Despite their increased cardiovascular risk and its continuous relationship with cholesterol, until recently only diabetic patients with marked dyslipidaemia were routinely offered lipid-lowering therapy. The secondary prevention statin trials led to more widespread cholesterol lowering in patients with coronary disease and diabetes. Here we review the results of recent randomized trials, which included substantial numbers of patients with diabetes and no vascular disease. RECENT FINDINGS: The MRC/BHF Heart Protection Study included 5963 participants with diabetes, of whom 2912 had no history of vascular disease at baseline. Patients were randomized to 40 mg simvastatin daily or matching placebo for 5 years, which, on average, reduced LDL by 1.0 mmol/l compared with placebo. Highly significant reductions of about one-quarter in major vascular events were seen both overall and in different types of patient with diabetes, including those with average and below average lipid levels. Recent data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial and the Anglo-Scandinavian Cardiac Outcomes Trial support these findings and are consistent with these effects. SUMMARY: Good quality, randomized trials including substantial numbers of patients with diabetes show that such patients obtain the same proportional benefit as other groups studied. Given their increased cardiovascular risk, these findings argue for a simple strategy of considering routine statin therapy for patients with type 2 diabetes and adult patients with type 1 diabetes, irrespective of lipid levels. As generic statins become available this could have a greater impact on the burden of cardiovascular disease in diabetes than restricted and targeted therapy.     

A Cluster Randomised Controlled Trial of a Pharmacist-Led Collaborative Intervention to Improve Statin Prescribing and Attainment of Cholesterol Targets in Primary Care

Background

Small trials with short term follow up suggest pharmacists’ interventions targeted at healthcare professionals can improve prescribing. In comparison with clinical guidance, contemporary statin prescribing is sub-optimal and achievement of cholesterol targets falls short of accepted standards, for patients with atherosclerotic vascular disease who are at highest absolute risk and who stand to obtain greatest benefit. We hypothesised that a pharmacist-led complex intervention delivered to doctors and nurses in primary care, would improve statin prescribing and achievement of cholesterol targets for incident and prevalent patients with vascular disease, beyond one year.

Methods

We allocated general practices to a 12-month Statin Outreach Support (SOS) intervention or usual care. SOS was delivered by one of 11 pharmacists who had received additional training. SOS comprised academic detailing and practical support to identify patients with vascular disease who were not prescribed a statin at optimal dose or did not have cholesterol at target, followed by individualised recommendations for changes to management. The primary outcome was the proportion of patients achieving cholesterol targets. Secondary outcomes were: the proportion of patients prescribed simvastatin 40 mg with target cholesterol achieved; cholesterol levels; prescribing of simvastatin 40 mg; prescribing of any statin and the proportion of patients with cholesterol tested. Outcomes were assessed after an average of 1.7 years (range 1.4–2.2 years), and practice level simvastatin 40 mg prescribing was assessed after 10 years.

Findings

We randomised 31 practices (72 General Practitioners (GPs), 40 nurses). Prior to randomisation a subset of eligible patients were identified to characterise practices; 40% had cholesterol levels below the target threshold. Improvements in data collection procedures allowed identification of all eligible patients (n = 7586) at follow up. Patients in practices allocated to SOS were significantly more likely to have cholesterol at target (69.5% vs 63.5%; OR 1.11, CI 1.00–1.23; p = 0.043) as a result of improved simvastatin prescribing. Subgroup analysis showed the primary outcome was achieved by prevalent but not incident patients. Statistically significant improvements occurred in all secondary outcomes for prevalent patients and all but one secondary outcome (the proportion of patients with cholesterol tested) for incident patients. SOS practices prescribed more simvastatin 40 mg than usual care practices, up to 10 years later.

Interpretation

Through a combination of educational and organisational support, a general practice based pharmacist led collaborative intervention can improve statin prescribing and achievement of cholesterol targets in a high-risk primary care based population.

Trial Registration

International Standard Randomised Controlled Trials Register ISRCTN61233866     

Twelve weeks’ treatment with a polyphenol-rich seaweed extract increased HDL cholesterol with no change in other biomarkers of chronic disease risk in overweight adults: A placebo-controlled randomized trial

Cardiovascular diseases (CVD) are the leading global cause of death. Strategies to reduce CVD risk are urgently needed. Polyphenols represent a class of bioactive compounds with potential to moderate biochemical risk factors for CVD (cholesterol, triglycerides, glucose, and inflammation). This double-blind, placebo-controlled, randomized parallel-groups trial investigated the effect of a polyphenol-rich seaweed (Fucus vesiculosus) extract on biochemical markers of CVD risk. Thirty-four overweight and obese adults (21 female, 13 male) with elevated low-density lipoprotein cholesterol (>2.0 mmol/L) were randomized to either the seaweed extract (2000 mg/d) or placebo for twelve weeks. Fasting blood samples were collected at baseline, week six and week twelve to assess biochemical markers. Tests of cognitive performance and mood were performed at baseline, week six and week twelve. A 9.5% (-2.3, 12.9) increase in high-density lipoprotein (HDL) cholesterol was identified following the seaweed extract (baseline: mean (SD) 1.28 (0.23) mmol/L, week 12: 1.35 (0.24) mmol/L) which was different to placebo (baseline: 1.38 (0.54) mmol/L, week 12: 1.35 (0.59) mmol/L) (P=.045). No changes were identified in low-density lipoprotein cholesterol, total cholesterol, triglycerides, glucose, insulin, interleukin (IL)-2, IL-6, IL-8, IL-10, or tumour necrosis factor-alpha levels in the blood, or in cognitive performance or mood between the treatment and placebo groups. Despite the small increase observed in HDL cholesterol, the polyphenol-rich seaweed extract did not change CVD risk factors in adults with high fasting lipids. A larger sample size would be required to confirm the clinical relevance of the changes in HDL cholesterol.     

Serum Lp(a) lipoprotein concentrations in insulin dependent diabetic patients with microalbuminuria.

OBJECTIVE--To compare the serum concentrations of lipoproteins and apolipoproteins in insulin dependent diabetic patients with and without microalbuminuria. DESIGN--Cross sectional study. SETTING--Paediatric and medical outpatient clinic at a university hospital. PATIENTS--76 insulin dependent diabetic patients: 41 with microalbuminuria (20 males, 21 females) and 35 controls without microalbuminuria (18 males, 17 females). The two groups were similar with respect to age, duration of disease, and haemoglobin A1c concentrations before the study. MAIN OUTCOME MEASURES--Serum concentrations of Lp(a) lipoprotein, total cholesterol, high density lipoprotein cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoproteins A-I, A-II, and B. RESULTS--Median serum Lp(a) lipoprotein concentration was 10.0 mg/100 ml in the microalbuminuric group and 4.9 mg/100 ml in the control group (p = 0.007). 17 (41%) of the microalbuminuric patients and five (14%) of the control patients had Lp(a) lipoprotein values above the upper quartile of a normal population. Median serum triglycerides concentrations in the microalbuminuric and control groups were 1.15 mmol/l and 0.88 mmol/l respectively (p = 0.03). Median very low density lipoprotein cholesterol concentration was 0.52 mmol/l in the microalbuminuric group and 0.40 mmol/l in the control group (p = 0.03). No significant differences in serum concentrations of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, or apolipoproteins A-I, A-II, and B were found between the groups. CONCLUSIONS--Serum concentrations of Lp(a) lipoprotein are twice as high in insulin dependent diabetic patients with microalbuminuria as in those without microalbuminuria. Increased concentrations of Lp(a) lipoprotein might partly explain the increased morbidity and mortality from cardiovascular disease observed among patients with diabetic nephropathy.     

Economic evaluation of ezetimibe combined with simvastatin for the treatment of primary hypercholesterolaemia

Objective

This study aims to assess the cost-effectiveness of ezetimibe plus simvastatin (E/S) versus atorvastatin or simvastatin monotherapy as second-line treatment of primary hypercholesterolaemia from the Dutch healthcare perspective.

Methods

The evaluation used a Markov model and patient data from the Dutch EASEGO study in which patients failing to reach goal low-density lipoprotein cholesterol levels on atorvastatin 10 mg or simvastatin 20 mg had their dose doubled or switched to ezetimibe 10 mg plus generic simvastatin 20 mg (E10/S20). The second scenario, based on Dutch guidelines, switched patients from simvastatin 40 mg to atorvastatin 40 mg, or ezetimibe 10 mg was added to simvastatin 40 mg (E10/S40). The key effectiveness input measure was change in total cholesterol/high-density lipoprotein ratio obtained from the EASEGO study. In conformity with published studies linking reduced lipid levels to reduced risk of cardiovascular events, the present model assumed that a lipid decrease with ezetimibe may be a signal for reduced risk of cardiovascular events. Model parameters were derived from published literature. Sensitivity analyses were performed for the key parameters.

Results

In the EASEGO scenario, incremental cost-effectiveness ratio for E10/S20 was €3497/quality-adjusted life-years (QALY) vs atorvastatin 20 mg and €26,417/QALY vs simvastatin 40 mg. In the Dutch guidelines scenario, E10/S40 was dominant (more effective and cost-saving) vs atorvastatin 40 mg. Varying model inputs had limited impact on the cost-effectiveness of E/S.

Conclusions

The analysis showed the cost-effectiveness of E/S versus atorvastatin 20 mg or simvastatin 40 mg (EASEGO scenario) at a threshold of €30,000/QALY and vs atorvastatin 40 mg was dominant (Dutch guidelines). Thus, E/S seems a valuable cost-effective second-line treatment option for patients not attaining lipid treatment goals.     

Dietary lipids and blood cholesterol: quantitative meta-analysis of metabolic ward studies.

OBJECTIVE: To determine the quantitative importance of dietary fatty acids and dietary cholesterol to blood concentrations of total, low density lipoprotein, and high density lipoprotein cholesterol. DESIGN: Meta-analysis of metabolic ward studies of solid food diets in healthy volunteers. SUBJECTS: 395 dietary experiments (median duration 1 month) among 129 groups of individuals. RESULTS: Isocaloric replacement of saturated fats by complex carbohydrates for 10% of dietary calories resulted in blood total cholesterol falling by 0.52 (SE 0.03) mmol/l and low density lipoprotein cholesterol falling by 0.36 (0.05) mmol/l. Isocaloric replacement of complex carbohydrates by polyunsaturated fats for 5% of dietary calories resulted in total cholesterol falling by a further 0.13 (0.02) mmol/l and low density lipoprotein cholesterol falling by 0.11 (0.02) mmol/l. Similar replacement of carbohydrates by monounsaturated fats produced no significant effect on total or low density lipoprotein cholesterol. Avoiding 200 mg/day dietary cholesterol further decreased blood total cholesterol by 0.13 (0.02) mmol/l and low density lipoprotein cholesterol by 0.10 (0.02) mmol/l. CONCLUSIONS: In typical British diets replacing 60% of saturated fats by other fats and avoiding 60% of dietary cholesterol would reduce blood total cholesterol by about 0.8 mmol/l (that is, by 10-15%), with four fifths of this reduction being in low density lipoprotein cholesterol.     

Impact on lipoprotein profile after long-term testosterone replacement in hypogonadal men.

Testosterone serum levels may influence the lipoprotein metabolism and possibly atherogenic risk. Our aim was to investigate the effects of long-term testosterone supplementation in hypogonadal men on multiple lipoprotein markers. 18 Hypogonadal men were studied before and after 3, 6, and 18 (n = 7) months of treatment with testosterone enanthate. During treatment, serum testosterone and estradiol increased, reaching normal levels (p < 0.0001 and 0.003, respectively). This was associated with a decrease in HDL cholesterol (from 1.40 +/- 0.10 mmol/l to 1.22 +/- 0.08 mmol/l, p < 0.001) after six months at the expense of HDL2 cholesterol (p < 0.01), as well as apoprotein A1 (from 139 +/- 3.4 mg/dl to 126 +/- 3.0 mg/dl, p < 0.005). Hepatic lipase activity increased (p < 0.05) and correlated positively with testosterone (r = 0.56, p < 0.02) and negatively with HDL cholesterol (r = - 0.58, p < 0.02). Total and LDL cholesterol, triglycerides, and apoprotein B did not increase. Among the seven patients who completed 18 months of treatment, triglycerides, total cholesterol, LDL and HDL cholesterol, as well as total cholesterol/HDL cholesterol ratio values did not differ from baseline while apoprotein A1 (p < 0.03) and HDL cholesterol (p < 0.015) remained decreased and hepatic lipase unchanged. Restoration of testosterone levels in hypogonadal men in this study did not reveal unfavorable changes based on total cholesterol/HDL cholesterol and LDL cholesterol/apoprotein B ratios, which are both atherogenic risk markers. Whether the changes in light of lipoprotein metabolism will adversely influence cardiovascular risk over time remains to be determined.     

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks. Ezetimibe and ezetimibe/simvastatin decreased fractional cholesterol absorption by 65% and 59%, respectively (P < 0.001 for both relative to placebo). Simvastatin did not significantly affect cholesterol absorption. Ezetimibe and ezetimibe/simvastatin increased fecal sterol excretion (corrected for dietary cholesterol), which also represents net steady state cholesterol synthesis, by 109% and 79%, respectively (P < 0.001). Ezetimibe, simvastatin, and ezetimibe/simvastatin decreased plasma LDL-cholesterol by 20, 38, and 55%, respectively. The coadministered therapy was well tolerated. The decreases in net cholesterol synthesis and increased fecal sterol excretion yielded nearly additive reductions in LDL-cholesterol for the coadministration of ezetimibe and simvastatin.     

Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure

Despite standard drug therapy, sympathetic nerve activity (SNA) remains high in heart failure (HF) patients making the sympathetic nervous system a primary drug target in the treatment of HF. Studies in rabbits with pacing-induced HF have demonstrated that statins reduce resting SNA, in part, due to reductions in reactive oxygen species (ROS). Whether these findings can be extended to the clinical setting of human HF remains unclear. We first performed a study in seven statin-na?ve HF patients (56 ± 2 yr; ejection fraction: 31 ± 4%) to determine if 1 mo of simvastatin (40 mg/day) reduces muscle SNA (MSNA). Next, to control for possible placebo effects and determine the effect of simvastatin on ROS, a double-blinded, placebo-controlled crossover design study was performed in six additional HF patients (51 ± 3 yr; ejection fraction: 22 ± 4%), and MSNA, ROS, and superoxide were measured. We tested the hypothesis that statin therapy decreases resting MSNA in HF patients and this would be associated with reductions in ROS. In study 1, simvastatin reduced resting MSNA (75 ± 5 baseline vs. 65 ± 5 statin bursts/100 heartbeats; P < 0.05). Likewise, in study 2, simvastatin also decreased resting MSNA (59 ± 5 placebo vs. 45 ± 6 statin bursts/100 heartbeats; P < 0.05). In addition, statin therapy significantly reduced total ROS and superoxide. As expected, cholesterol was reduced after simvastatin. Collectively, these findings indicate that short-term statin therapy concomitantly reduces resting MSNA and total ROS and superoxide in HF patients. Thus, in addition to lowering cholesterol, statins may also be beneficial in reducing sympathetic overactivity and oxidative stress in HF patients.     

Lipid screening: is it enough to measure total cholesterol concentration?

OBJECTIVES--To determine whether measurement of total cholesterol concentration is sufficient to identify most patients at lipoprotein mediated risk of coronary heart disease without measurement of triglyceride and high density lipoprotein (HDL) cholesterol concentrations. DESIGN--Cross sectional screening programme. SETTING--Six general practices in Oxfordshire. PATIENTS--1901 Men and 2068 women aged 25-59. MAIN OUTCOME MEASURE--Cardiovascular risk as assessed by fasting venous plasma concentrations of total cholesterol, triglyceride, and HDL cholesterol. RESULTS--2931 Patients (74% of those screened) had a total cholesterol concentration of less than 6.5 mmol/l. If the triglyceride concentration had not been measured in these patients isolated hypertriglyceridaemia (greater than or equal to 2.3 mmol/l) would have remained undetected in 185. Among these 185 patients, however, 123 were overweight or obese and only 18 (0.6% of those screened) had an increased risk associated with both a raised triglyceride concentration (greater than or equal to 2.3 mmol/l) and a low HDL cholesterol concentration (less than 0.9 mmol/l). Conversely, in the 790 patients with predominant hypercholesterolaemia (cholesterol concentration greater than or equal to 6.5 mmol/l and triglyceride concentration less than 2.3 mmol/l) measurement of HDL cholesterol concentration showed that 348 (9% of those screened) had only a moderately increased risk with a ratio of total to HDL cholesterol of less than 4.5 and 104 had a low risk with a ratio of less than 3.5. CONCLUSIONS--Fasting triglyceride and HDL cholesterol concentrations identify few patients at increased risk of coronary heart disease if the total cholesterol concentration is less than 6.5 mmol/l. HDL cholesterol and triglyceride concentrations should, however, be measured in patients with a total cholesterol concentration exceeding this value. Total cholesterol concentration alone may overestimate risk in a considerable number of these patients, and measurement of HDL cholesterol concentration allows a more precise estimate of risk. Measurement of the triglyceride concentration is required to characterise the lipoprotein abnormality. A patient should not be started on a drug that lowers lipid concentrations without having had a full lipoprotein assessment including measurement of HDL cholesterol concentration.     

Long term metabolic effects of two dietary methods of treating hyperlipidaemia.

OBJECTIVES--To compare the long term metabolic effects of two diets for treating hyperlipidaemia. DESIGN--Randomised controlled study: after three weeks of normal (control) diet, subjects were randomly allocated to one of two test diets and followed up for six months. SETTING--Lipid clinic of tertiary referral centre in Naples. SUBJECTS--63 subjects with primary type IIa and IIb hyperlipoproteinaemia entered the study, and 44 completed it. Exclusion criteria were taking drugs known to influence lipid metabolism, evidence of cardiovascular disease, homozygous familial hypercholesterolaemia, and body mass index over 30. INTERVENTIONS--Two test diets with reduced saturated fat (8%) and cholesterol (approximately 200 mg/day): one was also low in total fat and rich in carbohydrate and fibre, and the other was low in carbohydrate and fibre and rich in polyunsaturated and monounsaturated fats. MAIN OUTCOME MEASURES--Fasting plasma lipid and lipoprotein concentrations; blood glucose, insulin, and triglyceride concentrations before and after a test meal. RESULTS--In comparison with the control diet, both test diets induced significant and similar decreases in low density lipoprotein cholesterol concentrations (by a mean of 0.72 (SE 0.15) mmol/l, P < 0.001, for low total fat diet; by 0.49 (0.18) mmol/l, P < 0.05, for high unsaturated fat diet) and plasma triglyceride concentrations (by 0.21 (0.09) mmol/l, P < 0.05, for low total fat diet; by 0.39 (0.15) mmol/l, P < 0.05, for high unsaturated fat diet), while high density lipoprotein cholesterol concentrations after fasting and plasma glucose and insulin concentrations during test meals were not modified by either diet. CONCLUSIONS--Both test diets are suitable (alone or in combination) for treatment of hypercholesterolaemia.     

Randomised trial of lipid lowering dietary advice in general practice: the effects on serum lipids,lipoproteins, and antioxidants.

OBJECTIVE--To determine the relative efficacy in general practice of dietary advice given by a dietitian, a practice nurse, or a diet leaflet alone in reducing total and low density lipoprotein cholesterol concentration. DESIGN--Randomised six month parallel trial. SETTING--A general practice in Oxfordshire. SUBJECTS--2004 subjects aged 35-64 years were screened for hypercholesterolaemia; 163 men and 146 women with a repeat total cholesterol concentration of 6.0-8.5 mmol/l entered the trial. INTERVENTIONS--Individual advice provided by a dietitian using a diet history, a practice nurse using a structured food frequency questionnaire, or a detailed diet leaflet sent by post. All three groups were advised to limit the energy provided by fat to 30% or less and to increase carbohydrate and dietary fibre. MAIN OUTCOME MEASURES--Concentrations of total cholesterol and low density and high density lipoprotein cholesterol after six months; antioxidant concentration and body mass index. RESULTS--No significant differences were found at the end of the trial between groups in mean concentrations of lipids, lipoproteins, and antioxidants or body mass index. After data were pooled from the three groups, the mean total cholesterol concentration fell by 1.9% (0.13 mmol/l, 95% confidence interval 0.06 to 0.22, P < 0.001) to 7.00 mmol/l, and low density lipoprotein cholesterol also fell. The total carotenoid concentration increased by 53 nmol/l (95% confidence interval 3.0 to 103, P = 0.039). CONCLUSIONS--Dietary advice is equally effective when given by a dietitian, a practice nurse, or a diet leaflet alone but results in only a small reduction in total and low density lipoprotein cholesterol. To obtain a better response more intensive intervention than is normally available in primary care is probably necessary.     

Simvastatin decreases concentration of interleukin-2 in hypercholesterolemic patients after treatment for 12 weeks

Statins, HMG-CoA reductase inhibitors are drugs with a potent lipid-lowering effect. They are also able to inhibit proliferation of smooth muscle cells, T-lymphocytes, to restore endothelial activity and to inhibit inflammatory responses. These effects have been called the pleiotropic effect of statins. Statins have demonstrated contrast to the inflammatory activity of macrophages. The aim of the study was to assess the influence of simvastatin on serum levels of proinflammatory cytokines such as IL-2 and TNFalpha in hypercholesterolemic patients. METHODS: In 58 non-smoking men with total cholesterol (TC) >7.8 mmol/L, LDL-cholesterol>5.5 mmol/L and fasting triglycerides<4.6 mmol/L serum IL-2 and TNFalpha were determined at the beginning of the study, after 3 months diet and after 3 months of simvastatin therapy (20 mg/day). The control group was composed of 10 healthy volunteers with correct lipid values: TC<5.2 mmol/L, LDL-cholesterol <2.3 mmol/L, HDL-cholesterol >1.5 mmol/L and triglycerides<2.3 mmol/L. RESULTS: There were significant reductions in IL-2 concentration after 3 months diet (p=0.0059) and significant (p=0.0003) decrease of IL-2 after 3 months of simvastatin therapy. Meanwhile we observed a significant decrease of TNFalpha concentration after 3 months diet (p=0.0001) and no significant decrease after 3 months of simvastatin therapy.     

Relation between dose of bendrofluazide,antihypertensive effect,and adverse biochemical effects.

OBJECTIVE--To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension. DESIGN--Double blind parallel group trial of patients who were given placebo for six weeks and then randomly allocated to various doses of bendrofluazide (1.25, 2.5, 5, or 10 mg daily) or placebo for 12 weeks. SETTING--General practices in Zealand, Denmark. PATIENTS--257 Patients with newly diagnosed or previously treated hypertension, aged 25-70, who had a mean diastolic blood pressure of 100-120 mm Hg after receiving placebo for six weeks. MAIN OUTCOME MEASURES--Reduction in diastolic blood pressure and changes in biochemical variables (potassium, urate, glucose, fructosamine, total cholesterol, apolipoprotein A I, apolipoprotein B, and triglyceride concentrations). RESULTS--All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree (10-11 mm Hg). Clear relations between dose and effect were shown for potassium, urate, glucose, total cholesterol, and apolipoprotein B concentrations. The 1.25 mg dose increased only urate concentrations, whereas the 10 mg dose affected all the above biochemical variables. CONCLUSION--The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25-2.5 mg a day. Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects. Previous trials with bendrofluazide have used too high doses.     

Cross sectional survey of effectiveness of lipid lowering drugs in reducing serum cholesterol concentration in patients in 17 general practices

ObjectiveTo compare the effectiveness of lipid lowering drugs in lowering serum cholesterol concentrations.DesignCross sectional study.Setting17 practices within 17 primary care groups in Trent region, United Kingdom.ParticipantsPatients aged 35 years or over taking lipid lowering drugs and with at least two serum cholesterol concentrations recorded on computer.Results1353 of 2469 (54.8%) patients receiving lipid lowering treatment had a last recorded serum cholesterol concentration of ⩽5 mmol/l. Significantly more patients taking statins achieved the target value for serum cholesterol (5 mmol/l) than those taking fibrates (1307 (57%) v 46 (26%); P<0.0001). Atorvastatin and simvastatin were the most effective drugs in achieving the target. Significant differences were found between lipid lowering drugs for the pretreatment serum cholesterol concentration, the most recent cholesterol concentration, and the associated percentage reduction. Atorvastatin and simvastatin achieved the greatest percentage reduction in serum cholesterol concentrations (30.1%, 95% confidence interval 28.8% to 31.4%, and 28.0%, 26.7% to 29.3%, respectively). Although the mean serum cholesterol concentrations in this unselected population tended to be higher than those in clinical trials, the percentage reduction was consistent with the trials.ConclusionThe ability of individual statins to lower serum cholesterol concentration varied, with atorvastatin and simvastatin being the most effective. The percentage reductions agreed with those of randomised controlled trials indicating likely benefits in unselected patients in primary care. As the initial serum cholesterol concentrations were higher than those in randomised controlled trials, target serum cholesterol values of ⩽5 mmol/l may be unrealistic even for patients taking the most efficacious drugs. Also, the higher initial levels could mean that the absolute reduction in cardiovascular risk in primary care patients is greater than thought.

What is already known on this topic

Statins in patients with coronary heart disease help reduce further cardiovascular events and improve survivalThis seems to be a class effect of statins, although there may be important differences in effectiveness between themLess than half of patients in the community who take lipid lowering drugs achieve target serum cholesterol values

What this study adds

Statins vary in their ability to lower serum cholesterol concentration, with atorvastatin and simvastatin achieving the best resultsThe percentage reductions agreed with those found in randomised controlled trialsSince the initial serum cholesterol concentrations were higher than in trials, absolute risk reductions in primary care patients may be greater than thoughtTarget values of ⩽5 mmol/l may be unrealistic even for patients on the most efficacious drugs, because the initial mean cholesterol values of primary care patients are higher than those of patients in trials     

The Lescol(R) Intervention Prevention Study (LIPS): a double-blind,placebo-controlled,randomized trial of the long-term effects of fluvastatin after successful transcatheter therapy in patients with coronary heart disease

BACKGROUND: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit atherosclerosis and reduce both morbidity and mortality in patients with coronary heart disease. No randomised prospective study, however, has investigated the long-term effect of statins on clinical outcomes in patients who have undergone first successful transcatheter therapy. METHODS: The Lescol((R)) Intervention Prevention Study (LIPS) is a double-blind randomized trial designed to compare the effect of fluvastatin (Lescol) with that of placebo on the time which patients with serum cholesterol >/= 3.5 mmol/l and < 7.0 mmol/l (135-270 mg/dl) remain free of major adverse cardiac events (MACE) after successful first transcatheter therapy (TCT). Patients, aged 18-80 years inclusive, will be randomized in a 1 : 1 ratio to receive fluvastatin, 40 mg, or placebo, twice daily for three to five years. The primary endpoint is the survival time during which patients remain MACE free after first TCT. Secondary endpoints are the incidence of MACE, noncardiac death, hospitalization for other atherosclerotic diseases, changes in serum lipid concentrations and anginal status. SUMMARY: LIPS is unique because it is the first study that will investigate whether MACE can be prevented or reduced by fluvastatin in patients who have undergone successful first transcatheter therapy for coronary heart disease.     

VAP II analysis of lipoprotein subclasses in mixed hyperlipidemic patients on treatment with ezetimibe/simvastatin and fenofibrate

This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18-79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/simvastatin 10/20 mg/day + fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with more-pronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin + fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.