Excessive range of statin dose in Western Australian primary care.

BACKGROUND: Statins are very effective in reducing coronary disease and ischaemic stroke but guidelines although evolving have not been clear on statin dose. AIM: To audit and review community statin prescribing. METHODS: A retrospective audit of the type and dose of statin dispensed was undertaken at five pharmacies in and around Perth, the capital city of Western Australia. Patients were de-identified. RESULTS: Statins made up 6.5% of all prescriptions. Statin dose when adjusted for different potency effectively varied 64-fold between patients. Rosuvastatin and atorvastatin accounted for 79% of prescriptions, at a mean dose of 10 times the effective dose 50. CONCLUSION: The extraordinarily wide variation in statin dose is at odds with the more consistent doses of other drugs used in the management of arterial disease. Unnecessarily high statin dosing increases side-effects and may not improve clinical outcomes appreciably. Rational prescribing of statins based on the pharmacodynamic evidence, with lower doses in most patients, combined with close attention to reduction of smoking, blood pressure and weight, is likely to reduce arterial disease most efficiently and safely.

Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia.

BACKGROUND: We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B-48 and remnant-like particle-cholesterol (RLP-C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG-CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB-48 and RLP-C in FH patients after long- and short-term simvastatin therapy and after a wash-out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant-like emulsion labeled with cholesteryl (13)C-oleate. METHODS: Fifteen FH patients were studied after > 6 months 40 mg day(-1) simvastatin treatment (long-term), a wash-out period (4 weeks), and 4 weeks of simvastatin treatment (short-term). Apolipoprotein B-48 was determined by SDS-PAGE and Western blotting/enhanced chemiluminescence and RLP-C by an immunoseparation assay. The FCR of the chylomicron remnant-like emulsion was determined from the appearance of (13)CO(2) in the breath and by multicompartmental mathematical modelling. RESULTS: Both long- and short-term treatment with simvastatin were associated with decreases in the plasma concentration of apoB-48 (P < 0.05) and RLP-C (P < 0.001), but there was no significant change in the FCR of the emulsion. CONCLUSIONS: We suggest that long- and short-term treatments with simvastatin have comparable effects in decreasing the plasma concentration of triglyceride-rich remnants in heterozygous FH, as measured by fasting apoB-48 and RLP-C. The mechanisms for this may involve decreased production of hepatic and possibly intestinal lipoproteins, and/or up-regulation of hepatic receptor clearance pathways, but these changes are apparently not associated with a change in remnant clearance as measured kinetically by the (13)CO(2) breath test.

Chylomicron remnant metabolism in familial hypercholesterolaemia studied with a stable isotope breath test.

Chylomicron remnant metabolism was studied using a stable isotope breath test in 25 patients with familial hypercholesterolaemia (FH) (10 homozygotes, 15 heterozygotes), and in 15 normolipidaemic controls. A lipid emulsion mimicking the composition of chylomicron remnants and labelled with cholesteryl (13)C-oleate was injected intravenously; (13)CO(2) was measured subsequently in breath using isotope-ratio mass spectrometry. The fractional catabolic rate (pools/h) of the emulsion, derived from a compartmental model, did not differ significantly among the groups: homozygous FH mean 0.20 (S.E.M. 0.05), heterozygous FH 0.12 (0.02), controls 0.16 (0.03). We suggest that the catabolism of chylomicron remnants from plasma is not impaired in FH and that the hepatic uptake of these particles is not dependent on functional LDL receptors.

Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test.

We have developed a stable isotope breath test for the assessment of chylomicron remnant metabolism and report the results from the breath test in human subjects selected for disorders of chylomicron or remnant metabolism. In type I hyperlipemia, the phenotype is extreme hypertriglyceridemia due to a lack of lipoprotein lipase activity, which causes the failure of remnant formation. The type III dyslipidemia phenotype is caused by the inefficient removal of chylomicron remnants from plasma, generally because of homozygosity for apolipoprotein E2 alleles. The breath test was predicted to be abnormal in type III hyperlipemia, whereas a priori in type I hyperlipemia defective remnant clearance was not anticipated. Subjects were injected with lipid emulsions prepared with a composition similar to normal chylomicron remnants. The emulsions contained cholesteryl ester incorporating the stable nonradioactive isotope (13)C in the fatty acid moiety. End exhalation breath was collected at intervals after intravenous injection of the remnant-like emulsions and analyzed for (13)C enrichment by isotope-ratio mass spectrometry. Compared with the group of normolipemic men, the fractional catabolic rate of remnants measured by the breath test was significantly decreased (P = 0.006) in subjects with type III dyslipidemia. In the group with type I hyperlipemia, the fractional catabolic rate was not different (P = 0.233) from the control group. Therefore, the underlying capacity for remnant catabolism was normal in this group of markedly hypertriglyceridemic subjects. By short-circuiting the step of lipolysis, the remnant-like emulsion breath test provides direct information about remnant clearance and metabolism, which should assist in investigations of postprandial lipid metabolism.

Elevated apolipoprotein B-48 and remnant-like particle-cholesterol in heterozygous familial hypercholesterolaemia.

Apolipoprotein B-48 (apoB-48) is a marker of triglyceride-rich lipoprotein (TRL) remnants of intestinal origin. Chylomicron remnants are causally related to atherosclerosis. We have shown previously that fasting plasma apoB-48 may predict postprandial lipaemia. Remnant-like particle-cholesterol (RLP-C) may also reflect TRL remnants. We aimed to determine whether subjects with heterozygous familial hypercholesterolaemia (FH) had an accumulation of remnants of intestinal origin, as reflected by fasting plasma apoB-48 and RLP-C levels. The fasting plasma concentrations of apoB-48 and RLP-C were measured in 15 subjects with heterozygous FH and 15 age- and sex-matched, normolipidaemic subjects. ApoB-48 was determined using SDS-PAGE and a western blotting/enhanced chemi-luminescence technique. RLP-C was measured using an immuno-separation assay. Serum apolipoprotein B-100 (apoB-100) levels were measured using immunonephelometry; lipids were assayed enzymatically. Compared with controls, FH subjects had significantly elevated plasma concentrations of apoB-48 (29.3 median, 16.7-45.1 mg L-1 range vs. 12.8, 7.3-28.6; P < 0.001) and RLP-C (16.2, 1.5-114.3 mg dL-1 vs. 8.5, 5.0-13.5; P = 0.003), as well as serum total apoB-100 (1.9, 1.3-2.6 g L-1 vs. 1.0, 0.3-1.3; P < 0.001), LDL-cholesterol (8.1, 4.6-10.4 mmol L-1 vs. 3.5, 2.4-4.4; P < 0.001) and triglyceride (1.5, 0.6-5.6 mmol L-1 vs. 1.0, 0.4-1.8; P = 0.018). There was no significant difference in HDL cholesterol. The findings suggest that patients with heterozygous FH have elevated plasma concentrations of TRL remnants, including those of intestinal origin. This may be a consequence of decreased clearance of these particles by the LDL-receptor.

Influence of pattern of drinking on cardiovascular disease and cardiovascular risk factors--a review.

There is an established inverse relationship between the regular light consumption of alcohol (5-10 g/day) and the incidence of coronary artery disease (CAD). This association has several biologically plausible mechanisms with dose-dependent effects of alcohol to increase HDL cholesterol, lower plasma fibrinogen and inhibit platelet aggregation. However, such a protective effect against atheroma cannot be considered in isolation from known adverse effects on blood pressure and triglycerides or possible detrimental effects of episodic or binge drinking on several other cardiovascular end-points and risk factors. In subjects with pre-existing CAD, an alcoholic binge can increase both silent myocardial ischaemia and angina. During withdrawal following binge drinking, marked fluctuations in blood pressure together with heightened platelet activation and adverse changes in the balance of fibrinolytic factors, may offer an explanation for the reported association between episodic heavy drinking and ischaemic stroke. This has been seen particularly in young males and extends further to an increase in both subarachnoid haemorrhage and intracerebral haemorrhage after binge drinking. Intervention studies in man have shown acute increases in blood pressure in men who drink predominantly at weekends, compared to longer-term pressor effects in regular daily drinkers. We have been unable, however, to reproduce the finding of unfavourable effects of binge drinking on the lipid profile that have been reported in animal studies and man. Binge drinking may also induce cerebrovascular spasm or cause both ventricular and supraventricular arrhythmias, especially atrial fibrillation. Alcohol-induced arrhythmia has been postulated as the basis for alcohol-related sudden coronary death in those subjects with pre-existing CAD. Hence, further exploration of any protective association of alcohol against CAD needs to carefully consider the implications of pattern of drinking for the relationship. The modulating influences of co-timing of drinking with meals, cigarette smoking or illicit drug use also need to be evaluated. Without such vital information, public health advice on alcohol and CAD will be limited in its scope and potentially flawed in its impact.

Fibrates, dyslipoproteinaemia and cardiovascular disease.

Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on firmer ground. The mechanism of action of fibrates on lipoprotein metabolism has recently been elucidated at the molecular level and involves the activation of peroxisome proliferator-activated receptor-alpha 1 in the liver, with the net effect of improving the plasma transport rates of several lipoproteins. Other potential anti-atherothrombotic effects include the inhibition of coagulation and enhancement of fibrinolysis, as well as the inhibition of inflammatory mediators involved in atherogenesis. These consequences probably underpin the favourable effects of fibrates seen in recent angiographic and clinical trials. Two important clinical trials on the effect of gemfibrozil (Veterans Administration-HDL-Cholesterol Intervention Trial) and bezafibrate (Bezafibrate Infarction Prevention Study) have recently been completed in subjects with elevated triglyceride, low HDL and normal or near-normal LDL-cholesterol levels. The results testify to the efficacy of these agents in decreasing the incidence of cardiovascular events, particularly in patients with multiple risk factors and plasma triglyceride levels of over 2.2 mmol/l. The findings of these trials are compared with the statin-based Air Force/Texas Coronary Atherosclerosis Prevention Study, with a recommendation that future studies in appropriately selected patients should examine the synergistic effect of the fibrate/statin combination. The absolute risk reduction in the incidence of coronary events in the Veterans Administration-HDL-Cholesterol Intervention Trial compares favourably with the statin trials. The therapeutic aspects of the efficacy and safety of fibrates are reviewed. Besides primary mixed hyperlipidaemias, particular indications for the clinical use of fibrates include type 2 diabetes, the metabolic syndrome and renal insufficiency. The St Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study has suggested that fibrates may decrease the incidence of coronary events in type 2 diabetes, but this hypothesis will be more extensively tested in the Diabetes Atherosclerosis Intervention Study, Fenofibrate in Event Lowering in Diabetes Study and Lipids in Diabetes Study projects. Although significant new knowledge has accrued over the past few years concerning the fundamental and clinical aspects of fibrates, the success of these agents in clinical practice depends on the availability of methods for assessing cardiovascular risk as well as on treatment guidelines, which as presently designed and recommended may be inaccurate and suboptimal.

Effects of beta-blockers on the concentration and oxidizability of plasma lipids.

1. beta-blockers improve morbidity and mortality after myocardial infarction, probably by several mechanisms. We investigated potentially relevant effects of beta-blockers in vivo and in vitro on plasma lipid oxidizability. Forty-two healthy men were randomized to receive placebo (13), metoprolol (14) or propranolol (15). 2. At 4 weeks, the effects on heart rate, blood pressure and lipids appeared similar and subjects taking a beta-blocker were combined. Compared with placebo, those on a beta-blocker gained 0.5 kg in weight (P = 0.04), heart rate fell from 63 to 52 beats/min (P < 0.0001) and blood pressure fell from 116/74 to 113/69 mmHg (P < 0.005); high-density lipoprotein (HDL)-cholesterol fell from 1.26 to 1.11 mmol/l (P = 0.005), there being no change in the ratio of free to esterified cholesterol in HDL, and there was an apparent rise in serum triacylglycerols from 1.18 to 1.43 mmol/l (P = 0.15 when adjusted for weight gain). Low-density lipoprotein (LDL)-cholesterol and lipoprotein (a) did not change. In this study, the oxidizability of LDL was unaffected by beta-blocker therapy. beta-blockade was not associated with any change in LDL fatty acid profile, or beta-carotene or alpha-tocopherol content which might account for the reduced LDL oxidizability previously reported in patients treated with beta-blockers. Furthermore, neither atenolol nor propranolol, at concentrations up to 100 mumol/l, had any effect on in vitro oxidizability of LDL obtained from healthy volunteers. 3. In contrast to the favourable haemodynamic effects conferred by beta-blockers, the effects on weight and serum triacylglycerols and HDL-cholesterol appear to be adverse and we did not demonstrate any changes in lipid oxidizability which might be relevant to the protective effects of beta-blockers in patients with coronary disease.

The effects of alcohol on coagulation and fibrinolytic factors: a controlled trial.

Light-to-moderate alcohol intake is associated with a reduced incidence of ischaemic cardiovascular events, whilst heavy alcohol intake can predispose individuals to stroke. Alcohol-induced changes in coagulation and fibrinolysis may be relevant and are the subject of this controlled trial of varying alcohol intake in 55 predominantly beer-drinking men. Following 4 weeks stabilization maintaining usual drinking habits, participants were randomized to either continue usual alcohol intake or to restrict alcohol by changing to low alcohol beer for 4 weeks. In a final 4 week period, they crossed over to low or usual alcohol intake, respectively. Comparing combined low and usual alcohol periods, an increase in mean weekly alcohol intake from 92 to 410 ml (mean daily intake from 13 to 58 ml) was associated with a decrease in plasma fibrinogen (by 11%, P < 0.001) and platelet count (3%, P < 0.05), but increases in factor VII (7%, P = 0.001), tissue plasminogen activator (tPA; 16%, P = 0.01) and plasminogen activator inhibitor-1 (PAI-1; 21%, P < 0.001). The ratio, tPA/PAI-1, fell from 0.50 to 0.44 (P = 0.02) confirming the relatively greater increase in PAI-1 with alcohol consumption. Two lipid-associated natural anticoagulants, tissue factor pathway inhibitor and beta 2-glycoprotein-I, did not change. The substantial reduction in plasma fibrinogen with alcohol intake may well contribute to the apparent protection alcohol confers against ischaemic coronary and cerebral events. The increase in factor VII and relatively greater increase in PAI-1 than tPA with alcohol intake may attenuate this benefit and indeed may sufficiently predispose individuals to thrombosis to contribute to the increased incidence of ischaemic stroke seen in heavier drinkers. The balance of anticoagulant and procoagulant and fibrinolytic effects in any individual may vary depending on quantity and type of alcoholic beverage ingested, as well as on genetic and other variables, all of which merit further study.

A controlled trial of the effects of pattern of alcohol intake on serum lipid levels in regular drinkers.

To determine whether the effects of drinking pattern (predominantly weekend versus daily drinking) have differential effects on serum lipids, 55 healthy male drinkers were recruited on the basis of a regular alcohol intake, 210-500 ml absolute alcohol/week (approximately 3-6 standard drinks/day), with more than 60% consumed as beer. Fourteen subjects were categorised as predominantly weekend drinkers, while 41 subjects regularly drank on a daily basis. After maintenance of their drinking pattern during a 4-week familiarisation, subjects were randomised to either consume low alcohol beer (0.9%, v/v) only, or to maintain their usual drinking habit consuming full-strength beer (5%, v/v) for the next 4 weeks. They then switched to full-strength or low alcohol beer, respectively, for a further 4 weeks. Their drinking pattern remained constant during the study. In both weekend and daily drinkers, a reduction in alcohol intake (i.e. from 387 ml/week to 88 ml/week for weekend drinkers and from 418 ml/week to 95 ml/week for daily drinkers, respectively, P < 0.001) resulted in a similar 0.12 mmol/l fall in HDL-C (P < 0.01) with a concomitant significant fall in both apolipoproteins A-I and A-II. In daily drinkers total cholesterol fell by 0.28 mmol/l (P < 0.001) and triglyceride by 0.22 mmol/l (P < 0.01) with a reduction in alcohol intake, but no change in LDL-C was seen. In contrast, weekend drinkers total cholesterol was unchanged while triglyceride decreased by 0.26 mmol/l (P < 0.05) and LDL-C increased by 0.25 mmol/l (P < 0.01). Lp(a) increased with a reduction in alcohol intake in both daily (9.1 U/l, P < 0.05) and weekend drinkers (27.6 U/l, P = 0.07). Previous reports of a more atherogenic lipid profile with episodic versus regular daily drinking were not confirmed in this study and potentially favourable effects of alcohol to increase HDL-C and decrease Lp(a) were shown to be independent of drinking pattern in these moderate to heavy drinkers.

Influence of pattern of alcohol intake on blood pressure in regular drinkers: a controlled trial.

OBJECTIVE: To evaluate the effects of patterns of drinking (weekend versus daily drinking) on the pressor responses to alcohol in 55 male drinkers using clinic and 24 h ambulatory blood pressure monitoring. DESIGN: A randomized, controlled cross-over trial. METHODS: Recruitment required a regular alcohol intake of 210-500 ml absolute alcohol/week, with > 60% consumed as beer. Fourteen subjects were categorized as predominantly weekend drinkers, whereas the remaining 41 subjects regularly drank on a daily basis. After 4 weeks of familiarization, all subjects were randomly allocated to drinking low-alcohol beer (0.9% vol:vol) only or to maintain their usual drinking habits with provision of full-strength beer (5% vol:vol) for 4 weeks. They then switched back to their usual drinking habits or low-alcohol beer, respectively, for a further 4 weeks while maintaining their usual drinking pattern. RESULTS: Baseline ambulatory systolic blood pressure in weekend but not in daily drinkers was 2.4 mmHg higher on Monday than it was on Thursday (P = 0.02). This Monday-Thursday difference was lost during intervention. When subjects switched from the high-alcohol to the low-alcohol period the falls in ambulatory systolic blood pressure in weekend (3.1 mmHg, P < 0.001) and daily drinkers (2.2 mmHg, P < 0.001) were similar. Most of the fall was evident during week 1 of the low-alcohol period for weekend drinkers but not until week 4 for daily drinkers. CONCLUSION: The pressor response to alcohol consumption is similar in magnitude in weekend and daily drinkers, present throughout a 24 h period and has a rapid onset/offset in weekend drinkers but is more sustained in daily drinkers.

Carbohydrate-deficient transferrin as a marker of change in alcohol intake in men drinking 20 to 60 g of alcohol per day.

We evaluated carbohydrate-deficient transferrin (CDT) and gamma-glutamyltranspeptidase (gamma-GT) as markers of alcohol intake and change in alcohol intake in white Australian men aged 20 to 63 years who regularly drank 20 to 60 g of alcohol/day (2 to 6 standard drinks), either as weekend (n = 14) or daily drinkers (n = 41). After 4 weeks of familiarization on usual alcohol intake, men were provided with low alcohol beer (24 x 375 ml cans, 0.9%, v/v, two-weekly), and, for 4 weeks, consumed as much or as little as they wished with no additional alcohol permitted. In an alternate 4-week period, the same amount of full-strength beer (4.9%, v/v) was provided, whereas subjects continued their usual amount and pattern of alcohol consumption. The order of experimental conditions was randomized. Retrospective 7-day diaries documented weekly alcohol intake during 4 weeks of familiarization and 8 weeks of intervention. Mean alcohol intake was 345 g/week of alcohol (SD 97) during familiarization. During the last 4 weeks of intervention (study weeks 8 to 12), mean alcohol intake either increased by 360 g/week (SD 138) with the switch from low to high alcohol or decreased by 328 g/week (SD 120) with the reverse. During familiarization (study weeks 1 to 4), alcohol intake was significantly related independently (R2 = 0.21) to mean corpuscular volume (p = 0.008) and uric acid (p = 0.003), but not to gamma-GT (p = 0.22) nor CDT (p = 0.94). Change in alcohol intake was predicted independently (R2 = 0.60) by change in CDT (p < 0.0001) and gamma-GT (p = 0.0003), but not by change in uric acid or mean corpuscular volume. A 10% change in CDT gave 70% sensitivity and 80% specificity to detect a change of at least 2 standard drinks/day; respective values were 68% and 0 for 10% change in gamma-GT. Results were not related to drinking pattern, smoking, age, or weight. CDT, particularly when used as a continuous variable, may have a place in monitoring alcohol consumption, even in men whose alcohol intake is in the 20 to 60 g/day range.

Oxidative susceptibility of low-density lipoproteins--influence of regular alcohol use.

In population studies, a low-to-moderate intake of alcohol has been consistently linked to a lower risk of coronary artery disease. The recent suggestion that alcoholic beverages may be conferring this decrease in risk because they contain antioxidant phenolic compounds that reduce the oxidizability of low-density lipoprotein (LDL) has to be reconciled with the possible counteracting influence of a pro-oxidant effect of alcohol. In a controlled crossover study, we have now measured the oxidizability of LDL in 27 regular beer drinkers during consecutive 4-week periods, wherein they consumed a high versus low alcohol beer (4.9 vs. 0.9% alcohol v/v, respectively), with the two beers being similar in phenolic content. This resulted in a decrease in alcohol consumption by approximately 80% (408 +/- 25 ml/week vs. 75 +/- 11 ml/week). During the low alcohol period, there was no change in LDL vitamin E or its cholesterol or protein content. Analysis of LDL oxidation kinetics revealed an increase in oxidizability during the high alcohol phase. This was despite a decrease in arachidonic acid content of LDL and a corresponding increase in palmitic acid during high alcohol intake--a change in fatty acid composition that has the potential to favor a decrease in oxidizability. Our results suggest that alcohol ingestion increases LDL oxidation, despite reducing the polyunsaturated fatty acid composition. The overall effect of alcoholic beverages on LDL oxidation may be a balance between the pro-oxidant and antioxidant activity of its various constituents. The predominant pro-oxidant effect demonstrated in these beer drinkers, although not relevant to any potential decrease in coronary artery disease, may be important in the pathogenesis of alcohol-related disease in other organ systems.

Serum HDL cholesterol: should it be routinely measured?

HDL cholesterol is only one of many risk factors which can be used to predict coronary disease events, and the relationship between the benefits of lipid-lowering strategies and changes in HDL levels is, at present quite unclear.

Recent insights into dietary fats and cardiovascular disease.

1. Fat deposition in the arterial intima is fundamental to the atheroma process. Circulating lipoproteins are thought to be the source of much of the deposited fat. The interplay of dietary fat has not been fully clarified. 2. Observational studies have furnished evidence of relationships between the different dietary fats and clinical cardiovascular events. In these, total fat and in particular, saturated fat appear culprit. Mono-unsaturated (MUFA) and poly-unsaturated (PUFA) fats have less consistent relationships with cardiovascular disease, though all classes of fatty acid are found in atheroma. 3. Comparing the effects on lipoproteins of saturates, mono-unsaturates and polyunsaturates, they all increase high density lipoproteins (HDL) and reduce triglycerides when substituted isocalorically for carbohydrate. Saturates increase low density lipoproteins (LDL), while PUFA > MUFA reduce LDL. 4. Upon oxidative modification, lipoproteins are more liable to arterial deposition and, in vitro at least, LDL oxidizability is enhanced by enrichment with PUFA. 5. Trans-MUFA have some unique properties in that they somewhat resemble saturates and seem to predispose to coronary disease, quite possibly because of their adverse effects on LDL, HDL and Lp(a) levels. 6. omega-3 fatty acids seem unique among the dietary fats in that they inhibit thrombosis and platelet aggregation, and can lower blood pressure. 7. The net effect of these various potential influences of fatty acids on atherogenesis in vivo is unclear. It may well be that all fats, with the exception of the omega-3 class, are detrimental with response to atherogenesis. Modification of the diet, with particular attention to fat, has been demonstrated to reduce clinical coronary events in several studies.(ABSTRACT TRUNCATED AT 250 WORDS)