Coronary heart disease mortality in treated familial hypercholesterolaemia: Update of the UK Simon Broome FH register.

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. METHODS: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). RESULTS: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%-76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post-2008, while in women the corresponding values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29-2.08)), although in women the excess persisted (post-2008 3.65 (1.75-6.72)). CONCLUSIONS: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately.

Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA): a randomized double-blind placebo-controlled trial of high- vs. low-dose atorvastatin(1).

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.

All-cause and cardiovascular mortality in treated patients with severe hypertriglyceridaemia: A long-term prospective registry study.

OBJECTIVE: To examine all-cause and cardiovascular mortality in patients with severe hypertriglyceridaemia. METHODS: 337 patients aged less than 80 years (47 with diabetes, 75 women) with a fasting triglyceride concentration on at least two occasions of >5.0mmol/l were registered by 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2008 for 4353 person-years. The standardised mortality ratio (SMR) was calculated by comparison with the general population. RESULTS: The mean untreated total cholesterol concentration was 9.8 (SD 3.6)mmol/l for men and 11.9 (7.2)mmol/l for women and the corresponding geometric mean triglyceride concentration was 12.6 (inter-quartile range 7.3, 21.6) and 15.7 (8.2, 29.2)mmol/l. There were 70 deaths, including 35 from CHD and 7 from stroke. The SMR for CHD was raised at 327 (95% confidence intervals 228, 455; p<0.0001) and remained elevated after excluding patients with diabetes at registration (SMR=287, 95% CI 190, 419; p<0.0001), and after excluding patients with CHD at registration (SMR=259, 95% CI 158, 400; p=0.0003). The increased SMR was most marked in younger men aged 40-59 years (SMR=544, 95% CI 304, 897; p<0.0001). The SMR for stroke for patients aged 20-79 years was raised at 262 (95% CI 105, 540; p=0.04), as was all-cause mortality at 164 (95% CI 129, 208; p<0.001). CONCLUSION: Severe hypertriglyceridaemia is associated with a substantially increased mortality from cardiovascular disease, even in the absence of diabetes. In addition to lowering triglyceride concentrations to reduce the risk of pancreatitis, treatment should aim to reduce the overall cardiovascular risk.

Triglycerides and small dense low density lipoprotein in the discrimination of coronary heart disease risk in South Asian populations.

INTRODUCTION: Coronary heart disease (CHD) is exceptionally prevalent amongst globally dispersed migrant groups originating from the Indian subcontinent, but the contribution of dyslipidaemia to their increased risk remains poorly defined. METHODS: Fasting lipids and lipoproteins, apolipoproteins (Apo), low density lipoprotein (LDL) diameter and oxidised LDL were measured amongst rural Indians in India (n=294) and their migrant contemporaries in the UK (n=242). The performance of qualitative and quantitative measures of lipid metabolism were compared in the discrimination of WHO defined metabolic risk and raised Framingham CHD risk scores (>15%) using Receiver Operating Characteristic (ROC) curves. RESULTS: LDL diameter was correlated with triglycerides (R(2)=0.12, P<0.001) and with high density lipoprotein (HDL) cholesterol levels (R(2)=0.15, P<0.001) in both groups. Migrants had less small dense LDL (95% CI: 12.5-14.2%) vs. rural Indians (15.7-17.2, P<0.05). On ROC analysis, triglycerides were the only consistent discriminators of metabolic and CHD risk scores (all P< or =0.001). Apo B was also a strong indicator of raised CHD risk scores. Irrespective of site, individuals with raised triglycerides also had higher total cholesterol and Apo B, denser LDL, lower HDL and more oxidised LDL (all P< or =0.01). DISCUSSION: Fasting triglycerides reflect both qualitative and quantitative aspects of lipid metabolism, and are a comprehensive discriminator of CHD risk in this South Asian population.

Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo. RESULTS: In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of -18.58%, (95% CI: -19.67 to -17.48, P < 0.00001) compared with placebo. Significant (P < 0.00001) changes were also found in total cholesterol (-13.46%, 95% CI: -14.22 to -12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (-8.06%, 95% CI: -10.92 to -5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo. CONCLUSIONS: In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.

Apolipoproteins, cardiovascular risk and statin response in type 2 diabetes: the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: Controversy surrounds whether the ratio of apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) is the best lipoprotein discriminator of CHD risk in non-diabetic populations, but the issue has never been investigated in type 2 diabetes. METHODS: In 2,627 participants without known vascular disease in the Collaborative Atorvastatin Diabetes Study, ApoB, ApoA-I, LDL-cholesterol (LDLC) and HDL-cholesterol (HDLC) were assayed at baseline. RESULTS: There were 108 CHD and 59 stroke endpoints over 3.9 years. The ApoB:A-I ratio at baseline was the lipoprotein variable most closely predicting CHD risk both by comparison of the hazard ratio for a 1 SD change or tertiles of frequency distribution. The areas under the receiver-operator curve for the ApoB:ApoA-I and the LDLC to HDLC [corrected] ratios, although not significantly different from each other, were greater (p = 0.0005 and p = 0.0125 respectively) than that of non-HDLC:HDLC. The 27% decrease in the ApoB:ApoA-I ratio on atorvastatin predicted a 32% (95% CI 5.4-51.2%) risk reduction in CHD, close to the 36% decrease observed. Neither the ApoB:ApoA-I nor any other lipoprotein concentration or ratio predicted the stroke outcome. CONCLUSIONS/INTERPRETATION: Overall, the ApoB:ApoA-I ratio improved on the non-HDLC:HDLC ratio in predicting CHD, but, depending on the assessment chosen, its superiority over LDLC:HDLC may be marginal. The statin-induced decrease in stroke risk may not be lipoprotein mediated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327418. FUNDING: The study was supported by unrestricted grants from Diabetes UK, the Department of Health and Pfizer to the University of Manchester and to University College, London.

Estimated 10-year cardiovascular risk in a British population: results of a national screening project.

OBJECTIVE: To estimate 10-year cardiovascular disease (CVD) risk using the risk equation and risk categories of the Joint British Societies' Guidelines on Prevention of Cardiovascular Disease in Clinical Practice (2005). METHODS: A cross-sectional CVD screening programme was conducted in 35 towns in Great Britain. In total, 27,776 men and 43,261 women aged at least 18 years were screened. The estimated 10-year risk of CVD was calculated and directly standardised to the population of Great Britain. RESULTS: The age standardised combined prevalence of known CVD, diabetes, lipid-lowering or antihypertensive drug therapy, which preclude multifactorial risk assessment, was 18.0% for men and 18.1% for women. CVD risk was calculated for 56,863 individuals, and the age-standardised prevalence of an estimated 10-year CVD risk < 10% was 42.7% (95% CI: 42.2-43.1) for men and 60.4% (95% CI: 60.1-60.7) for women; 10% to < 20% was 19.6% (19.1-20.6) and 15.6% (15.2-15.9); and > or = 20% was 19.6% (19.1-20.0) and 6.0% (5.8-6.2) respectively. After aggregating known CVD, diabetes, antihypertensive or lipid-lowering drug therapy, or an estimated CVD risk of > or = 20%, the combined standardised prevalence of high CVD risk for individuals aged 50 years or more was 74.1% (73.5-74.8) for men (n = 14,787) and 45.5% (44.8-46.2) for women (n = 24,400). CONCLUSIONS: Using current risk thresholds, there is a substantial unmet need for primary prevention of CVD, particularly among middle-aged men. The results emphasise the scale of intervention that a strategy of individual risk assessment and pharmacological intervention requires.

Human cholesterol metabolism and therapeutic molecules.

There has been a fascinating interplay between the discovery of some of the key enzymes, receptors and transporters in cholesterol biosynthesis and transfer and the development of drugs for the regulation of cholesterol metabolism. The discovery of the low-density lipoprotein (LDL) receptor led to the realization that circulating LDL cholesterol could be decreased when hepatic LDL receptor expression was stimulated by decreasing intrahepatic cholesterol levels. The first class of drugs which operate in this way were the bile-acid sequestrating agents, which, by interrupting the enterohepatic circulation of bile acids, deplete the liver of cholesterol used to replenish the pool of bile salts. Ezetimibe, which was developed to block cholesterol absorption from the intestine, led to the discovery of the Nieman-Pick C1-Like 1 sterol transporter channel. The statins, which have proved enormously successful in preventing cardiovascular disease, were discovered amongst fungal metabolites which inhibit hydroxyl methyl CoA reductase, the rate-limiting enzyme for hepatic cholesterol biosynthesis. Drugs which block enzymes at other stages of the cholesterol biosynthetic pathway, particularly the squalene synthase inhibitors, are entering the clinical phase of their development. Drugs which interfere with hepatic very low-density lipoprotein assembly in the liver, such as microsomal triglyceride transfer protein inhibitors and apolipoprotein B mRNA antisense oligonucleotides, are currently undergoing evaluation. Cholesteryl ester transfer protein (CETP) inhibitors, which decrease cholesteryl ester heteroexchange within the circulation, have undergone development to the point of clinical evaluation, and this will eventually settle the controversy about whether CETP is pro- or antiatherogenic.

Ethnic differences in myocardial infarction in patients with hypertension: effects of diabetes mellitus.

BACKGROUND: It has been reported that hypertension carries a greater risk of myocardial infarction (MI) in South Asians living in the UK than in the indigenous British population. This has been attributed to some specifically Asian susceptibility factor. DESIGN: Using a longitudinal approach, we investigated the relationship between coronary heart disease (CHD) risk factors amongst hypertension patients attending Sandwell and City Hospitals, and the onset of cardiovascular events over a 5-year follow-up period. RESULTS: A total of 350 Caucasian (83.7% male) and 104 South Asian (66.3% male) patients with hypertension [age 63.7 (7.6) years and 57.1 (11.1) years respectively, P < 0.001] were followed-up for a mean (SD) period of 64.7(12.1) months. There were 11 (6.4/1000 patient years) cases of MI in Caucasian patients vs. 11 (17.8/1000 patient years) in South Asians, with event-free survival times being significantly lower amongst South Asians (log-rank test P = 0.04). The prevalence of diabetes mellitus was 22.9% higher amongst South Asians (P < 0.001), whilst mean serum cholesterol and fasting triglyceride levels were higher amongst Caucasians (P = 0.001). There were no ethnic differences in HDL cholesterol concentrations, the use of tobacco, statin therapy or anti-platelet therapies (all P = NS), or in composite endpoint (MI, angina, peripheral vascular disease, stroke, revascularization or death; P = 0.74). On Cox regression analysis of all independent cardiovascular risk variables, associated treatments and ethnicity, MI risk was associated with diabetes mellitus (odds ratio 3.77, 95%CI 1.55-9.15, P = 0.003) but not ethnicity per se (P = 0.26). CONCLUSION: Increased risk of MI in hypertensive South Asians in the United Kingdom appears to be the result of a higher prevalence of diabetes mellitus. Further work is required to understand the pathophysiological basis with which diabetes increases CHD risk in this ethnic group.

Stroke prediction and stroke prevention with atorvastatin in the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS: Patients with Type 2 diabetes have an elevated risk of stroke. The role of lipid levels and diabetes-specific factors in risk prediction of stroke is unclear, and estimates of efficacy of lipid-lowering therapy vary between trials. We examined predictors of stroke and the effect of atorvastatin on specific stroke subtypes in Type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) [a trial of 2838 participants with mean low-density lipoprotein cholesterol < 4.14 mmol/l, no history of macrovascular disease and randomized to atorvastatin 10 mg daily or placebo]. METHODS: Median follow-up was 3.9 years. Cox regression models were used to estimate the effect of atorvastatin on stroke rate and risk of stroke associated with baseline risk factors. Risk factors that predicted stroke in univariate models were examined in a multivariable model. RESULTS: Independent risk factors predicting stroke were age [10-year increments; hazard ratio (HR) 2.3, P < 0.001], microalbuminuria (albumin : creatinine ratio > 2.5 mg/mmol; HR 2.0, P = 0.007) and glycaemic control (HbA(1c) > 10%; HR 2.7, P = 0.007). Women were at lower risk of stroke (HR 0.3, P = 0.004). Lipids did not predict stroke. Of 60 first strokes, 47 were non-haemorrhagic, 13 were indeterminate and none was definitely haemorrhagic. Atorvastatin treatment was associated with 50% reduction in non-haemorrhagic stroke (95% confidence interval 9%-72%P = 0.024), similar to the 48% reduction (11%-69%) for all strokes combined. CONCLUSIONS: Diabetes-specific risk factors are important predictors of stroke in Type 2 diabetes. Despite the lack of association between baseline lipids and first stroke, there was a reduction of 50% of non-haemorrhagic strokes associated with atorvastatin treatment in the CARDS population.

Cost-effectiveness of primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes: results from the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: We estimated the cost-effectiveness of atorvastatin treatment in the primary prevention of cardiovascular disease in patients with type 2 diabetes using data from the Collaborative Atorvastatin Diabetes Study (CARDS). SUBJECTS AND METHODS: A total of 2,838 patients, who were aged 40 to 75 years and had type 2 diabetes without a documented history of cardiovascular disease and without elevated LDL-cholesterol, were recruited from 32 centres in the UK and Ireland and randomly allocated to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). These subjects were followed-up for a median period of 3.9 years. Direct treatment costs and effectiveness were analysed to provide estimates of cost per endpoint-free year over the trial period for alternative definitions of endpoint, and of cost per life-year gained and cost per quality-adjusted life-year (QALY) gained over a patient's lifetime. RESULTS: Over the trial period, the incremental cost-effectiveness ratio (ICER) was estimated to be 7,608 pounds per year free of any CARDS primary endpoint; the ICER was calculated to be 4,896 pounds per year free of any cardiovascular endpoint and 4,120 pounds per year free of any study endpoint. Over lifetime, the incremental cost per life-year gained was 5,107 pounds and the cost per QALY was 6,471 pounds (costs and benefits both discounted at 3.5%). CONCLUSIONS/INTERPRETATION: Primary prevention of cardiovascular disease with atorvastatin is a cost-effective intervention in patients with type 2 diabetes, with the ICER for this intervention falling within the current acceptance threshold ( 20,000 pounds per QALY) specified by the National Institute for Health and Clinical Excellence (NICE).

Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.

AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. PATIENTS AND METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.

American, British and European recommendations for statins in the primary prevention of cardiovascular disease applied to British men studied prospectively.

OBJECTIVE: To compare national and international recommendations for statin treatment in the primary prevention of cardiovascular disease (CVD) in middle-aged men. DESIGN: Application of the current American, British and European recommendations to results of a prospective study. PARTICIPANTS: Men aged 49-65 years (n = 1653) who participated in the Caerphilly Prospective Study. MAIN OUTCOME MEASURES: Proportion of patients who would receive statin treatment, the number needed to treat (NNT) to prevent one first CVD event (myocardial infarction or stroke) over 10 years and the potential number of events prevented over 10 years in the whole population (population impact) by the use of statins in accordance with each set of guidelines, assuming a reduction of risk in the range 10-50% from the observed events and baseline risk factors. RESULTS: 212 events were noted. For an anticipated reduction in first CVD events of 30% with statin treatment, the NNT was 26.0, if the whole population was treated. The lowest NNT was 12.1 for the National Service Framework, achieved when only 14% of the men received a statin. This prevented the lowest number of events (19.2/212), however, and had the smallest population impact on CVD incidence (-9.1%). The American and earlier Joint British Societies guidelines, although giving NNTs of around 21, prevented more events and had a greater population impact of -21.6% to -23.3%. They did, however, target about 60% of the male population. The British Hypertension Society guidelines and new Joint British Societies recommendations achieved the greatest population impact of -27% while maintaining the NNT at 22.2. They did, however, target three quarters of this population. CONCLUSION: Even effective preventive treatment will have little impact in preventing disease if patients at typical risk are not treated. Whether cholesterol lowering on such a scale should be attempted with drugs raises philosophical, psychological and economic considerations, particularly in view of the high likelihood of individual benefit from statin treatment. More effective nutritional policies to reduce serum cholesterol on a population level and reduce the requirement for statins in primary prevention should also be considered.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Impact of migration on coronary heart disease risk factors: comparison of Gujaratis in Britain and their contemporaries in villages of origin in India.

The causes of the excess coronary heart disease (CHD) risk in South Asian migrants from the Indian subcontinent remain unclear. Comparisons of CHD risk factors amongst South Asian migrants living in Britain with those of the general UK population provide only a partial explanation. We compared Gujaratis in Britain with similar, non-migrant Gujaratis in India, to test the hypothesis that differences in CHD risk factors associated with migration would be more informative. Randomly sampled Gujaratis aged 25-79 years living in Sandwell (n = 242) were compared with age-, gender- and caste-matched contemporaries remaining in their villages of origin in Navsari, India (n = 295). Lifestyle indices, food intake and physical activity, were assessed with standardised questionnaires and energy expenditure and metabolic parameters measured. British Gujaratis had higher, mean body mass indices by 6 (4.5-7.4) kg/m(2) mean (95% CI), and greater dietary energy intake, fat intake, blood pressure, fasting serum cholesterol, apolipoprotein B, triglycerides, non-esterified fatty acid (NEFA) and C-reative protein concentrations than Gujaratis in India. Dietary folate and serum folate and Vitamin B(12) were lower and plasma homocysteine was higher in India. Smoking was less prevalent and high-density lipoprotein cholesterol tended to be higher in Britain. Diabetes prevalence was high in both populations and impaired fasting or 2 h post-glucose challenge plasma glucose was even more prevalent in Gujarat. In India, however, where insulin secretion and NEFA were lower diabetes and impaired glucose tolerance were less frequently accompanied by excess metabolic CVD risk factors. In conclusion, exposure to increased fat intake and obesity related to migration is likely to explain the disproportionate combination of established and emerging CHD risk factors prevalent in Gujaratis in Britain. Strategies to improve nutrition and to identify and treat cardiovascular risk factors such as dyslipidaemia and hypertension are urgently required.

Familial hypercholesterolaemia commonly presents with Achilles tenosynovitis.

BACKGROUND: Patients with heterozygous familial hypercholesterolaemia (HeFH) develop tendon xanthomata (TX), most commonly in their Achilles tendons. Even before tendons are chronically enlarged, tenosynovitis may occur and medical advice be sought. Untreated HeFH carries a high risk of premature coronary heart disease, which can be ameliorated by early diagnosis. OBJECTIVE: To determine the prevalence of episodes of Achilles tendon pain in HeFH before its diagnosis. METHODS: Patients with definite HeFH (Simon Broome criteria) attending a lipid clinic were identified. They completed a questionnaire asking about symptoms relating to their Achilles tendons. Unaffected spouses or cohabiting partners served as controls. RESULTS: 133 patients (47% men) and 87 controls (51% men) participated. TX had been recognised by the referring physicians in <5% of cases. However, 62 (46.6% (95% confidence interval (CI) 38.1 to 55.1)) patients had experienced one or more episodes of pain in one or both Achilles tendons lasting >3 days, whereas only 6 (6.9% (1.6 to 12.2)) controls had done so (difference p<0.001; likelihood ratio 6.75). Typically, in the patients with HeFH the pain lasted 4 days (median). It was described as severe or very severe in 24/62 (38.7% (30.4 to 47.0)) patients with HeFH, but never more than moderate in controls. 35 (26.3% (18.8 to 33.8)) patients with HeFH had consulted a doctor about Achilles tendon pain, but in no case had this led to a diagnosis of HeFH. None of the controls had consulted a doctor. CONCLUSIONS: Measurement of serum cholesterol in patients presenting with painful Achilles tendon could lead to early diagnosis of HeFH.

Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: The aim of this study was to determine the pattern of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin on cardiovascular events in patients with type 2 diabetes and no prior history of cardiovascular disease (CVD). MATERIALS AND METHODS: A post hoc analysis of data from the Collaborative Atorvastatin Diabetes Study (CARDS), a randomised, placebo-controlled trial of 2,838 patients with type 2 diabetes, was performed. Patients received atorvastatin (10 mg daily) or placebo and were evaluated for cardiovascular and other outcomes over a median follow-up period of 3.9 years. Cox proportional hazards modelling was carried out, and the hazard ratios calculated for various times after randomisation to treatment were investigated. RESULTS: A reduction in the primary endpoint of major CVD events was apparent and statistically significant as soon as 18 months after treatment initiation. The effect of atorvastatin on CHD events was apparent by 6 months, and at 1 year was similar to the 37% relative risk reduction observed at trial closure. CONCLUSIONS/INTERPRETATION: Atorvastatin alters the pathogenesis of CVD rapidly, such that the effect on cardiovascular events is apparent within months of initiation of therapy.

Paraoxonase polymorphisms and self-reported chronic ill-health in farmers dipping sheep.

BACKGROUND: Serum paraoxonase (PON1) provides protection against organophosphate induced toxicity. Recently we reported that the frequency of paraoxonase polymorphisms in sheep dippers with self-reported chronic ill-health differed from that in dippers with a similar dipping history but no ill-health. As these analyses may have included subjects with conditions unrelated to organophosphate exposure, the aim of this study was to examine whether the risk associated with PON1 polymorphisms varied using a more homogenous case and referent population. METHODS: Each subject completed a detailed symptom questionnaire and their general practitioner was asked whether there was any history of neurological disease that could be confused with the effects of organophosphate poisoning. Subjects were then excluded both on clinical grounds and where identified as atypical on discriminant analysis. RESULTS: Risk associated with the PON1 192 and 55 genotypes altered little with these changes in the population. CONCLUSIONS: These findings are consistent with the hypothesis that organophosphates contribute to the self-reported ill-health of sheep dippers.