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.

Impact of atorvastatin and omega-3 ethyl esters 90 on plasma plant sterol concentrations and cholesterol synthesis in type 2 diabetes: a randomised placebo controlled factorial trial.

OBJECTIVE: To determine the effects of statin treatment and omega-3 polyunsaturated fatty acid supplementation on plasma plant sterol concentrations and cholesterol synthesis in patients with type 2 diabetes. METHODS: Plant sterol concentrations and lanosterol (a marker of cholesterol synthesis) were measured using a high sensitivity assay to assess the effect of double-blind daily treatment for 4 months with atorvastatin 20mg or placebo and, in a 2 × 2 factorial design, omega-3 ethyl esters 90 2g or placebo. RESULTS: 658 patients were included in a per protocol analysis. The 4 treatment groups had similar mean [SD] age (63.5 years [11.7]), HbA(1c) (6.9% [1.1]) and diabetes duration (median 4 years [inter-quartile range 2, 8]). Atorvastatin treatment alone reduced low density lipoprotein (LDL) cholesterol by 1.4 mmol/l (44%, p<0.001), triglycerides by 0.3 mmol/l (20%, p<0.0001) and lanosterol by 0.36 µmol/l (72%, p<0.001). There was no significant placebo adjusted change in median [95% confidence intervals] total plant sterol concentrations (-0.77 µmol/l [inter-quartile range -2.13, 0.59]), although they were increased significantly with omega-3-acid EE90 treatment (3.23 µmol/l [1.28, 5.17]). There was a 27% smaller reduction in LDL cholesterol with atorvastatin treatment in low cholesterol synthesisers with high absorption, defined by changes at or above the median lanosterol and campesterol levels, respectively, compared with the obverse group (difference 0.42 mmol/l [0.21, 0.62]). CONCLUSION: Treatment with atorvastatin in type 2 diabetes did not change median total plasma plant sterol concentrations, but LDL cholesterol was reduced most efficaciously in high cholesterol synthesisers with low intestinal cholesterol absorption. CLINICAL TRIAL REGISTRATION INFORMATION: Current controlled trials number ISRCTN: 76737502 (http://isrctn.org).

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.

Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients.

AIMS: Current screening methods, such as single strand conformational polymorphism (SSCP) and denaturing high performance liquid chromatography (dHPLC) that are used for detecting mutations in familial hypercholesterolaemia (FH) subjects are time consuming, costly and only 80-90% sensitive. Here we have tested high-resolution melt (HRM) analysis for mutation detection using the Rotor-Gene(6000) realtime rotary analyser. Methods and subjects Polymerase chain reaction and melt conditions (HRM) for 23 fragments of the LDL-receptor gene, a region of exon 26 in the APOB gene (including p.R3527Q) and exon 7 of the PCSK9 gene (including p.D374Y) were optimized. Two double stranded DNA saturating dyes, LC-Green and Syto9, were compared for sensitivity. Eighty-two samples with known mutations were used as positive controls. Twenty-eight Greek FH heterozygous patients and two homozygous patients from the UK and Croatia were screened. RESULTS: HRM was able to identify all the positive control mutations tested, with similar results with either dye. Eight different variations were found in 17 of the 28 Greek FH patients for an overall detection rate of 61%: c.41delT (1), p.W165X (1), p.C173R (3), p.S286R (2), p.V429M (4), p.G549D (4), p.V613I (1), and a previously unreported mutation p.F694V (1) which is predicted to be FH-causing by functional algorithms. Mutations were found in both the homozygous patients; p.Q92X (Croatia) and p.Y489C (UK); both patients were homozygous for their respective mutations. CONCLUSIONS: HRM is a sensitive, robust technique that could significantly reduce the time and cost of screening for mutations in a clinical setting.

Cost-effectiveness analysis of the use of a high-intensity statin compared to a low-intensity statin in the management of patients with familial hypercholesterolaemia.

OBJECTIVES: To estimate, using probabilistic decision-analytic modelling techniques, the cost effectiveness of treating familial hypercholesterolaemia (FH) patients with high-intensity statins compared to treatment with low-intensity statins. For the purpose of this economic analysis, and based on their known differences, statins were categorised as high intensity if they produce greater LDL-cholesterol reductions than simvastatin 40 mg (e.g., simvastatin 80 mg and appropriate doses of atorvastatin and rosuvastatin or combination of statins + ezetimibe). METHODS: A lifetime Markov model was developed to estimate the incremental cost per quality adjusted life year (QALY) of treating a hypothetical cohort of 1000 FH patients aged between 20 and 70 years. Baseline coronary heart disease risks reported in the NICE TA 94 on statins, and age-adjusted risk of cardiovascular disease reported in the FH population, were used to populate the model. A meta-analysis estimate of the reduction in cardiovascular events from using high-intensity compared with low-intensity statins was obtained from published trials. Results were interpreted using a cost-effectiveness threshold of pound20 000/QALY. RESULTS: Fewer cardiovascular events and deaths were predicted to occur in the group treated with higher-intensity statins, and the incremental cost-effectiveness ratio (ICER) was estimated at pound11 103/QALY. The ICER remained below the pound20 000 threshold for 20-39-year-olds and 40-59-year-olds, but rose above this threshold in individuals aged over 60 years. One-way sensitivity analysis showed that results were most sensitive to variation in treatment effect on mortality and the cost of high-intensity statins. CONCLUSIONS: Modelling demonstrates that high-intensity statins are cost-effective for the treatment of younger FH patients. If, as is likely, the relative price of high-intensity statins fall in the future as they come off patent, then their cost effectiveness will improve further.

Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

OBJECTIVES: To determine whether self-monitoring of blood glucose (SMBG), either alone or with additional instruction in incorporating the results into self-care, is more effective than usual care in improving glycaemic control in non-insulin-treated diabetes. DESIGN: An open, parallel group randomised controlled trial. SETTING: 24 general practices in Oxfordshire and 24 in South Yorkshire, UK. PARTICIPANTS: Patients with non-insulin-treated type 2 diabetes, aged > or = 25 years and with glycosylated haemoglobin (HbA1c) > or = 6.2%. INTERVENTIONS: A total of 453 patients were individually randomised to one of: (1) standardised usual care with 3-monthly HbA1c (control, n = 152); (2) blood glucose self-testing with patient training focused on clinician interpretation of results in addition to usual care (less intensive self-monitoring, n = 150); (3) SMBG with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (more intensive self-monitoring, n = 151). MAIN OUTCOME MEASURES: The primary outcome was HBA1c at 12 months, and an intention-to-treat analysis, including all patients, was undertaken. Blood pressure, lipids, episodes of hypoglycaemia and quality of life, measured with the EuroQol 5 dimensions (EQ-5D), were secondary measures. An economic analysis was also carried out, and questionnaires were used to measure well-being, beliefs about use of SMBG and self-reports of medication taking, dietary and physical activities, and health-care resource use. RESULTS: The differences in 12-month HbA1c between the three groups (adjusted for baseline HbA1c) were not statistically significant (p = 0.12). The difference in unadjusted mean change in HbA1c from baseline to 12 months between the control and less intensive self-monitoring groups was -0.14% [95% confidence interval (CI) -0.35 to 0.07] and between the control and more intensive self-monitoring groups was -0.17% (95% CI -0.37 to 0.03). There was no evidence of a significantly different impact of self-monitoring on glycaemic control when comparing subgroups of patients defined by duration of diabetes, therapy, diabetes-related complications and EQ-5D score. The economic analysis suggested that SMBG resulted in extra health-care costs and was unlikely to be cost-effective if used routinely. There appeared to be an initial negative impact of SMBG on quality of life measured on the EQ-5D, and the potential additional lifetime gains in quality-adjusted life-years, resulting from the lower levels of risk factors achieved at the end of trial follow-up, were outweighed by these initial impacts for both SMBG groups compared with control. Some patients felt that SMBG was helpful, and there was evidence that those using more intensive self-monitoring perceived diabetes as having more serious consequences. Patients using SMBG were often not clear about the relationship between their behaviour and the test results. CONCLUSIONS: While the data do not exclude the possibility of a clinically important benefit for specific subgroups of patients in initiating good glycaemic control, SMBG by non-insulin-treated patients, with or without instruction in incorporating findings into self-care, did not lead to a significant improvement in glycaemic control compared with usual care monitored by HbA1c levels. There was no convincing evidence to support a recommendation for routine self-monitoring of all patients and no evidence of improved glycaemic control in predefined subgroups of patients.

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.

AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.

Atorvastatin in Factorial with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD): a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to examine the impact of statin or omega-3-acid ethyl esters 90 (omega-3 EE90; omega-3-acid ethyl esters 90 refers to a mixture of ethyl esters of n-3 fatty acids) on estimated cardiovascular disease (CVD) risk in community-based people with type 2 diabetes but without known CVD and not taking lipid-lowering therapy. METHODS: A central computer randomised 800 patients in 59 UK general practices to atorvastatin (n = 401, 20 mg/day) or placebo (n = 399) and omega-3 EE90 (n = 397, 2 g/day) or placebo (n = 403) in a concealed factorial manner. Participants with LDL-cholesterol <2.6 mmol/l, triacylglycerol <1.5 mmol/l and estimated 10-year CVD risk <20% were compared at 4 months. RESULTS: Mean (SD) age was 63.5 (11.7) years, HbA(1c) 6.9 (1.1) % and known diabetes duration (median [interquartile range]) was 4 (2-8) years. Fifty-seven per cent were men, 90% white and 74% had an estimated 10-year CVD risk >or=20%. Of 732 patients with 4-month data, more allocated atorvastatin (n = 371) compared with placebo (n = 361) achieved LDL-cholesterol <2.6 mmol/l (91% vs 24%, p < 0.001) and had estimated 10-year CVD risks <20% (38% vs 26%, p < 0.001). No differences were seen between those allocated omega-3 EE90 (n = 371) compared with placebo (n = 361) for participants achieving triacylglycerol <1.5 mmol/l (65% vs 60%, p = 0.18) or estimated 10-year CVD risks <20% (34% vs 30%, p = 0.18). There were no side effects of note. CONCLUSIONS/INTERPRETATION: Many community-based diabetic patients without known CVD remain at high CVD risk despite statin treatment and require additional risk-reduction strategies. The impact of omega-3 EE90 on CVD risk will remain uncertain until clinical endpoint trial results are available. TRIAL REGISTRATION: ISRCT no. 76737502.

Effects of short-term low- and high-carbohydrate diets on postprandial metabolism in non-diabetic and diabetic subjects.

BACKGROUND AND AIM: Low-fat high-carbohydrate diets raise plasma triacylglycerol (TG) concentrations. To test whether the nature of the carbohydrate affects metabolic responses, we conducted a randomized cross-over study using a short-term, intensive dietary modification. METHODS AND RESULTS: Eight non-diabetic subjects and four subjects with diet-controlled type 2 diabetes participated. They followed three isoenergetic diets, each for 3 days: high-fat (50% energy from fat), high-starch and high-sugar (each 70% energy from carbohydrate). Normal foods were provided. We measured plasma TG and glucose concentrations, fasting and after a standard test meal, on day 4 following each dietary period. Fasting TG concentrations were greatest following the high-sugar diet (mean+/-SEM for all subjects 1900+/-420micromol/l) and lowest following high-fat (1010+/-130micromol/l) (P=0.001); high-starch (mean 1500+/-310) and high-fat did not differ significantly (P=0.06). There was a greater effect in the diabetic subjects (diet x diabetes status interaction, P=0.008). Postprandial TG concentrations were similarly affected by prior diet (P<0.001) with each diet different from the others (P

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.

Self-monitoring of blood glucose changed non-insulin-treated Type 2 diabetes patients' beliefs about diabetes and self-monitoring in a randomized trial.

AIMS: To determine whether differences in beliefs about diabetes and its treatment resulted from different intensities of self-monitoring of blood glucose (SMBG) in non-insulin treated patients with Type 2 diabetes in the Diabetes Glycaemic Education and Monitoring (DiGEM) trial. METHODS: Patients (n = 453) were randomized to usual care, less-intensive SMBG and more intensive SMBG. Beliefs about diabetes were measured with a standard questionnaire (the revised Illness Perceptions Questionnaire; IPQ-R). Changes in beliefs were analysed using analysis of covariance (ancova) with adjustment for baseline values. Mediation analyses assessed whether differences in behavioural outcomes between groups could be attributed to differences in beliefs. RESULTS: Completed questionnaires were returned by 339 patients (74.8%). Respondents were mean (+/- sd) age 65.9 +/- 10 years and with diabetes duration of 4.8 +/- 4.7 years (median 36, range 1-384 months). Concerns about the consequences of diabetes increased in both self-monitoring groups, relative to control subjects [P = 0.004; Cohen's d standardized effect size = 0.19 less intensive and d = 0.36 more intensive monitoring]. No other beliefs about diabetes differed between groups. Beliefs about the importance of self-testing increased in both self-monitoring groups relative to the usual-care group (P < 0.001; d = 0.57 less intensive and d = 0.63 more intensive monitoring). Changes in psychological well-being did not differ between groups, but control patients reported greater increases in general (P = 0.014) and specific (P < 0.001) dietary adherence than did patients in the self-monitoring groups. These outcomes were not mediated by intervention-related changes in beliefs. CONCLUSIONS: Despite changes in some beliefs about diabetes differing between groups there were no corresponding changes in self-reported health behaviours. This suggests that changes in illness beliefs resulting from SMBG do not cause changes in diabetes-related health behaviours.

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.

Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus.

BACKGROUND: People with type 2 diabetes mellitus are at increased risk from cardiovascular disease. Dietary omega-3 polyunsaturated fatty acids (PUFAs) are known to reduce triglyceride levels, but their impact on cholesterol levels, glycemic control and vascular outcomes are not well known. OBJECTIVES: To determine the effects of omega-3 PUFA supplementation on cardiovascular outcomes, cholesterol levels and glycemic control in people with type 2 diabetes mellitus. SEARCH STRATEGY: We carried out a comprehensive search of The Cochrane Library, MEDLINE, EMBASE, bibliographies of relevant papers and contacted experts for identifying additional trials. SELECTION CRITERIA: All randomised controlled trials were included where omega-3 PUFA supplementation or dietary intake was randomly allocated and unconfounded in people with type 2 diabetes. Authors of large trials were contacted for missing information. DATA COLLECTION AND ANALYSIS: Trials were assessed for inclusion. Authors were contacted for missing information. Data was extracted and quality assessed independently in duplicate. Fixed-effect meta-analysis was carried out. MAIN RESULTS: Twenty three randomised controlled trials (1075 participants) were included with a mean treatment duration of 8.9 weeks. The mean dose of omega-3 PUFA used in the trials was 3.5 g/d. No trials with vascular events or mortality endpoints were identified. Among those taking omega-3 PUFA triglyceride levels were significantly lowered by 0.45 mmol/L (95% confidence interval (CI) -0.58 to -0.32, P < 0.00001) and VLDL cholesterol lowered by -0.07 mmol/L (95% CI -0.13 to 0.00, P = 0.04). LDL cholesterol levels were raised by 0.11 mmol/L (95% CI 0.00 to 0.22, P = 0.05). No significant change in or total or HDL cholesterol, HbA1c, fasting glucose, fasting insulin or body weight was observed. The increase in VLDL remained significant only in trials of longer duration and in hypertriglyceridemic patients. The elevation in LDL cholesterol was non-significant in subgroup analyses. No adverse effects of the intervention were reported. AUTHORS' CONCLUSIONS: Omega-3 PUFA supplementation in type 2 diabetes lowers triglycerides and VLDL cholesterol, but may raise LDL cholesterol (although results were non-significant in subgroups) and has no statistically significant effect on glycemic control or fasting insulin. Trials with vascular events or mortality defined endpoints are needed.

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.

Meta-analysis of the effects of n-3 polyunsaturated fatty acids on lipoproteins and other emerging lipid cardiovascular risk markers in patients with type 2 diabetes.

AIMS/HYPOTHESIS: To determine the effects of marine-derived n-3 polyunsaturated fatty acids (PUFA) on established and emerging lipid and lipoprotein cardiovascular risk markers in patients with type 2 diabetes. MATERIALS AND METHODS: We performed a systematic review and meta-analysis of randomised controlled trials comparing dietary or non-dietary intake of n-3 PUFA with placebo in patients with type 2 diabetes by searching databases from 1966 to December 2006. Changes in the following variables were recorded triacylglycerol; total cholesterol; HDL, LDL and VLDL and their subfractions; lipid ratios; apolipoproteins; and cholesterol particle sizes. RESULTS: There were 23 trials on non-dietary supplementation, involving 1,075 subjects with a mean treatment duration of 8.9 weeks, with sufficient data to permit pooling. Compared with placebo, n-3 PUFA had a statistically significant effect on four outcomes, reducing levels of (1) triacylglycerol (18 trials, 969 subjects) by 25% (mean 0.45 mmol/l; 95% CI -0.58 to -0.32; p < 0.00001); (2) VLDL-cholesterol (7 trials, 238 subjects) by 36% (0.07 mmol/l; 95% CI -0.13 to 0.00; p = 0.04); and (3) VLDL-triacylglycerol (6 trials, 178 subjects) by 39.7% (0.44 mmol/l; 95% CI -0.83 to -0.05; p = 0.03); while slightly increasing LDL (16 trials, 565 subjects) by 5.7% (0.11 mmol/l; 95% CI 0.00 to 0.22; p = 0.05). There were no significant effects on total cholesterol, apolipoproteins, lipid subfractions or ratios. CONCLUSIONS/INTERPRETATION: In addition to recognised triacylglycerol-lowering effects, n-3 PUFA supplementation decreases VLDL-cholesterol and VLDL-triacylglycerol, but may have an adverse effect on LDL-cholesterol. Larger and longer term clinical trials are required to conclusively establish the effect of n-3 PUFA on cardiovascular risk markers and outcomes in type 2 diabetic patients.

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).

Can we identify adolescents at high risk for nephropathy before the development of microalbuminuria?

AIMS: To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. METHODS: Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0-16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. RESULTS: The albumin excretion phenotype showed reasonable correlation between age 11-15 years and age 16-18 years in both cohorts, indicative of good 'tracking'. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11-15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA(1c) > 9% at aged 11-15 years. CONCLUSIONS: Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA(1c), it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.

Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.

AIMS: To assess efficacy and safety of HMG-CoA reductase inhibitor (statin) treatment in children and adolescents with heterozygous familial hypercholesterolaemia. METHODS: MEDLINE, EMBASE, COCHRANE and Current Controlled Trials databases were searched. Study design, efficacy, and safety outcome-measures were extracted. Results of parallel-group randomised placebo controlled trials with low density (LDL) and high density lipoprotein cholesterol (HDL), and triglycerides as outcomes were pooled using standard meta-analytical methods. RESULTS: One hundred and fifty seven of 1060 identified papers studied familial hypercholesterolaemia, and 18 papers reported 7 prospective case series, 1 non-randomised trial, 2 trials with active treatment control groups, and 8 parallel-group randomised placebo controlled trials (RCT). The RCTs randomised 947 children, aged 8-18 years, for periods of 6-96 weeks with an estimated 850 person-years follow-up. There were no differences in clinical or laboratory adverse reactions between placebo and active treatment. Statins lowered LDL 32.5% (95% CI 24.3, 40.7), increased HDL 3.4% (0.8, 6.0), lowered triglycerides 3.0% (-11.6, 17.6), attenuated progression of carotid medial thickness, and improved endothelial function. CONCLUSIONS: Statin monotherapy is efficacious, well tolerated and safe in the short-term, although long-term safety remains unclear. Current evidence supports treatment of children at highest cardiovascular risk, but results of on-going, longer-term studies may extend these indications.

Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes.

AIM/HYPOTHESIS: To determine whether marine-derived n-3 polyunsaturated fatty acids (n-3 PUFA) (also known as omega-3 fatty acids) have beneficial effects on haematological and thrombogenic risk markers in addition to dyslipidaemia, in patients with type 2 diabetes. METHODS: A systematic review and meta-analysis of randomised controlled trials comparing dietary or non-dietary intake of n-3 PUFA with placebo in type 2 diabetes was conducted by systematically searching databases from 1966 to February 2006. Changes in C-reactive protein, IL-6, TNF-alpha, platelet function, fibrinogen, factor VII, von Willebrand factor, endothelial function, heart rate and blood pressure were recorded. Inclusion of studies, data extraction and quality were assessed independently in duplicate. RESULTS: Twelve trials involving 847 subjects with a mean treatment duration of 8.5 weeks included sufficient data to permit pooling. Compared with placebo, n-3 PUFA supplementation had a significant effect on two outcomes: reducing the level of diastolic blood pressure (five trials, 248 subjects) by a mean of 1.8 mm Hg (95% CI 0.0-3.6, p = 0.05) and increasing factor VII (two trials, 116 subjects) by 24.9% (95% CI 7.2-42.6, p = 0.006). There were no significant effects on systolic blood pressure, fibrinogen or heart rate. CONCLUSIONS/INTERPRETATION: These results suggest that, in addition to the recognised effects on dyslipidaemia, n-3 PUFA decreases diastolic blood pressure, and appears to increase factor VII. Larger and more rigorously conducted clinical trials are required to establish conclusively the role of n-3 PUFA in cardiovascular risk markers and clinical outcomes in type 2 diabetes.