HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.

BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials). INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. FUNDING: The funding sources are cited at the end of the paper.

Smoking, hypercholesterolaemia and hypertension as risk factors for cognitive impairment in older adults.

BACKGROUND: the prevalence of all types of cognitive impairment, including dementia, is increasing but knowledge of aetiological factors is still evolving. OBJECTIVE: this study aimed to evaluate the association between cardiovascular risk factors and cognitive function in older persons. DESIGN, SETTING AND SUBJECTS: a population-based cohort design involving 2,312 men and women (aged 50-75) enrolled in the University of Edinburgh Aspirin for Asymptomatic Atherosclerosis trial. METHODS: cognitive tests included the Mill Hill Vocabulary Scale, auditory verbal learning test (AVLT), digit symbol test, verbal fluency test (VFT), Raven's Progressive Matrices and the trail making test. A 'g' score (measure of general intelligence) was computed for each subject. Regression analysis was used to evaluate the association between relevant variables. RESULTS: higher diastolic BP was negatively associated with AVLT (ß = -0.153, P < 0.01), and with an estimated decline on AVLT (ß = -0.125, P < 0.01). Smoking was negatively associated with all the cognitive variables except VFT. The total cholesterol level was not associated with cognitive function or estimated decline. CONCLUSIONS: smoking and elevated blood pressure may be risk factors for cognitive decline, and thus potential targets for preventive and therapeutic interventions.

Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial.

CONTEXT: A low ankle brachial index (ABI) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events. Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments. OBJECTIVE: To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population. DESIGN, SETTING, AND PARTICIPANTS: The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind randomized controlled trial conducted from April 1998 to October 2008, involving 28,980 men and women aged 50 to 75 years living in central Scotland, free of clinical cardiovascular disease, recruited from a community health registry, and had an ABI screening test. Of those, 3350 with a low ABI (< or = 0.95) were entered into the trial, which was powered to detect a 25% proportional risk reduction in events. INTERVENTIONS: Once daily 100 mg aspirin (enteric coated) or placebo. MAIN OUTCOME MEASURES: The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Two secondary end points were (1) all initial vascular events defined as a composite of a primary end point event or angina, intermittent claudication, or transient ischemic attack; and (2) all-cause mortality. RESULTS: After a mean (SD) follow-up of 8.2 (1.6) years, 357 participants had a primary end point event (13.5 per 1000 person-years, 95% confidence interval [CI], 12.2-15.0). No statistically significant difference was found between groups (13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group; hazard ratio [HR], 1.03; 95% CI, 0.84-1.27). A vascular event comprising the secondary end point occurred in 578 participants (22.8 per 1000 person-years; 95% CI, 21.0-24.8) and no statistically significant difference between groups (22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group; HR, 1.00; 95% CI, 0.85-1.17). There was no significant difference in all-cause mortality between groups (176 vs 186 deaths, respectively; HR, 0.95; 95% CI, 0.77-1.16). An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants (2.5 per 1000 person-years) in the aspirin group and 20 (1.5 per 1000 person-years) in the placebo group (HR, 1.71; 95% CI, 0.99-2.97). CONCLUSION: Among participants without clinical cardiovascular disease, identified with a low ABI based on screening a general population, the administration of aspirin compared with placebo did not result in a significant reduction in vascular events. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN66587262.

Intelligence and persisting with medication for two years: Analysis in a randomised controlled trial.

The study examined whether verbal intelligence is associated with persisting to take medication for up to two years. The design is a prospective follow-up of compliance with taking medication in high-risk individuals participating in a randomised, placebo-controlled trial set in Central Scotland. Participants were 1993 people aged between 50 and 77 years with an ankle brachial index

Improvement in prediction of coronary heart disease risk over conventional risk factors using SNPs identified in genome-wide association studies.

OBJECTIVE: We examined whether a panel of SNPs, systematically selected from genome-wide association studies (GWAS), could improve risk prediction of coronary heart disease (CHD), over-and-above conventional risk factors. These SNPs have already demonstrated reproducible associations with CHD; here we examined their use in long-term risk prediction. STUDY DESIGN AND SETTING: SNPs identified from meta-analyses of GWAS of CHD were tested in 840 men and women aged 55-75 from the Edinburgh Artery Study, a prospective, population-based study with 15 years of follow-up. Cox proportional hazards models were used to evaluate the addition of SNPs to conventional risk factors in prediction of CHD risk. CHD was classified as myocardial infarction (MI), coronary intervention (angioplasty, or coronary artery bypass surgery), angina and/or unspecified ischaemic heart disease as a cause of death; additional analyses were limited to MI or coronary intervention. Model performance was assessed by changes in discrimination and net reclassification improvement (NRI). RESULTS: There were significant improvements with addition of 27 SNPs to conventional risk factors for prediction of CHD (NRI of 54%, P<0.001; C-index 0.671 to 0.740, P = 0.001), as well as MI or coronary intervention, (NRI of 44%, P<0.001; C-index 0.717 to 0.750, P = 0.256). ROC curves showed that addition of SNPs better improved discrimination when the sensitivity of conventional risk factors was low for prediction of MI or coronary intervention. CONCLUSION: There was significant improvement in risk prediction of CHD over 15 years when SNPs identified from GWAS were added to conventional risk factors. This effect may be particularly useful for identifying individuals with a low prognostic index who are in fact at increased risk of disease than indicated by conventional risk factors alone.

Accrual and drop out in a primary prevention randomised controlled trial: qualitative study.

BACKGROUND: Recruitment and retention of participants are critical to the success of a randomised controlled trial. Gaining the views of potential trial participants who decline to enter a trial and of trial participants who stop the trial treatment is important and can help to improve study processes. Limited research on these issues has been conducted on healthy individuals recruited for prevention trials in the community. METHODS: Semi-structured interviews with people who were eligible but had declined to participate in the Aspirin for Asymptomatic Atherosclerosis (AAA) trial (N = 11), and AAA trial participants who had stopped taking the trial medication (N = 11). A focus group with further participants who had stopped taking the trial medication (N = 6). (Total participants N = 28). RESULTS: Explanations for declining to participate could be divided into two groups: the first group were characterised by a lack of necessity to participate and a tendency to prioritise other largely mundane problems. The second group's concern was with a high level of perceived risk from participating.Explanations for stopping trial medication fell into four categories: side effects attributed to the trial medication; starting on aspirin or medication contraindicating to aspirin; experiencing an outcome event, and changing one's mind. CONCLUSIONS: These results indicate that when planning trials (especially in preventive medicine) particular attention should be given to designing appropriate recruitment materials and processes that fully inform potential recruits of the risks and benefits of participation. TRIAL REGISTRATION: ISRCTN66587262.

Scottish smoke-free legislation and trends in smoking cessation.

AIM: To investigate trends in smoking cessation before and after the introduction of Scottish smoke-free legislation and to assess the perceived influence of the legislation on giving up smoking and perceptions of the legislation in smokers. DESIGN, SETTING AND PARTICIPANTS: Longitudinal data on smoking cessation were obtained from 1998 to 2007 on a cohort of 3350 Scottish adults aged between 50 and 75 years at baseline. All members of the cohort were participating in a clinical trial of aspirin in people at moderately increased risk of cardiovascular events. A subgroup of 474 participants who had smoked in the year prior to the introduction of legislation in March 2006 also completed a questionnaire on the influence and perceptions of the smoke-free legislation following its introduction. MEASUREMENTS: Smoking status was recorded yearly, including dates of quitting and restarting. Participants who gave up smoking for at least 3 months were recorded as having quit smoking. The questionnaire included scales on whether the smoke-free legislation had helped/influenced cessation, made the individual think about/prompt them to quit and perceptions of the legislation. FINDINGS: The odds of smokers quitting annually increased throughout the 7-year period prior to introduction of the smoke-free legislation to 2 years afterwards (odds ratio 1.09, 95% confidence interval 1.05-1.12, P<0.001). During 2006, the pattern of quarterly quitting rates changed, with an increase in quit rates (to 5.1%) in the 3-month period prior to introduction of the legislation (January-March 2006). Socio-economic status was not related to smoking cessation. In the subgroup completing the questionnaire (n=474), 57 quit smoking between June 2005 and May 2007 and 43.9% of these said that the smoke-free legislation had helped them to quit. Most (>70%) smokers were positive about the legislation, especially those from more affluent compared with more deprived communities (P=0.01). CONCLUSIONS: The Scottish smoke-free legislation was associated with an increase in the rate of smoking cessation in the 3-month period immediately prior to its introduction. Overall quit rates in the year the legislation was introduced and the subsequent year were consistent with a gradual increase in quit rates prior to introduction of the legislation. Socio-economic status was not related to smoking cessation, but individuals from more affluent communities were more positive about the legislation.

Frequency of a low ankle brachial index in the general population by age, sex and deprivation: cross-sectional survey of 28,980 men and women.

OBJECTIVES: An increasing interest is observed in the use of the ankle brachial index (ABI, ratio of systolic blood pressure at the ankle to that in the arm) to assess cardiovascular risk. The aim of this study was to provide information on the distribution of ABI in a large healthy population, essential for planning implementation of ABI measurement in preventive strategies in the general population. STUDY DESIGN AND SETTING: Cross-sectional survey of the ABI was conducted in 28,980 men and women aged over 50 years, living in central Scotland and free of clinical cardiovascular disease. RESULTS: The ABI was approximately normally distributed in both men (mean 1.06, SD 0.13) and women (mean 1.01, SD 0.11). A total of 10.9% of participants had an ABI

Relationship between lifetime smoking, smoking status at older age and human cognitive function.

Cigarette smoking is a major risk factor for clinical cardiovascular disease and may also be associated with poorer cognitive functioning in older age. We measured lifetime cigarette smoking, smoking status and cognitive function in over 2,000 men and women from the general population aged over 50 years with subclinical atherosclerosis (ankle brachial pressure index