Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we ...compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
To determine whether a history of severe hypoglycemia was associated with an increased risk of subsequent macrovascular events in people with type 2 diabetes and to explore possible mediation of this ...association by inflammation.
A cohort of 1,066 adults aged 60-75 years with type 2 diabetes was evaluated prospectively. Baseline history of severe hypoglycemia and plasma levels of the inflammatory markers C-reactive protein, fibrinogen, interleukin-6, and tumor necrosis factor-α were recorded. Their association with incident macrovascular events after 4 years was explored.
At baseline, 87 participants (8.2%) reported one or more episodes of severe hypoglycemia within the preceding year, and at follow-up 99 participants (9.3%) had suffered a new macrovascular event. Hypoglycemia was associated with increased odds of macrovascular events (odds ratio OR 2.11 95% CI 1.06, 4.21, P = 0.035), including coronary heart events (OR 2.44 95% CI 1.13, 5.26, P = 0.023), largely due to increased myocardial infarction (OR 4.02 95% CI 1.54, 10.48, P = 0.004). Hypoglycemia was also associated with increased levels of inflammatory markers, including a general inflammation factor derived using principal-components analysis (P = 0.030, after adjustment for cardiometabolic risk factors). However, the significant association between hypoglycemia and macrovascular events persisted after adjustment for inflammatory markers.
The odds of suffering a macrovascular event were higher in patients with type 2 diabetes who had a history of severe hypoglycemia. There was no evidence that a proinflammatory state had a major role in mediating this association.
Older people with type 2 diabetes are at increased risk of developing cognitive impairment, for which several potential risk factors have been proposed. The present article reviews evidence in people ...with type 2 diabetes for associations of cognitive impairment with a range of vascular, metabolic, and psychosocial risk factors, many of which have a higher prevalence in people with type 2 diabetes than in non-diabetic adults of a similar age. Definitive research studies in this field are few in number. The risk factors may be involved in causal pathways or may act as useful markers of cerebrovascular damage (or both), and for which relatively consistent evidence is available, include poor glycemic control, hypoglycemia, microvascular disease, inflammation, and depression. For macrovascular disease, the strength of the association with cognitive impairment appears to depend on which vascular system has been examined. A role for pre-morbid ability in young adulthood as influencing the risk of both diabetes and cognitive impairment has also been suggested. The importance of considering inter-relationships between risk factors when investigating their potential contribution to cognitive impairment in future investigations is discussed.
People with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Hypoglycemia is a candidate risk factor, but the direction of association between episodes of severe ...hypoglycemia and cognitive decline in type 2 diabetes remains uncertain.
In the Edinburgh Type 2 Diabetes Study, cognitive function was assessed in 831 adults with type 2 diabetes (aged 60-75 years) at baseline and after 4 years. Scores on seven neuropsychological tests were combined into a standardized general ability factor g. Self-reported history of severe hypoglycemia at baseline (history of hypoglycemia) and at follow-up (incident hypoglycemia) was recorded.
A history of hypoglycemia was reported by 9.3% of subjects, and 10.2% reported incident hypoglycemia. Incident hypoglycemia was associated with poorer cognitive ability at baseline (age- and sex-adjusted odds ratio for lowest tertile of g 2.04 95% CI 1.25-3.31, P = 0.004). Both history of hypoglycemia and incident hypoglycemia were also associated with greater cognitive decline during follow-up (mean follow-up g adjusted for age, sex, and baseline g -0.25 vs. 0.03 P = 0.02 and -0.28 vs. 0.04 P = 0.01, respectively), including after addition of vascular risk factors and cardiovascular and microvascular disease to the models (-0.23 vs. 0.03 P = 0.04 and -0.21 vs. 0.05 P = 0.03, respectively).
The relationship between cognitive impairment and hypoglycemia appeared complex, with severe hypoglycemia associated with both poorer initial cognitive ability and accelerated cognitive decline.
Ketone bodies (KBs) are an alternative energy supply for brain functions when glucose is limited. The most abundant ketone metabolite, 3-β-hydroxybutyrate (BOHBUT), has been suggested to prevent or ...delay cognitive impairment, but the evidence remains unclear. We triangulated observational and Mendelian randomization (MR) studies to investigate the association and causation between KBs and cognitive function.
In observational analyses of 5506 participants aged ≥ 45 years from the Whitehall II study, we used multiple linear regression to investigate the associations between categorized KBs and cognitive function scores. Two-sample MR was carried out using summary statistics from an in-house KBs meta-analysis between the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium and Kettunen et al. (N = 45,031), and publicly available summary statistics of cognitive performance and Alzheimer's disease (AD) from the Social Science Genetic Association Consortium (N = 257,841), and the International Genomics of Alzheimer's Project (N = 54,162), respectively. Both strong (P < 5 × 10
) and suggestive (P < 1 × 10
) sets of instrumental variables for BOHBUT were applied. Finally, we performed cis-MR on OXCT1, a well-known gene for KB catabolism.
BOHBUT was positively associated with general cognitive function (β = 0.26, P = 9.74 × 10
). In MR analyses, we observed a protective effect of BOHBUT on cognitive performance (inverse variance weighted: β
= 7.89 × 10
, P
= 1.03 × 10
; weighted median: β
= 8.65 × 10
, P
= 9.60 × 10
) and a protective effect on AD (β
= - 0.31, odds ratio: OR = 0.74, P
= 3.06 × 10
). Cis-MR showed little evidence of therapeutic modulation of OXCT1 on cognitive impairment.
Triangulation of evidence suggests that BOHBUT has a beneficial effect on cognitive performance. Our findings raise the hypothesis that increased BOHBUT may improve general cognitive functions, delaying cognitive impairment and reducing the risk of AD.
The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent.
To determine ...whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score.
Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion.
Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke.
Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease.
We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women.
The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.
Atherosclerotic cardiovascular diseases (CVD) is the leading cause of death in diabetes, but the full range of biomarkers reflecting atherosclerotic burden and CVD risk in people with diabetes is ...unknown. Metabolomics may help identify novel biomarkers potentially involved in development of atherosclerosis. We investigated the serum metabolomic profile of subclinical atherosclerosis, measured using ankle brachial index (ABI), in people with type 2 diabetes, compared with the profile for symptomatic CVD in the same population.
The Edinburgh Type 2 Diabetes Study is a cohort of 1,066 individuals with type 2 diabetes. ABI was measured at baseline, years 4 and 10, with cardiovascular events assessed at baseline and during 10 years of follow-up. A panel of 228 metabolites was measured at baseline using nuclear magnetic resonance spectrometry, and their association with both ABI and prevalent CVD was explored using univariate regression models and least absolute shrinkage and selection operator (LASSO). Metabolites associated with baseline ABI were further explored for association with follow-up ABI and incident CVD.
Mean (standard deviation, SD) ABI at baseline was 0.97 (0.18, N = 1025), and prevalence of CVD was 35.0%. During 10-year follow-up, mean (SD) change in ABI was + 0.006 (0.178, n = 436), and 257 CVD events occurred. Lactate, glycerol, creatinine and glycoprotein acetyls levels were associated with baseline ABI in both univariate regression βs (95% confidence interval, CI) ranged from - 0.025 (- 0.036, - 0.015) to - 0.023 (- 0.034, - 0.013), all p < 0.0002 and LASSO analysis. The associations remained nominally significant after adjustment for major vascular risk factors. In prospective analyses, lactate was nominally associated with ABI measured at years 4 and 10 after adjustment for baseline ABI. The four ABI-associated metabolites were all positively associated with prevalent CVD odds ratios (ORs) ranged from 1.29 (1.13, 1.47) to 1.49 (1.29, 1.74), all p < 0.0002, and they were also positively associated with incident CVD ORs (95% CI) ranged from 1.19 (1.02, 1.39) to 1.35 (1.17, 1.56), all p < 0.05.
Serum metabolites relating to glycolysis, fluid balance and inflammation were independently associated with both a marker of subclinical atherosclerosis and with symptomatic CVD in people with type 2 diabetes. Additional investigation is warranted to determine their roles as possible etiological and/or predictive biomarkers for atherosclerotic CVD.
Aims/hypothesis
Our aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and ...stroke.
Methods
A total of 1066 men and women with type 2 diabetes, aged 65–74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (
n
= 1028).
Results
A total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 95% CI 1.02, 1.58 and HR 0.74 95% CI 0.57, 0.95, respectively), including with stroke alone (HR 1.30 95% CI 1.01, 1.66 and HR 0.73 95% CI 0.56, 0.97, respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 95% CI 1.01, 1.58 and HR 0.73 95% CI 0.56, 0.94, respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 95% CI 0.57, 0.95 and HR 0.72 95% CI 0.54, 0.97, respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance.
Conclusions/interpretation
Arteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.
Graphical abstract
OBJECTIVE: Type 2 diabetes is an established risk factor for development of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). We aimed to determine the prevalence and clinical ...correlates of these conditions in a large cohort of people with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 939 participants, aged 61-76 years, from the Edinburgh Type 2 Diabetes Study (ET2DS)--a large, randomly selected population of people with type 2 diabetes--underwent liver ultrasonography. Ultrasound gradings of steatosis were compared with magnetic resonance spectroscopy in a subgroup. NAFLD was defined as hepatic steatosis in the absence of a secondary cause (screened by questionnaire assessing alcohol and hepatotoxic medication use, plasma hepatitis serology, autoantibodies and ferritin, and record linkage to determine prior diagnoses of liver disease). Binary logistic regression was used to analyze independent associations of characteristics with NAFLD. RESULTS: Hepatic steatosis was present in 56.9% of participants. After excluding those with a secondary cause for steatosis, the prevalence of NAFLD in the study population was 42.6%. Independent predictors of NAFLD were BMI, lesser duration of diabetes, HbA₁c, triglycerides, and metformin use. These remained unchanged after exclusion of participants with evidence of hepatic fibrosis from the group with no hepatic steatosis. CONCLUSIONS: Prevalences of hepatic steatosis and NAFLD were high in this unselected population of older people with type 2 diabetes, but lower than in studies in which ultrasound gradings were not compared with a gold standard. Associations with features of the metabolic syndrome could be used to target screening for this condition.
Drug target Mendelian randomization (MR) studies use DNA sequence variants in or near a gene encoding a drug target, that alter the target's expression or function, as a tool to anticipate the effect ...of drug action on the same target. Here we apply MR to prioritize drug targets for their causal relevance for coronary heart disease (CHD). The targets are further prioritized using independent replication, co-localization, protein expression profiles and data from the British National Formulary and clinicaltrials.gov. Out of the 341 drug targets identified through their association with blood lipids (HDL-C, LDL-C and triglycerides), we robustly prioritize 30 targets that might elicit beneficial effects in the prevention or treatment of CHD, including NPC1L1 and PCSK9, the targets of drugs used in CHD prevention. We discuss how this approach can be generalized to other targets, disease biomarkers and endpoints to help prioritize and validate targets during the drug development process.
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