UK Biobank is a UK-wide cohort of 502,655 people aged 40-69, recruited from National Health Service registrants between 2006-10, with healthcare data linkage. Type 2 diabetes is a key exposure and ...outcome. We developed algorithms to define prevalent and incident diabetes for UK Biobank. The algorithms will be implemented by UK Biobank and their results made available to researchers on request.
We used UK Biobank self-reported medical history and medication to assign prevalent diabetes and type, and tested this against linked primary and secondary care data in Welsh UK Biobank participants. Additionally, we derived and tested algorithms for incident diabetes using linked primary and secondary care data in the English Clinical Practice Research Datalink, and ran these on secondary care data in UK Biobank.
For prevalent diabetes, 0.001% and 0.002% of people classified as "diabetes unlikely" in UK Biobank had evidence of diabetes in their primary or secondary care record respectively. Of those classified as "probable" type 2 diabetes, 75% and 96% had specific type 2 diabetes codes in their primary and secondary care records. For incidence, 95% of people with the type 2 diabetes-specific C10F Read code in primary care had corroborative evidence of diabetes from medications, blood testing or diabetes specific process of care codes. Only 41% of people identified with type 2 diabetes in primary care had secondary care evidence of type 2 diabetes. In contrast, of incident cases using ICD-10 type 2 diabetes specific codes in secondary care, 77% had corroborative evidence of diabetes in primary care. We suggest our definition of prevalent diabetes from UK Biobank baseline data has external validity, and recommend that specific primary care Read codes should be used for incident diabetes to ensure precision. Secondary care data should be used for incident diabetes with caution, as around half of all cases are missed, and a quarter have no corroborative evidence of diabetes in primary care.
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.
Recent in vitro and animal experiments suggest that peroxisome proliferation-activated receptor gamma (PPARɣ) agonist medications, such as antidiabetic glitazone (GTZ) drugs, are neuroprotective in ...models of Parkinson's disease (PD). These findings have not been tested in humans. We hypothesized that individuals prescribed GTZ drugs would have a lower incidence of PD compared to individuals prescribed other treatments for diabetes.
Using primary care data from the United Kingdom Clinical Practice Research Datalink (CPRD), we conducted a retrospective cohort study in which individuals with diabetes who were newly prescribed GTZ (GTZ-exposed group) were matched by age, sex, practice, and diabetes treatment stage with up to five individuals prescribed other diabetes treatments (other antidiabetic drug-exposed group). Patients were followed up from 1999 until the first recording of a PD diagnosis, end of observation in the database, or end of the study (1 August 2013). An incidence rate ratio (IRR) was calculated using conditional Poisson regression, adjusted for possible confounders. 44,597 GTZ exposed individuals were matched to 120,373 other antidiabetic users. 175 GTZ-exposed individuals were diagnosed with PD compared to 517 individuals in the other antidiabetic drug-exposed group. The incidence rate (IR) of PD in the GTZ-exposed group was 6.4 per 10,000 patient years compared with 8.8 per 10,000 patient years in those prescribed other antidiabetic treatments (IRR 0.72, 95% confidence interval CI 0.60-0.87). Adjustments for potential confounding variables, including smoking, other medications, head injury, and disease severity, had no material impact (fully adjusted IRR 0.75, 0.59-0.94). The risk was reduced in those with current GTZ prescriptions (current GTZ-exposed IRR 0.59, 0.46-0.77) but not reduced among those with past prescriptions (past GTZ-exposed IRR 0.85, 0.65-1.10). Our study only included patients with diabetes who did not have a PD diagnosis when they were first prescribed GTZ, and thus, it cannot establish whether GTZ use prevents or slows the progression of PD.
In patients with diabetes, a current prescription for GTZ is associated with a reduction in incidence of PD. This suggests PPAR gamma pathways may be a fruitful drug target in PD.
Continuous wave near infrared spectroscopy (CW NIRS) provides non-invasive technology to measure relative changes in oxy- and deoxy-haemoglobin in a dynamic environment. This allows determination of ...local skeletal muscle O2 saturation, muscle oxygen consumption (V˙O2) and blood flow. This article provides a brief overview of the use of CW NIRS to measure exercise-limiting factors in skeletal muscle.
NIRS parameters that measure O2 delivery and capacity to utilise O2 in the muscle have been developed based on response to physiological interventions and exercise. NIRS has good reproducibility and agreement with gold standard techniques and can be used in clinical populations where muscle oxidative capacity or oxygen delivery (or both) are impaired. CW NIRS has limitations including: the unknown contribution of myoglobin to the overall signals, the impact of adipose tissue thickness, skin perfusion during exercise, and variations in skin pigmentation. These, in the main, can be circumvented through appropriate study design or measurement of absolute tissue saturation.
CW NIRS can assess skeletal muscle O2 delivery and utilisation without the use of expensive or invasive procedures and is useable in large population-based samples, including older adults.
•An overview of CW NIRS to measure O2 utilisation and delivery is presented.•CW NIRS is cheap, non-invasive, portable and useable in population-based samples.•It is useful for understanding underlying mechanisms of deterioration in capacity.
Circulating microRNAs (miRNAs) have emerged as novel biomarkers of diabetes. The current study focuses on the role of circulating miRNAs in patients with type 1 diabetes and their association with ...diabetic retinopathy. A total of 29 miRNAs were quantified in serum samples (n = 300) using a nested case-control study design in two prospective cohorts of the DIabetic REtinopathy Candesartan Trial (DIRECT): PROTECT-1 and PREVENT-1. The PREVENT-1 trial included patients without retinopathy at baseline; the PROTECT-1 trial included patients with nonproliferative retinopathy at baseline. Two miRNAs previously implicated in angiogenesis, miR-27b and miR-320a, were associated with incidence and with progression of retinopathy: the odds ratio per SD higher miR-27b was 0.57 (95% CI 0.40, 0.82; P = 0.002) in PREVENT-1, 0.78 (0.57, 1.07; P = 0.124) in PROTECT-1, and 0.67 (0.50, 0.92; P = 0.012) combined. The respective odds ratios for higher miR-320a were 1.57 (1.07, 2.31; P = 0.020), 1.43 (1.05, 1.94; P = 0.021), and 1.48 (1.17, 1.88; P = 0.001). Proteomics analyses in endothelial cells returned the antiangiogenic protein thrombospondin-1 as a common target of both miRNAs. Our study identifies two angiogenic miRNAs, miR-320a and miR-27b, as potential biomarkers for diabetic retinopathy.
Type 2 diabetes is 2-3 times more prevalent in people of South Asian and African/African Caribbean ethnicity than people of European ethnicity living in the UK. The former 2 groups also experience ...excess atherosclerotic cardiovascular disease (ASCVD) complications of diabetes. We aimed to study ethnic differences in statin initiation, a cornerstone of ASCVD primary prevention, for people with type 2 diabetes.
Observational cohort study of UK primary care records, from 1 January 2006 to 30 June 2019. Data were studied from 27,511 (88%) people of European ethnicity, 2,386 (8%) people of South Asian ethnicity, and 1,142 (4%) people of African/African Caribbean ethnicity with incident type 2 diabetes, no previous ASCVD, and statin use indicated by guidelines. Statin initiation rates were contrasted by ethnicity, and the number of ASCVD events that could be prevented by equalising prescribing rates across ethnic groups was estimated. Median time to statin initiation was 79, 109, and 84 days for people of European, South Asian, and African/African Caribbean ethnicity, respectively. People of African/African Caribbean ethnicity were a third less likely to receive guideline-indicated statins than European people (n/N %: 605/1,142 53% and 18,803/27,511 68%, respectively; age- and gender-adjusted HR 0.67 95% CI 0.60 to 0.76, p < 0.001). The HR attenuated marginally in a model adjusting for total cholesterol/high-density lipoprotein cholesterol ratio (0.77 95% CI 0.69 to 0.85, p < 0.001), with no further diminution when deprivation, ASCVD risk factors, comorbidity, polypharmacy, and healthcare usage were accounted for (fully adjusted HR 0.76 95% CI 0.68, 0.85, p < 0.001). People of South Asian ethnicity were 10% less likely to receive a statin than European people (1,489/2,386 62% and 18,803/27,511 68%, respectively; fully adjusted HR 0.91 95% CI 0.85 to 0.98, p = 0.008, adjusting for all covariates). We estimated that up to 12,600 ASCVD events could be prevented over the lifetimes of people currently affected by type 2 diabetes in the UK by equalising statin prescribing across ethnic groups. Limitations included incompleteness of recording of routinely collected data.
In this study we observed that people of African/African Caribbean ethnicity with type 2 diabetes were substantially less likely, and people of South Asian ethnicity marginally less likely, to receive guideline-indicated statins than people of European ethnicity, even after accounting for sociodemographics, healthcare usage, ASCVD risk factors, and comorbidity. Underuse of statins in people of African/African Caribbean or South Asian ethnicity with type 2 diabetes is a missed opportunity to prevent cardiovascular events.
We aimed to estimate multimorbidity trajectories and quantify socioeconomic inequalities based on childhood and adulthood socioeconomic position (SEP) in the risks and rates of multimorbidity ...accumulation across adulthood.
Participants from the UK 1946 National Survey of Health and Development (NSHD) birth cohort study who attended the age 36 years assessment in 1982 and any one of the follow-up assessments at ages 43, 53, 63, and 69 years (N = 3,723, 51% males). Information on 18 health conditions was based on a combination of self-report, biomarkers, health records, and prescribed medications. We estimated multimorbidity trajectories and delineated socioeconomic inequalities (based on childhood and adulthood social class and highest education) in multimorbidity at each age and in longitudinal trajectories. Multimorbidity increased with age (0.7 conditions at 36 years to 3.7 at 69 years). Multimorbidity accumulation was nonlinear, accelerating with age at the rate of 0.08 conditions/year (95% CI 0.07 to 0.09, p < 0.001) at 36 to 43 years to 0.19 conditions/year (95% CI 0.18 to 0.20, p < 0.001) at 63 to 69 years. At all ages, the most socioeconomically disadvantaged had 1.2 to 1.4 times greater number of conditions on average compared to the most advantaged. The most disadvantaged by each socioeconomic indicator experienced an additional 0.39 conditions (childhood social class), 0.83 (adult social class), and 1.08 conditions (adult education) at age 69 years, independent of all other socioeconomic indicators. Adverse adulthood SEP was associated with more rapid accumulation of multimorbidity, resulting in 0.49 excess conditions in partly/unskilled compared to professional/intermediate individuals between 63 and 69 years. Disadvantaged childhood social class, independently of adulthood SEP, was associated with accelerated multimorbidity trajectories from age 53 years onwards. Study limitations include that the NSHD cohort is composed of individuals of white European heritage only, and findings may not be generalizable to the non-white British population of the same generation and did not account for other important dimensions of SEP such as income and wealth.
In this study, we found that socioeconomically disadvantaged individuals have earlier onset and more rapid accumulation of multimorbidity resulting in widening inequalities into old age, with independent contributions from both childhood and adulthood SEP.
A frailty index (FI) counts health deficit accumulation. Besides traditional risk factors, it is unknown whether the health deficit burden is related to the appearance of cardiovascular disease. In ...order to answer this question, the same multidimensional FI looking at 45-health deficits was serially calculated per participant at 4 time periods (0-16, 19-44, 45-54 and 60-64 years) using data from the 1946 Medical Research Council (MRC) British National Survey of Health and Development (NSHD)-the world's longest running longitudinal birth cohort with continuous follow-up. From these the mean and total FI for the life-course, and the step change in deficit accumulation from one time period to another was derived. Echocardiographic data at 60-64 years provided: ejection fraction (EF), left ventricular mass indexed to body surface area (LVmassi, BSA), myocardial contraction fraction indexed to BSA (MCF
) and E/e'. Generalized linear models assessed the association between FIs and echocardiographic parameters after adjustment for relevant covariates. 1375 participants were included. For each single new deficit accumulated at any one of the 4 time periods, LVmass
increased by 0.91-1.44% (p < 0.013), while MCF
decreased by 0.6-1.02% (p < 0.05). A unit increase in FI at age 45-54 and 60-64, decreased EF by 11-12% (p < 0.013). A single health deficit step change occurring between 60 and 64 years and one of the earlier time periods, translated into higher odds (2.1-78.5, p < 0.020) of elevated LV filling pressure. Thus, the accumulation of health deficits at any time period of the life-course associates with a maladaptive cardiac phenotype in older age, dominated by myocardial hypertrophy and poorer function.
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.
Aims/hypothesis
The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and ...Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes.
Methods
In total, 708 participants (aged mean±SD 73 ± 7 years, 56% male) were recruited from the Southall and Brent Revisited (SABRE) study, a UK population-based cohort comprised of Europeans (
n
= 311) and South Asian (
n
= 232) and African Caribbean (
n
= 165) migrants. Measurements of exercise capacity using a 6 min stepper test (6MST), including measurement of oxygen consumption (
V
̇
O
2
) and grip strength, were performed. Skeletal muscle was assessed using near infrared spectroscopy (NIRS); measures included changes in tissue saturation index (∆TSI%) with exercise and oxidative capacity (muscle oxygen consumption recovery, represented by a time constant τ). Analysis was by multiple linear regression.
Results
When adjusted for age and sex, in South Asians and African Caribbeans, exercise capacity was reduced compared with Europeans (
V
̇
O
2
ml min
−1
kg
−1
: β = −1.2 95% CI –1.9, −0.4,
p
= 0.002, and β −1.7 95% CI –2.5, −0.8,
p
< 0.001, respectively). South Asians had lower and African Caribbeans had higher strength compared with Europeans (strength kPa: β = −9 95% CI –12, −6),
p
< 0.001, and β = 6 95% CI 3, 9,
p
< 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% %: β = −0.9 95% CI –1.7, −0.1),
p
= 0.024; τ s: β = 11 95% CI 3, 18,
p
= 0.006). Ethnic differences in
V
̇
O
2
and grip strength remained despite adjustment for type 2 diabetes or HbA
1c
(and fat-free mass for grip strength). However, the differences between Europeans and South Asians were no longer statistically significant after adjustment for other possible mediators or confounders (including physical activity, waist-to-hip ratio, cardiovascular disease or hypertension, smoking, haemoglobin levels or β-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA
1c
and was also no longer statistically significant after adjusting for other confounders; however, τ remained significantly longer in South Asians vs Europeans despite adjustment for all confounders.
Conclusions/interpretation
Reduced exercise capacity in South Asians and African Caribbeans is unexplained by higher rates of type 2 diabetes. Poorer exercise tolerance in these populations, and impaired muscle function and perfusion in South Asians, may contribute to the higher morbidity burden of UK ethnic minority groups in older age.
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