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Aim To understand the relationship between HbA1c and brain health across the entire glycaemic spectrum. Materials and Methods We used data from the UK Biobank cohort consisting of 500,000 individuals aged 40–69 years. HbA1c and diabetes diagnosis were used to define baseline glycaemic categories. Our outcomes included incident all‐cause dementia, vascular dementia (VD), Alzheimer's dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. The reference group was normoglycaemic individuals (HbA1c ≥35 &

AimsTo investigate the relationship between glycaemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomisation (MR).MethodsUK Biobank (n~500,000) individuals, aged 40-69 years at baseline. Our exposures were genetic instruments for type-2 diabetes (163 variants) and HbA1c (52 variants) and our outcomes were reaction time (RT - milliseconds), visual memory (number of incorrect responses), hippocampal and white matter hyperintensity volumes (both mm3), Alzheimer’s disease (AD). To study potential bidirectional effects, we then investigated the associations between genetic variants for RT (43 variants) and clinical type-2 diabetes and measured HbA1c. We used conventional inverse-variance weighted (IVW) MR, alongside standard MR sensitivity analyses.ResultsUsing IVW, genetic liability to type-2 diabetes was not associated with reaction time (exponentiated ß=1.00, 95%CI=1.00; 1.00), visual memory (expß=1.00, 95%CI=0.99; 1.00), white matter hyperintensity volume (expß=0.98, 95%CI=0.93; 1.03), hippocampal volume (coefficient mm3=0.00, 95%CI=-0.01; 0.01) or risk of AD (OR 0.97, 95%CI=0.89; 1.06). HbA1c was not associated with reaction time (expß=1.01, 95%CI=1.00; 1.01), white matter hyperintensity volume (expß=0.88, 95%CI=0.73; 1.07), hippocampal volume (coefficient=-0.02, 95%CI=-0.10; 0.06), risk of AD (OR 0.94, 95%CI=0.47; 1.86), but HbA1c was associated with visual memory (expß=1.06, 95%CI=1.05; 1.07) using a weighted median approach. IVW showed no evidence that reaction time was associated with diabetes (OR 0.96, 95%CI=0.63; 1.46) or HbA1c (coefficient=-0.08, 95%CI=-0.57; 0.42). MR-Egger intercept p-values indicated no major issues with unbalanced horizontal pleiotropy (all p>0.05).ConclusionsOverall, we observed little evidence of causal associations between glycaemia and cognition, structural brain and dementia phenotypes.AbbreviationsAlzheimer’s dementia (AD)Benjamini-Hochberg false discovery rate (BH-FDR)Genome-wide association study (GWAS)Hippocampal volume (HV)Hospital episode statistics (HES)International Classification of Diseases (ICD)Inverse variance weighted (IVW)Magnetic resonance imaging (MRI)Mendelian randomization (MR)Quality control (QC)Reaction time (RT)Simulation extrapolation (SIMEX)UK Biobank (UKB)Visual memory (VM)Weighted median Estimator (WME)White matter hyperintensity volume (WMHV)

The right drug, for the right patient, at the right time. Who wouldn’t want this? For diabetologists, after decades of domination by biguanides and sulfonylureas, only briefly punctuated by thiazolidinediones, the choice of early-stage glucose-lowering agents has recently more than doubled, now including glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP-4) and sodium–glucose cotransporter 2 (SGLT2) inhibitors. Armed with this greater choice, can we now fulfill the promise of precision medicine? Half of the 500 million people in the world with diabetes live in either China or the Indian subcontinent (1). Aside from simple demographics, these huge numbers are largely due to the greater diabetes susceptibility experienced by both populations. In this issue, Gan and associates (2) hypothesize that pathophysiological differences contributing to this greater susceptibility may be associated with different glycemic responses to diabetes medication. This is not unreasonable; 20% of new drug approvals show differences in exposure or response by ethnicity (3). They performed a systematic review and meta-analysis of published randomized clinical trials comparing absolute change in HbA1c from baseline to either 24 or 52 weeks in studies that recruited predominantly (>70%) Asians versus studies that recruited predominantly (>70%) whites. They report that SGLT2 and, possibly, DPP-4 inhibitors are more effective in lowering HbA1c in Asians than in whites. There was no ethnic difference in efficacy of GLP-1 receptor agonists. Their findings are somewhat at odds with previous work. The most striking observation, of an ∼0.3% lower HbA1c in Asians than in whites in response to SGLT2 inhibitors, contrasts with a previous meta-analysis reporting no ethnic difference (4), though an agent-specific analysis did show modest superiority of dapagliflozin (0.16%) in Asians versus non-Asians. Gan et al. …

Aims/hypothesis Excess risks of type 2 diabetes in UK South Asians (SA) and African Caribbeans (AC) compared with Europeans remain unexplained. We studied risks and determinants of type 2 diabetes in first- and second-generation (born in the UK) migrants, and in those of mixed ethnicity. Methods Data from the UK Biobank, a population-based cohort of ~500,000 participants aged 40–69 at recruitment, were used. Type 2 diabetes was assigned using self-report and HbA1c. Ethnicity was both self-reported and genetically assigned using admixture level scores. European, mixed European/South Asian (MixESA), mixed European/African Caribbean (MixEAC), SA and AC groups were analysed, matched for age and sex to enable comparison. In the frames of this cross-sectional study, we compared type 2 diabetes in second- vs first-generation migrants, and mixed ethnicity vs non-mixed groups. Risks and explanations were analysed using logistic regression and mediation analysis, respectively. Results Type 2 diabetes prevalence was markedly elevated in SA (599/3317 = 18%) and AC (534/4180 = 13%) compared with Europeans (140/3324 = 4%). Prevalence was lower in second- vs first-generation SA (124/1115 = 11% vs 155/1115 = 14%) and AC (163/2200 = 7% vs 227/2200 = 10%). Favourable adiposity (i.e. lower waist/hip ratio or BMI) contributed to lower risk in second-generation migrants. Type 2 diabetes in mixed populations (MixESA: 52/831 = 6%, MixEAC: 70/1045 = 7%) was lower than in comparator ethnic groups (SA: 18%, AC: 13%) and higher than in Europeans (4%). Greater socioeconomic deprivation accounted for 17% and 42% of the excess type 2 diabetes risk in MixESA and MixEAC compared with Europeans, respectively. Replacing self-reported with genetically assigned ethnicity corroborated the mixed ethnicity analysis. Conclusions/interpretation Type 2 diabetes risks in second-generation SA and AC migrants are a fifth lower than in first-generation migrants. Mixed ethnicity risks were markedly lower than SA and AC groups, though remaining higher than in Europeans. Distribution of environmental risk factors, largely obesity and socioeconomic status, appears to play a key role in accounting for ethnic differences in type 2 diabetes risk. Graphical abstract

We investigated the relationship between glycemia and cognitive function, brain structure and incident dementia using bidirectional Mendelian randomization (MR). Data were from the UK Biobank (n = ∼500,000). Our exposures were genetic instruments for type 2 diabetes (157 variants) and HbA1c (51 variants) and our outcomes were reaction time (RT), visual memory, hippocampal volume (HV), white matter hyperintensity volume (WMHV), and Alzheimer dementia (AD). We also investigated associations between genetic variants for RT (43 variants) and diabetes and HbA1c. We used conventional inverse-variance–weighted (IVW) MR alongside MR sensitivity analyses. Using IVW, genetic liability to type 2 diabetes was not associated with RT (exponentiated β [expβ] = 1.00 [95% CI 1.00; 1.00]), visual memory (expβ = 1.00 [95% CI 0.99; 1.00]), WMHV (expβ = 0.99 [95% CI 0.97; 1.01]), HV (β-coefficient mm3 = −2.30 [95% CI −12.39; 7.78]) or AD (odds ratio [OR] 1.15 [95% CI 0.87; 1.52]). HbA1c was not associated with RT (expβ = 1.00 [95% CI 0.99; 1.02]), visual memory (expβ = 0.99 [95% CI 0.96; 1.02]), WMHV (expβ = 1.03 [95% CI 0.88; 1.22]), HV (β = −21.31 [95% CI −82.96; 40.34]), or risk of AD (OR 1.09 [95% CI 0.42; 2.83]). IVW showed that reaction time was not associated with diabetes risk (OR 0.94 [95% CI 0.54; 1.65]), or with HbA1c (β-coefficient mmol/mol = −0.88 [95% CI = −1.88; 0.13]) after exclusion of a pleiotropic variant. Overall, we observed little evidence of causal association between genetic instruments for type 2 diabetes or peripheral glycemia and some measures of cognition and brain structure in midlife.

IntroductionDiabetes is observed to increase cancer risk, leading to hypothesized direct effects of either hyperglycemia or medication. We investigated associations between glycosylated hemoglobin (HbA1c) across the whole glycemic spectrum and incidence of 16 cancers in a population sample with comprehensive adjustment for risk factors and medication.Research design and methodsLinked data from the UK Biobank and UK cancer registry for all individuals with baseline HbA1c and no history of cancer at enrollment were used. Incident cancer was based on International Classification of Diseases – 10th Edition diagnostic codes. Age-standardized incidence rates were estimated by HbA1c category. Associations between HbA1c, modeled as a restricted cubic spline, and cancer risk were estimated using Cox proportional hazards models.ResultsAmong 378 253 individuals with average follow-up of 7.1 years, 21 172 incident cancers occurred. While incidence for many of the 16 cancers was associated with hyperglycemia in crude analyses, these associations disappeared after multivariable adjustment, except for pancreatic cancer (HR 1.55, 95% CI 1.22 to 1.98 for 55 vs 35 mmol/mol), and a novel finding of an inverse association between HbA1c and premenopausal breast cancer (HR 1.27, 95% CI 1.00 to 1.60 for 25 vs 35 mmol/mol; HR 0.71, 95% CI 0.54 to 0.94 for 45 vs 35 mmol/mol), not observed for postmenopausal breast cancer. Adjustment for diabetes medications had no appreciable impact on HRs for cancer.ConclusionsApart from pancreatic cancer, we did not demonstrate any independent positive association between HbA1c and cancer risk. These findings suggest that the potential for a cancer-inducing, direct effect of hyperglycemia may be misplaced.

Objective: To understand the relationship across the glycaemic spectrum with incident dementia, brain structure, and cognitive decline. Research Design and Methods: UK Biobank participants, aged 40-69 at recruitment. HbA1c and diabetes diagnosis define baseline glycaemic categories. Outcomes included incident vascular dementia (VD), Alzheimers dementia (AD), hippocampal volume (HV), white matter hyperintensity (WMH) volume, cognitive function and decline. All results are in reference to normoglycaemic individuals (HbA1c 35

It is unknown whether associations between blood pressure (BP) and stroke vary between Europeans and South Asians, despite higher stroke rates in the latter. We report findings from a UK cohort study of 1375 European and 1074 South Asian men, not receiving antihypertensive medication, aged 40 to 69 years at baseline (1988–1991). Assessment included BP, blood tests, anthropometry, and questionnaires. Incident stroke was established at 20 years from death certification, hospital and primary care records, and participant report. South Asians had higher systolic BP, diastolic BP, and mean arterial pressure than Europeans, and similar pulse pressure. Associations between systolic BP or diastolic BP and stroke were stronger in South Asians than Europeans, after adjustment for age, smoking status, waist/hip ratio, total/high-density lipoprotein-cholesterol ratio, diabetes mellitus, fasting glucose, physical activity, and heart rate (systolic BP: Europeans [odds ratio, 1.22; 95% confidence interval, 0.98–1.51], South Asians [1.56; 1.24–1.95]; ethnic difference P =0.04; diastolic BP: Europeans [0.90; 0.71–1.13], South Asians [1.68; 1.32–2.15]; P

OBJECTIVE We examined longitudinal associations between prediabetes and cardiovascular disease (CVD) (coronary heart disease [CHD] and stroke) in Europeans and South Asians. RESEARCH DESIGN AND METHODS This was a U.K. cohort study of 1,336 Europeans and 1,139 South Asians, aged 40–69 years at baseline (1988–1991). Assessment included blood pressure, blood tests, anthropometry, and questionnaires. Prediabetes was determined by OGTT or HbA1c, using either International Expert Committee (IEC) (HbA1c 6.0–6.5% [42–48 mmol/mol]) or American Diabetes Association (ADA) (HbA1c 5.7–6.5% [39–48 mmol/mol]) cut points. Incident CHD and stroke were established at 20 years from death certification, hospital admission, primary care record review, and participant report. RESULTS Compared with normoglycemic individuals, IEC-defined prediabetes was related to both CHD and CVD risk in Europeans but not South Asians (subhazard ratio for CHD 1.68 [95% CI 1.19, 2.38] vs. 1.00 [0.75, 1.33], ethnicity interaction P = 0.008, and for CVD 1.49 [1.08, 2.07] vs. 1.03 [0.78, 1.36], ethnicity interaction P = 0.04). Conversely, IEC-defined prediabetes was associated with stroke risk in South Asians but not Europeans (1.73 [1.03, 2.90] vs. 0.85 [0.44, 1.64], ethnicity interaction P = 0.11). Risks were adjusted for age, sex, smoking, total-to-HDL cholesterol ratio, waist-to-hip ratio, systolic blood pressure, and antihypertensive use. Associations were weaker for OGTT or ADA-defined prediabetes. Conversion from prediabetes to diabetes was greater in South Asians, but accounting for time to conversion did not account for these ethnic differences. CONCLUSIONS Associations between prediabetes and CVD differed by prediabetes diagnostic criterion, type of CVD, and ethnicity, with associations being present for overall CVD in Europeans but not South Asians. Substantiation of these findings and investigation of potential explanations are required.

OBJECTIVE Structured patient education programs can reduce the risk of diabetes-related complications. However, people appear to have difficulties attending face-to-face education and alternatives are needed. This review looked at the impact of computer-based diabetes self-management interventions on health status, cardiovascular risk factors, and quality of life of adults with type 2 diabetes. RESEARCH DESIGN AND METHODS We searched The Cochrane Library, Medline, Embase, PsycINFO, Web of Science, and CINAHL for relevant trials from inception to November 2011. Reference lists from relevant published studies were screened and authors contacted for further information when required. Two authors independently extracted relevant data using standard data extraction templates. RESULTS Sixteen randomized controlled trials with 3,578 participants met the inclusion criteria. Interventions were delivered via clinics, the Internet, and mobile phones. Computer-based diabetes self-management interventions appear to have small benefits on glycemic control: the pooled effect on HbA1c was −0.2% (−2.3 mmol/mol [95% CI −0.4 to −0.1%]). A subgroup analysis on mobile phone–based interventions showed a larger effect: the pooled effect on HbA1c from three studies was −0.50% (−5.46 mmol/mol [95% CI −0.7 to −0.3%]). There was no evidence of improvement in depression, quality of life, blood pressure, serum lipids, or weight. There was no evidence of significant adverse effects. CONCLUSIONS Computer-based diabetes self-management interventions to manage type 2 diabetes appear to have a small beneficial effect on blood glucose control, and this effect was larger in the mobile phone subgroup. There was no evidence of benefit for other biological, cognitive, behavioral, or emotional outcomes.

Background: Stroke risk is greater in South Asians than Europeans. We sought to compare associations between blood pressure (BP) and stroke by ethnicity and determine how BP contributes to ethnic differences in disease. Methods: Population sample of 1510 European and 1195 South Asian men recruited between 1988-1991, mean age 52 7yrs. Incident fatal and nonfatal strokes were captured over 20 years of follow-up. Cox models demonstrated associations between mean arterial BP (MAP) and stroke. Results: South Asians had more incident strokes than Europeans (5.6 (4.7,6.7) versus 4.7 (4.0,5.6) per 1000 person years, age-adjusted hazard ratio:1.40 (1.08,1.76), pZ0.01) and higher MAPs than Europeans (97 12 versus 93 12mmHg, p