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Type 2 diabetes mellitus (T2DM) disproportionately affects individuals of nonwhite ethnic origin. Timely and appropriate initiation and intensification of glucose-lowering therapy is key to reducing the risk of major vascular outcomes. Given that ethnic inequalities in outcomes may stem from differences in therapeutic management, the aim of this study was to identify ethnic differences in the timeliness of initiation and intensification of glucose-lowering therapy in individuals newly diagnosed with T2DM in the United Kingdom. An observational cohort study using the Clinical Practice Research Datalink was conducted using 162,238 adults aged 18 and over diagnosed with T2DM between 1990 and 2017 (mean age 62.7 years, 55.2% male); 93% were of white ethnicity (n = 150,754), 5% were South Asian (n = 8,139), and 2.1% were black (n = 3,345). Ethnic differences in time to initiation and intensification of diabetes treatment were estimated at three time points (initiation of noninsulin monotherapy, intensification to noninsulin combination therapy, and intensification to insulin therapy) using multivariable Cox proportional hazards regression adjusted for factors a priori hypothesised to be associated with initiation and intensification: age, sex, deprivation, glycated haemoglobin (HbA1c), body mass index (BMI), smoking status, comorbidities, consultations, medications, calendar year, and clustering by practice. Odds of experiencing therapeutic inertia (failure to intensify treatment within 12 months of HbA1c >7.5% [58 mmol/mol]), were estimated using multivariable logistic regression adjusted for the same hypothesised confounders. Noninsulin monotherapy was initiated earlier in South Asian and black groups (South Asian HR 1.21, 95% CI 1.08-1.36, p < 0.001; black HR 1.29, 95% CI 1.05-1.59, p = 0.017). Correspondingly, no ethnic differences in therapeutic inertia were evident at initiation. Intensification with noninsulin combination therapy was slower in both nonwhite ethnic groups relative to white (South Asian HR 0.80, 95% CI 0.74-0.87, p < 0.001; black HR 0.79, 95% CI 0.70-0.90, p < 0.001); treatment inertia at this stage was greater in nonwhite groups relative to white (South Asian odds ratio [OR] 1.45, 95% CI 1.23-1.70, p < 0.001; black OR 1.43, 95% CI 1.09-1.87, p = 0.010). Intensification to insulin therapy was slower again for black groups relative to white groups (South Asian HR 0.49, 95% CI 0.41-0.58, p < 0.001; black HR 0.69, 95% CI 0.53-0.89, p = 0.012); correspondingly, treatment inertia was significantly higher in nonwhite groups at this stage relative to white groups (South Asian OR 2.68, 95% CI 1.89-3.80 p < 0.001; black OR 1.82, 95% CI 1.13-2.79, p = 0.013). At both stages of treatment intensification, nonwhite groups had fewer HbA1c measurements than white groups. Limitations included variable quality and completeness of routinely recorded data and a lack of information on medication adherence. In this large UK cohort, we found persuasive evidence that South Asian and black groups intensified to noninsulin combination therapy and insulin therapy more slowly than white groups and experienced greater therapeutic inertia following identification of uncontrolled HbA1c. Reasons for delays are multifactorial and may, in part, be related to poorer long-term monitoring of risk factors in nonwhite groups. Initiatives to improve timely and appropriate intensification of diabetes treatment are key to reducing disparities in downstream vascular outcomes in these populations.

Aims/hypothesisExcess 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.MethodsData 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.ResultsType 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/interpretationType 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.

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell’s C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small.

High blood pressure is a major risk factor for cardiovascular disease and is influenced by both environmental and genetic factors. Epigenetic processes including DNA methylation potentially mediate the relationship between genetic factors, the environment and cardiovascular disease. Despite an increased risk of hypertension and cardiovascular disease in individuals of South Asians compared to Europeans, it is not clear whether associations between blood pressure and DNA methylation differ between these groups. We performed an epigenome-wide association study and differentially methylated region (DMR) analysis to identify DNA methylation sites and regions that were associated with systolic blood pressure, diastolic blood pressure and hypertension. We analyzed samples from 364 European and 348 South Asian men (first generation migrants to the UK) from the Southall And Brent REvisited cohort, measuring DNA methylation from blood using the Illumina Infinium® HumanMethylation450 BeadChip. One CpG site was found to be associated with DBP in trans-ancestry analyses (i.e. both ethnic groups combined), while in Europeans alone seven CpG sites were associated with DBP. No associations were identified between DNA methylation and either SBP or hypertension. Comparison of effect sizes between South Asian and European EWAS for DBP, SBP and hypertension revealed little concordance between analyses. DMR analysis identified several regions with known relationships with CVD and its risk factors. This study identified differentially methylated sites and regions associated with blood pressure and revealed ethnic differences in these associations. These findings may point to molecular pathways which may explain the elevated cardiovascular disease risk experienced by those of South Asian ancestry when compared to Europeans.

Previous studies have found that diabetes and its mechanistic factors (e.g., glycaemia) are associated with poorer cognitive and brain health. There is also growing evidence of sex differences in how diabetes manifests itself and impacts the brain. The mechanisms through which this association manifests itself are still poorly understood, but the possible role of inflammation has been proposed. This study aims to explore whether the relationship between mid-life glycaemia and brain volumes in later-life in women is mediated by systemic inflammation. The sample consisted of female participants from the National Survey of Health and Development (NSHD) who underwent neuroimaging as part of the Insight 46 sub-study. Path analysis models were then constructed between glycaemic markers (age 60−64) and brain health outcomes (age 69−71) with adjustments for social and metabolic confounders (age 60−64). Although fasting glucose was associated with higher GlycA levels (β = 0.05 [0.01, 0.10], p = 0.005), associations with CRP and IL-6 were weaker and not statistically significant (e.g., IL-6: β = 0.10 [−0.04, 0.30], p = 0.102). However, we did not find evidence that inflammatory markers were associated with brain volume outcomes (e.g., IL-6 and whole brain volume: β = −3.4 [−8.1, 1.3], p = 0.092; IL-6 and grey matter volume: β = −0.4 [−1.9, 1.0], p = 0.512). Consequently, indirect (mediated) effects via systemic inflammation were not observed. This suggests that alternative mechanisms beyond inflammation may contribute to the relationship between mid-life glycaemia and later-life brain health.

Background MicroRNA-146a-5p (miR-146a-5p) is a key regulator of inflammatory processes. Expression of miR-146a-5p is altered in target organs of diabetic complications and deficiency of miR-146a-5p has been implicated in their pathogenesis. We investigated if serum miR-146a-5p levels were independently associated with micro/macrovascular complications of type 1 diabetes (DM1). Methods A nested case–control study from the EURODIAB PCS of 447 DM1 patients was performed. Cases (n = 294) had one or more complications of diabetes, whereas controls (n = 153) did not have any complication. Total RNA was isolated from all subjects and miR-146a-5p levels measured by qPCR. Both the endogenous controls U6 snRNA and the spike (Cel-miR-39) were used to normalize the results. Logistic regression analysis was carried out to investigate the association of miR-146a-5p with diabetes complications. Results MiR-146a-5p levels were significantly lower in cases [1.15 (0.32–3.34)] compared to controls [1.74 (0.44–6.74) P = 0.039]. Logistic regression analysis showed that levels of miR-146a-5p in the upper quartile were inversely associated with reduced odds ratio (OR) of all complications (OR 0.34 [95% CI 0.14–0.76]) and particularly with cardiovascular diseases (CVD) (OR 0.31 [95% CI 0.11–0.84]) and diabetic retinopathy (OR 0.40 [95% CI 0.16–0.99]), independently of age, sex, diabetes duration, A1c, hypertension, AER, eGFR, NT-proBNP, and TNF-α. Conclusions In this large cohort of DM1 patients, we reported an inverse and independent association of miR-146a-5p with diabetes chronic complications and in particular with CVD and retinopathy, suggesting that miR-146a-5p may be a novel candidate biomarker of DM1 complications.

Diabetic retinopathy remains a leading cause of visual loss in people of working age. We examined whether candesartan treatment could slow the progression and, secondly, induce regression of retinopathy in people with type 2 diabetes. We did a randomised, double-blind, parallel-group, placebo-controlled trial in 309 centres worldwide. We recruited normoalbuminuric, normotensive, or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to candesartan 16 mg once a day or placebo. After a month, the dose was doubled to 32 mg once per day. Investigators and patients were unaware of the treatment allocation status. Progression of retinopathy was the primary endpoint, and regression was a secondary endpoint. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00252694. 1905 participants (aged 37–75 years) were randomised to candesartan (n=951) or placebo (n=954). 161 (17%) patients in the candesartan group and 182 (19%) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale. The risk of progression of retinopathy was non-significantly reduced by 13% in patients on candesartan compared with those on placebo (hazard ratio [HR] 0·87, 95% CI 0·70–1·08, p=0·20). Regression on active treatment was increased by 34% (1·34, 1·08–1·68, p=0·009). HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial. An overall change towards less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1·17, 95% CI 1·05–1·30, p=0·003). Adverse events did not differ between the treatment groups. Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy. AstraZeneca and Takeda.

Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. 1421 participants (aged 18–50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18–55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0·82 (95% CI 0·67–1·00, p=0·0508) for incidence of retinopathy and 1·02 (0·80–1·31, p=0·85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0·65 (0·48–0·87, p=0·0034), which was attenuated but still significant after adjustment for baseline characteristics (0·71, 0·53–0·95, p=0·046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1·16, 95% CI 1·05–1·30, p=0·0048) and DIRECT-Protect 1 (1·12, 95% CI 1·01–1·25, p=0·0264). Adverse events did not differ between the treatment groups. Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression. AstraZeneca and Takeda.

Apart from glycemic control, there is no treatment for diabetic neuropathy. Thus, identifying potentially modifiable risk factors is crucial for the development of new therapies. In addition to glycemic control, the incidence of neuropathy in type 1 diabetes is associated with potentially modifiable cardiovascular risk factors including a raised triglyceride level, body-mass index, smoking, and hypertension. Diabetic neuropathy is a common cause of morbidity and death among patients with diabetes, generating a huge economic burden. 1 Apart from tight glycemic control, no other evidence-based treatments are known to ameliorate or prevent neuropathy. The duration and level of hyperglycemia are important determinants of microvascular complications of diabetes, including neuropathy. 2 The relative effect of cardiovascular risk factors specifically associated with diabetes (e.g., hypertension, dyslipidemia, and increased weight) or not associated with diabetes (smoking) on the development of neuropathy are incompletely elucidated. The Diabetes Control and Complications Trial (DCCT) reported a 60 percent reduction in neuropathy in the intensively treated . . .