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Aims/hypothesis Data are inconsistent regarding the associations between age, age at diagnosis of diabetes, diabetes duration and subsequent vascular complications. Methods The associations between age (or age at diagnosis), diabetes duration and major macrovascular events, all-cause death and major microvascular events were examined in 11,140 patients with type 2 diabetes randomly allocated to intensive or standard glucose control in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Rates were calculated by 5 year baseline age (or age at diagnosis) and diabetes duration strata. Risks were estimated using Cox models adjusted for treatment assignment and HbA 1c . Results The mean age (±SD) was 65.8 ± 6.4 years, age at diagnosis was 57.8 ± 8.7 years and diabetes duration was 7.9 ± 6.4 years. Diabetes duration was associated with the risk of macrovascular events (HR 1.13 [95% CI 1.08, 1.17]), microvascular events (1.28 [1.23, 1.33]) and death (1.15 [1.10, 1.20]) whereas age (or age at diagnosis) was only associated with the risk of macrovascular events (1.33 [1.27, 1.39]) and death (1.56 [1.48, 1.64]). No interaction was observed between diabetes duration, age and the risk of macrovascular events or death (both p  > 0.4). However, an interaction was observed between diabetes duration, age and the risk of microvascular events ( p  = 0.002), such that the effects of increasing diabetes duration were greatest at younger rather than older age. Conclusions/interpretation In patients with type 2 diabetes, age or age at diagnosis and diabetes duration are independently associated with macrovascular events and death whereas only diabetes duration is independently associated with microvascular events and this effect is greater in the youngest patients.

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

Hypertension, cardiovascular disease and kidney failure are associated with persistent hyperglycaemia and the subsequent development of nephropathy in people with diabetes. Diabetic nephropathy is associated with widespread vascular disease affecting both the kidney and the heart from an early stage. However, the risk of diabetic nephropathy in people with type 1 diabetes is strongly genetically determined, as documented in familial transmission studies. The search for the underlying genes has been extensive, using specific hypotheses, sibling linkage studies and genome-wide association studies (GWAS). The role of the angiotensinI-converting enzyme/kininase II ( ACE ) gene and genetic variability in ACE levels as a susceptibility and prognostic factor for diabetic nephropathy has been well documented in people with type 1 diabetes. The ACE gene insertion/deletion polymorphism, which is associated with plasma and tissue ACE levels, has been the most studied genomic variant in diabetic nephropathy. Recently, this polymorphism has also been associated with longevity in people with type 1 diabetes. The ACE I/D polymorphism has also been associated with vascular, extra-renal complications including myocardial infarction and lower-limb amputation in this population. Other genes and loci have been identified in linkage studies and GWAS, such as the COL4A3 gene or a region on chromosome 3q with the adiponectin gene. Replication was not always attempted and was rarely achieved, even for GWAS. Overall, effect sizes remain modest and no major gene has been identified, despite the strength of the genetic effect in transmission studies. We searched bibliographic databases for studies reporting genomic variants associated with diabetic nephropathy and meta-analyses of such studies. We selected important relevant studies for further discussion in this narrative review. This brief review attempts to summarise the current knowledge on the genetics of diabetic nephropathy and associated cardiovascular disease in people with type 1 diabetes, and discusses some conceptual and methodological issues relevant to the interpretation of past studies and the design of future ones. Graphical abstract Genetic determinism of diabetic nephropathy and associated cardiovascular disease in people with type 1 diabetes. Close-up on the AngiotensinI-Converting Enzyme gene. ACE, Angiotensin1-converting enzyme; I/D, ACE gene Insertion/Deletion Polymorphism; DN, diabetic nephropathy; CVD cardiovascular disease; ESKD, End-Stage Kidney Disease. ✔Genetically protected individuals

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor 1 . Although some MRAP2 mutations have been described in people with obesity 1 – 3 , their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance 4 . The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets. Large-scale sequencing of coding exons of MRAP2 in 9,418 adults and adolescents identifies loss-of-function mutations that are associated with monogenic obesity, hypertension and hyperglycemia.

Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA1c] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA1c had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference −0·01% points [95% CI −0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. Novo Nordisk.

Aims/hypothesisSome studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear.MethodsWe used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study’s primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation.ResultsA total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min−1 (1.73 m)−2 (SD 17) and the median urinary albumin/creatinine ratio was 14 μg/mg (interquartile range 7–38). The mean eGFR slope was −0.63 ml min−1 (1.73 m)−2 year−1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <−1.63 ml min−1 [1.73 m]−2 year−1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, −1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]).Conclusions/interpretationOur study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality.Trial registry numberClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286

Aims/hypothesisRecently, safety data signalled an increased risk of amputations in people taking canagliflozin, a sodium−glucose cotransporter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolaemia, diuretics should also increase that risk. The aim of this study was to analyse the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes.MethodsSURDIAGENE (SUivi Rénal, DIAbète de type 2 et GENEtique) is a prospective observational cohort that includes people with type 2 diabetes enrolled from 2002 to 2012 and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Primary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularisation (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline in a Cox-adjusted model.ResultsAt baseline, of the 1459 participants included, 670 were taking diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p < 0.001). The HR for LLE in users vs non-users was 2.08 (95% CI 1.49, 2.93), p < 0.001. This association remained significant in a multivariable-adjusted model (1.49 [1.01, 2.19]; p = 0.04) and similar after considering death as a competing risk (subhazard ratio 1.89 [1.35, 2.64]; p < 0.001). When separated, LLA but not LLR, was associated with the use of diuretics: 2.01 (1.14, 3.54), p = 0.02 and 1.05 (0.67, 1.64), p = 0.84, respectively, in the multivariable-adjusted model.Conclusions/interpretationAmong people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA.

We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease. D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35-0.70) whereas Pbac (1.56, 95%CI 1.12-2.15) was directly correlated. Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease.

OBJECTIVE: Water intake alters vasopressin secretion. Recent findings reveal an independent association between plasma copeptin, a surrogate for vasopressin, and risk of diabetes. RESEARCH DESIGN AND METHODS: Participants were 3,615 middle-aged men and women, with normal baseline fasting glycemia (FG), who were recruited in a 9-year follow-up study. Odds ratios (ORs) and 95% CIs for the incidence of hyperglycemia (FG ≥6.1 mmol/L or treatment for diabetes) were calculated according to daily water intake classes based on a self-administered questionnaire. RESULTS: During follow-up, there were 565 incident cases of hyperglycemia. After adjustment for confounding factors, ORs (95% CIs) for hyperglycemia associated with classes of water intake (<0.5 L, n = 677; 0.5 to <1.0 L, n = 1,754; and >1.0 L, n = 1,184) were 1.00, 0.68 (0.52–0.89), and 0.79 (0.59–1.05), respectively (P = 0.016). CONCLUSIONS: Self-reported water intake was inversely and independently associated with the risk of developing hyperglycemia.

Introduction Studies on the association between lipid levels and lipid-lowering treatment and the risk of dementia and/or cognitive decline (CD) have shown conflicting results and are few in individuals with type 2 diabetes (T2D). The aim was to evaluate the relationship of baseline LDL cholesterol levels and statin treatment with the development of dementia/CD in patients with T2D from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial. Methods Dementia was diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), and CD was defined as at least a 3-point decrement in the Mini Mental State Examination score. Exposures were baseline LDL cholesterol levels, statin treatment at baseline, and statin treatment initiation during the first 18 months of follow-up. Multinomial logistic regression was used to estimate the odds ratio (OR) and 95% CI for the composite of dementia/CD. Results Of 11,140 participants, 1827 (16.4%) developed dementia/CD over the 5-year follow up. The OR (95% CI) of dementia/CD were 1.06 (1.00–1.14) per standard deviation higher in baseline LDL cholesterol and 0.90 (0.79–1.03) for participants with vs without statin treatment. Conclusion We observed an association between LDL levels, but not statin treatment, and incident dementia/CD. Although causality cannot be determined by our study, the results are in line with multiple randomised controlled trials. However, to understand the long-term effects of lipid levels and statin treatment on dementia/CD, studies of longer follow-up are still needed.