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Background: The relationship between ankle blood pressure (BP) and cardiovascular disease remains unclear. We examined the relationships between known and new ankle BP indices and major cardiovascular outcomes in people with and without type 2 diabetes. Methods: We used data from 3 large trials with measurements of ankle systolic BP (SBP), ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). The primary outcome was a composite of cardiovascular mortality, myocardial infarction, hospitalization for heart failure, or stroke. Secondary outcomes included death from cardiovascular causes, total (fatal and non-fatal) myocardial infarction, hospitalization for heart failure, and total stroke. Results: Among 42,929 participants (age 65.6 years, females 31.3%, type 2 diabetes 50.1%, 53 countries), the primary outcome occurred in 7230 (16.8%) participants during 5 years of follow-up (19.4% in people with diabetes, 14.3% in those without diabetes). The incidence of the outcome increased with lower ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, multivariable-adjusted hazard ratios (HRs, 95% CI) of the outcome for each lower fourth were 1.05 (0.98–1.12), 1.17 (1.08–1.25), and 1.54 (1.54–1.65) for ankle SBP; HR 1.06 (0.99–1.14), 1.26 (1.17–1.35), and 1.48 (1.38–1.58) for ABI; and HR 1.02 (0.95–1.10), 1.15 (1.07–1.23), and 1.48 (1.38–1.58) for APPD. The largest effect size was noted for ankle SBP (HRs 1.05 [0.90–1.21], 1.21 [1.05–1.40], and 1.93 [1.68–2.22]), and APPD (HRs 1.08 [0.93–1.26], 1.30 [1.12–1.50], and 1.97 [1.72–2.25]) with respect to hospitalization for heart failure, while only a marginal association was observed for stroke. The relationships were similar in people with and without diabetes (all p for interaction > 0.05). Conclusions: Inverse and independent associations were observed between ankle BP and cardiovascular events, similarly in people with and without type 2 diabetes. The largest associations were observed for heart failure and the smallest for stroke. Including ankle BP indices in routine clinical assessments may help to identify people at highest risk of cardiovascular outcomes. Ankle blood pressure indices and incidence of major cardiovascular outcomes. Expanded MACE, a composite of death from cardiovascular causes, myocardial infarction,hospitalization for heart failure, or stroke. BP, blood pressure; CV, cardiovascular; HHF, hospitalization for heart failure; HR, Hazard ratio (for the lowest fourth of blood pressure indice compared to the highest); MACE, major adverse cardiovascular events; MI, myocardial infarction; Total, fatal and non-fatal MI or stroke. [ABSTRACT FROM AUTHOR]

Aim: To assess clinical and biochemical measurements that can identify people with dysglycaemia (i.e. diabetes or pre‐diabetes) who remain free of serious outcomes during follow‐up. Materials and Methods: We conducted exploratory analyses using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study to identify independent determinants of outcome‐free status in 12 537 middle‐aged and older adults with prediabetes and early type 2 diabetes from 40 countries. Serious outcome‐free status was defined as the absence of major cardiovascular outcomes, kidney or retinal outcomes, peripheral artery disease, dementia, cancer, any hospitalization, or death during follow‐up. Results: In total, 3328 (26.6%) participants remained free of serious outcomes during a median follow‐up of 6.2 years (IQR 5.8, 6.7). Independent clinical determinants of outcome‐free status included younger age, female sex, non‐White ethnicity, shorter diabetes duration, absence of previous cardiovascular disease, current or former smokers, higher grip strength, Mini‐Mental State Examination score, and ankle‐brachial index, lower body mass index and kidney disease index, and non‐use of renin‐angiotensin system drugs and beta‐blockers. In a subset of 8401 people with baseline measurements of 238 biomarkers, growth differentiation factor 15, kidney injury molecule‐1, N‐terminal pro‐brain natriuretic peptide, uromodulin, C‐reactive protein, factor VII and ferritin were independent determinants. The combination of clinical determinants and biomarkers best identified participants who remained outcome‐free (C‐statistics 0.71, 95% confidence interval 0.70‐0.73; net reclassification improvement 0.55, 95% confidence interval 0.48‐0.58). Conclusions: A set of routinely measured clinical characteristics and seven protein biomarkers identify middle‐aged and older people with prediabetes or early type 2 diabetes as least likely to experience serious outcomes during follow‐up. [ABSTRACT FROM AUTHOR]

It has long been known that some patients with type 2 diabetes (T2DM) can experience sustained metabolic improvement to near-normal levels of glycemia either spontaneously or after medical intervention. Now recognized as remission of diabetes, this intriguing state is currently more feasible than ever before due to profound advances in metabolic surgery, pharmacologic therapy, and regimens of lifestyle modification. This enhanced capacity to induce remission has revealed new pathophysiologic insights, including the presence of a reversible component of the pancreatic beta-cell dysfunction that otherwise drives the chronic progressive nature of T2DM. In doing so, it has changed the therapeutic landscape by offering new potential management objectives and considerations for patients and providers. However, the excitement around these developments must also be tempered by the sobering realities of our current understanding of remission, including the recognition that this condition may not be permanent (resulting in glycemic relapse over time) and that beta-cell function may not be normalized in the setting of remission. These limitations highlight both the many gaps in our current understanding of remission and the caution with which clinical discussions must be handled for clear patient-directed communication of the pros and cons of targeting this outcome in practice. In this mini-review, we consider this rapidly growing literature, including its implications and its limitations, and thereby seek to provide objective balanced perspectives on targeting remission of T2DM in current clinical care. [ABSTRACT FROM AUTHOR]

Aims: To estimate the incidence of a major adverse cardiovascular event (MACE) and a composite kidney outcome across estimated glomerular filtration rate (eGFR) and urine albumin‐to‐creatinine ratio (UACR) levels, and to determine whether efpeglenatide's effect varies with these indices. Materials and Methods: AMPLITUDE‐O trial data were used to estimate the relationship of eGFR, UACR, and Kidney Disease Improving Global Outcomes (KDIGO) category to the hazard of MACE and the kidney composite. Interactions on these outcomes between eGFR and the UACR, and between each of these variables and efpeglenatide were also assessed. Results: Baseline eGFR and UACR were available for 3983 participants (mean age 64.5 years). During a median follow‐up of 1.8 years, the hazards of MACE and the kidney composite for the lowest versus highest eGFR third were 1.6 (95% confidence interval [CI] 1.2, 2.2) and 2.3 (95% CI 1.9, 2.8), respectively. The hazards for the highest versus the lowest UACR third were 2.3 (95% CI 1.8, 3.1) and 18.0 (95% CI 12.7, 25.5), respectively, and for the high‐ versus low‐risk KDIGO categories the hazards were 2.4 (95% CI 1.8, 3.1) and 16.0 (95% CI 11.6, 22.0), respectively. eGFR and UACR were independent determinants of both outcomes, but negatively interacted with each other for the kidney outcome. Efpeglenatide's effect on both outcomes did not vary with any kidney disease measure (all interaction p values ≥0.26). Conclusions: In high‐risk people with diabetes, eGFR, UACR, and KDIGO category have different relationships to incident cardiovascular and kidney outcomes. The beneficial effect of efpeglenatide on these outcomes is independent of kidney‐related risk category. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether adiposity depots modulate vaspin levels and whether vaspin predicts type 2 diabetes (T2D) risk, through epidemiological and genetic analyses. RESEARCH DESIGN AND METHODS: We assessed the relationship of plasma vaspin concentration with incident and prevalent T2D and adiposity-related variables in 1) the Prospective Urban and Rural Epidemiology (PURE) biomarker substudy (N = 10,052) and 2) the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial (N = 7,840), using regression models. We then assessed whether vaspin is causally associated with T2D and whether genetic variants associated with MRI-measured adiposity depots modulate vaspin levels, using two-sample Mendelian randomization (MR). RESULTS: A 1-SD increase in circulating vaspin levels was associated with a 16% increase in incident T2D in the PURE cohort (hazard ratio 1.16; 95% CI 1.09–1.23; P = 4.26 × 10−7) and prevalent T2D in the ORIGIN cohort (odds ratio [OR] 1.16; 95% CI 1.07–1.25; P = 2.17 × 10−4). A 1-unit increase in BMI and triglyceride levels was associated with a 0.08-SD (95% CI 0.06–0.10; P = 2.04 × 10−15) and 0.06-SD (95% CI 0.04–0.08; P = 4.08 × 10−13) increase, respectively, in vaspin in the PURE group. Consistent associations were observed in the ORIGIN cohort. MR results reinforced the association between vaspin and BMI-adjusted T2D risk (OR 1.01 per 1-SD increase in vaspin level; 95% CI 1.00–1.02; P = 2.86 × 10−2) and showed that vaspin was increased by 0.10 SD per 1-SD decrease in genetically determined gluteofemoral adiposity (95% CI 0.02–0.18; P = 2.01 × 10−2). No relationships were found between subcutaneous or visceral adiposity and vaspin. CONCLUSIONS: These findings support that higher vaspin levels are related to increased T2D risk and reduced gluteofemoral adiposity, positioning vaspin as a promising clinical predictor for T2D. [ABSTRACT FROM AUTHOR]

Aim: Non‐surgical options for inducing type 2 diabetes remission are limited. We examined whether remission can be achieved by combining lifestyle approaches and short‐term intensive glucose‐lowering therapy. Methods: In this trial, 160 patients with type 2 diabetes on none to two diabetes medications other than insulin were randomised to (a) an intervention comprising lifestyle approaches, insulin glargine/lixisenatide and metformin, or (b) standard care. Participants with glycated haemoglobin (HbA1c) <7.3% (56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for an additional 52 weeks. The primary outcome was diabetes relapse defined as HbA1c ≥6.5% (48 mmol/mol) at 24 weeks or thereafter, capillary glucose ≥10 mmol/L on ≥50% of readings, or use of diabetes medications, analysed as time‐to‐event. Main secondary outcomes included complete or partial diabetes remission at 24, 36, 48 and 64 weeks defined as HbA1c <6.5% (48 mmol/mol) off diabetes medications since 12 weeks after randomisation. A hierarchical testing strategy was applied. Results: The intervention significantly reduced the hazard of diabetes relapse by 43% (adjusted hazard ratio 0.57, 95% confidence interval 0.40‐0.81; p =.002). Complete or partial diabetes remission was achieved in 30 (38.0%) intervention group participants versus 16 (19.8%) controls at 24 weeks and 25 (31.6%) versus 14 (17.3%) at 36 weeks [relative risk 1.92 (95% confidence interval 1.14‐3.24) and 1.83 (1.03‐3.26), respectively]. The relative risk of diabetes remission in the intervention versus control group was 1.88 (1.00‐3.53) at 48 weeks and 2.05 (0.98‐4.29) at 64 weeks. Conclusions: A 12‐week intensive intervention comprising insulin glargine/lixisenatide, metformin and lifestyle approaches can induce remission of diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function–related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants. RESEARCH DESIGN AND METHODS: Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function–related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2). RESULTS: The post hoc composite kidney function–related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62–0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58–0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (−1.37 vs. −1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups. CONCLUSIONS: The estimated 25% reduced hazard of a kidney function–related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

In early type 2 diabetes, the strategy of "induction" with short-term intensive insulin therapy followed by "maintenance" with metformin can stabilize pancreatic beta-cell function in some patients but not others. We thus sought to elucidate determinants of sustained stabilization of beta-cell function. In this secondary analysis of ClinicalTrials.Gov NCT02192424, adults with ≤5-years diabetes duration were randomized to 3-weeks induction insulin therapy (glargine/lispro) followed by metformin maintenance either with or without intermittent 2-week courses of insulin every 3-months for 2-years. Sustained stabilization (higher beta-cell function at 2-years than at baseline) was achieved in 55 of 99 participants. Independent predictors of sustained stabilization were the change in beta-cell function during induction and changes in hepatic insulin resistance and alanine aminotransferase during maintenance. Thus, initial reversibility of beta-cell dysfunction during induction and subsequent preservation of hepatic insulin sensitivity during maintenance are associated with sustained stabilization of beta-cell function following short-term insulin and metformin. ClinicalTrials.Gov NCT02192424 In early type 2 diabetes, "induction" with short-term insulin therapy followed by "maintenance" with metformin can stabilize beta-cell function. The authors show that initial reversibility of beta-cell dysfunction followed by preserved hepatic insulin sensitivity determine sustained stabilization. [ABSTRACT FROM AUTHOR]

Keywords: GLP-1 receptor agonists; lixisentatide; natriuretic peptides; randomized controlled trial EN GLP-1 receptor agonists lixisentatide natriuretic peptides randomized controlled trial 1125 1129 5 03/08/23 20230401 NES 230401 BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) lower glucose, weight and blood pressure, and reduce cardiovascular and kidney outcomes in people with type 2 diabetes (T2D).[1], [2], [3] Although mechanisms for their effects remain unclear, small recent studies have reported that they may reduce natriuretic peptides.[4] B-type natriuretic peptide (BNP) and its inactive precursor N-terminal-pro BNP (NT-proBNP) were measured at baseline and follow-up in the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial. GLP-1 receptor agonists, lixisentatide, natriuretic peptides, randomized controlled trial 2 Abbreviation: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; COPD, chronic obstructive pulmonary disease; GFR, glomerular filtration rate; NT-proBNP, N terminal, pro-hormone B-type natriuretic peptide. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. [Extracted from the article]

Background: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain. Methods: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ2 statistic for trend. Results: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5–0.86]; P =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63–1.06]; P =0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P =0.011; HR, 0.85 for 4 mg, P =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P <0.0001; HR, 0.73 for 4 mg, P =0.0009), MACE or any death (HR, 0.67 for 6 mg, P =0.0021; HR, 0.81 for 4 mg, P =0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P =0.0072; HR, 0.97 for 4 mg, P =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P =0.0002; HR, 0.81 for 4 mg, P =0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018). Conclusions: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496298. [ABSTRACT FROM AUTHOR]

Aim: To compare the efficacy and safety of a simple daily titration algorithm compared with a weekly dose adjustment of iGlarLixi in people with type 2 diabetes. Materials and Methods: LixiLan ONE CAN (NCT03767543), a randomized, 26‐week, open‐label, multicentre phase 3 trial conducted in Canada, involved 265 people with type 2 diabetes and an HbA1c of ≥7.5% to ≤ 10.5% or less (≥58 to ≤91 mmol/mol) on basal insulin for 6 months or longer. Participants were randomized 1:1 with instructions to self‐titrate iGlarLixi daily (1 unit/day) or once weekly (2 or 4 units/week) to a common target fasting plasma glucose of 4.4 to 5.6 mmol/L (79 to 101 mg/dl). The primary objective was to show non‐inferiority of the daily versus weekly titration algorithm. Results: At 26 weeks, daily titration of iGlarLixi was not inferior to a weekly titration for both the prespecified primary endpoint of change in HbA1c from baseline (least square [LS] mean change: −1.24% vs. −0.92%, respectively; LS mean difference: 0.32%; 95% CI [0.07, 0.57]; P <.0001) and for the secondary endpoint of change in weight from baseline (LS mean change: −0.22 vs. +0.81 kg, respectively; LS mean difference: 1.03 kg; 95% CI [0.01, 2.06]; P <.0001). Indeed, for both the primary and secondary outcome, the daily titration of iGlarLixi was superior. There were no statistically significant differences in hypoglycaemia incidence between the two titration strategies during the 26‐week study. Conclusion: A daily titration algorithm for switching basal insulin to iGlarLixi was shown to be non‐inferior and superior for glycaemic control and weight compared with weekly titration. [ABSTRACT FROM AUTHOR]

Aim: To assess cardiovascular, glycaemic, weight and safety outcomes of long‐term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher. Materials and Methods: Intention‐to‐treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%. Results: Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin‐treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment‐by‐baseline HbA1c group interaction was significant for HbA1c change from baseline (P <.001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results. Conclusions: The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once‐weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit–risk profile and can be considered in patients with comparatively well‐controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits. [ABSTRACT FROM AUTHOR]

Objective: To use protein biomarkers to identify people with type 2 diabetes at high risk of cardiovascular outcomes and death.Research Design and Methods: Biobanked serum from 4,957 ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial participants was analyzed. Forward-selection Cox models identified independent protein risk factors for major adverse cardiovascular events (MACE) and death that were compared with a previously validated biomarker panel.Results: NT-proBNP and osteoprotegerin predicted both outcomes. In addition, trefoil factor 3 predicted MACE, and angiopoietin-2 predicted death (C = 0.70 and 0.79, respectively, compared with 0.63 and 0.66 for clinical variables alone). These proteins had all previously been identified and validated. Notably, C statistics for just NT-proBNP plus clinical risk factors were 0.69 and 0.78 for MACE and death, respectively.Conclusions: NT-proBNP and other proteins independently predict cardiovascular outcomes in people with type 2 diabetes following acute coronary syndrome. Adding other biomarkers only marginally increased NT-proBNP's prognostic value. [ABSTRACT FROM AUTHOR]

Background: Health coaching is an emerging intervention that has been shown to improve clinical and patient-relevant outcomes for type 2 diabetes. Advances in artificial intelligence may provide an avenue for developing a more personalized, adaptive, and cost-effective approach to diabetes health coaching. Objective: We aim to apply Q-learning, a widely used reinforcement learning algorithm, to a diabetes health-coaching data set to develop a model for recommending an optimal coaching intervention at each decision point that is tailored to a patient’s accumulated history. Methods: In this pilot study, we fit a two-stage reinforcement learning model on 177 patients from the intervention arm of a community-based randomized controlled trial conducted in Canada. The policy produced by the reinforcement learning model can recommend a coaching intervention at each decision point that is tailored to a patient’s accumulated history and is expected to maximize the composite clinical outcome of hemoglobin A1c reduction and quality of life improvement (normalized to [ 0, 1 ], with a higher score being better). Our data, models, and source code are publicly available. Results: Among the 177 patients, the coaching intervention recommended by our policy mirrored the observed diabetes health coach’s interventions in 17.5% (n=31) of the patients in stage 1 and 14.1% (n=25) of the patients in stage 2. Where there was agreement in both stages, the average cumulative composite outcome (0.839, 95% CI 0.460-1.220) was better than those for whom the optimal policy agreed with the diabetes health coach in only one stage (0.791, 95% CI 0.747-0.836) or differed in both stages (0.755, 95% CI 0.728-0.781). Additionally, the average cumulative composite outcome predicted for the policy’s recommendations was significantly better than that of the observed diabetes health coach’s recommendations (tn-1=10.040; P<.001). Conclusions: Applying reinforcement learning to diabetes health coaching could allow for both the automation of health coaching and an improvement in health outcomes produced by this type of intervention. [ABSTRACT FROM AUTHOR]

Background: The estimated glomerular filtration rate (eGFR) and the albumin-to-creatinine ratio (ACR) are risk factors for diabetes-related outcomes. A composite that captures information from both may provide a simpler way of assessing risk. Methods: 9115 of 9901 Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) participants with both an ACR and eGFR at baseline were included in this post hoc epidemiologic analysis. The hazard of higher baseline levels of 1/eGFR and natural log transformed ACR (calculated as ln [ACR × 100] to eliminate negative values) and their interaction for incident major adverse cardiovascular events (MACE), kidney outcomes, and deaths was estimated. The hazard of the geometric mean of these two baseline measures (the kidney disease index or KDI) was also assessed. Results: A non-linear relationship was observed between 1/eGFR and all three outcomes, and between ln [ACR × 100] and the kidney outcome. There was also a negative interaction between these two risk factors with respect to MACE and death. Conversely, a linear relationship was noted between the KDI and all three outcomes. People in the highest KDI fifth experienced the highest incidence of MACE, death, and the kidney outcome (4.43, 4.56, and 5.55/100 person-years respectively). C statistics for the KDI were similar to those for eGFR and albuminuria. Conclusions: The KDI combines the baseline eGFR and ACR into a novel composite risk factor that has a simple linear relationship with incident serious outcomes in people with diabetes and additional CV risk factors. Trial Registration clinicaltrials.gov NCT01394952. [ABSTRACT FROM AUTHOR]

Aim: To assess the occurrence of atrial fibrillation or atrial flutter (atrial arrhythmias [AA]) in patients with type 2 diabetes treated with once‐weekly subcutaneous dulaglutide versus placebo. Materials and Methods: Patients without electrocardiographic (ECG)‐confirmed AA at baseline and randomized in the REWIND trial were assessed for the development of AA based on an annual ECG. Additional analyses included whether dulaglutide compared with placebo reduced the composite outcome of AA or death, AA or cardiovascular death, AA or stroke and AA or heart failure. Results: Among 9543 participants (mean age 66 ± 7 years, with cardiovascular risk factors and 31% with previous cardiovascular disease) without AA at entry in the trial, 524 patients (5.5%) had at least one episode of AA during the median 5.4 years of follow‐up. Incident AA occurred in 269 of the 4769 participants allocated to dulaglutide (5.6%), at a rate of 10.7 per 1000 person‐years, versus 255 of the 4774 allocated to placebo (5.3%), at a rate of 10.5 per 1000 person‐years (P =.59). There was also no effect of dulaglutide on the composite outcome of AA and death or AA and heart failure. Conclusion: This post hoc analysis of data from the REWIND trial showed that treatment with dulaglutide was not associated with a reduced incidence of AA in this at‐risk group of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association of a multicomponent advanced glycation end product (AGE) panel with decline in kidney function and its utility in predicting renal function loss (RFL) when added to routine clinical measures in type 2 diabetes.Research Design and Methods: Carboxymethyl and carboxyethyl lysine and methylglyoxal, 3-deoxyglucosone, and glyoxal hydroimidazolones were measured in baseline serum and plasma samples, respectively, from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (n = 1,150) and Veterans Affairs Diabetes Trial (VADT) (n = 447) participants. A composite AGE score was calculated from individual AGE z scores. The primary outcome was a sustained 30% decline in estimated glomerular filtration rate (eGFR) (30% RFL in both cohorts). Secondary outcomes (in ACCORD) were 40% RFL, macroalbuminuria, and high-risk chronic kidney disease (hrCKD).Results: After adjustment for baseline and follow-up HbA1c and other risk factors in ACCORD, the AGE score was associated with reduction in eGFR (β-estimate -0.66 mL/min ⋅ 1.73 m2 per year; P = 0.001), 30% RFL (hazard ratio 1.42 [95% CI 1.13-1.78]; P = 0.003), 40% RFL (1.40 [1.13-1.74]; P = 0.003), macroalbuminuria (1.53 [1.13-2.06]; P = 0.006), and hrCKD (1.88 [1.37-2.57]; P < 0.0001). AGE score improved net reclassification (NRI) and relative integrated discrimination (IDI) for 30% RFL (NRI 23%; P = 0.02) (relative IDI 7%; P = 0.009). In VADT, the AGE score calculated by the ACCORD-derived coefficients was associated with 30% RFL (1.37 [1.03-1.82); P = 0.03) and improved NRI (24%; P = 0.03) but not IDI (P = 0.18).Conclusions: These data provide further support for a causal role of AGEs in diabetic nephropathy independently of glycemic control and suggest utility of the composite AGE panel in predicting long-term decline in renal function. [ABSTRACT FROM AUTHOR]

Improvement of glucose levels into the normal range can occur in some people living with diabetes, either spontaneously or after medical interventions, and in some cases can persist after withdrawal of glucose-lowering pharmacotherapy. Such sustained improvement may now be occurring more often due to newer forms of treatment. However, terminology for describing this process and objective measures for defining it are not well established, and the long-term risks versus benefits of its attainment are not well understood. To update prior discussions of this issue, an international expert group was convened by the American Diabetes Association to propose nomenclature and principles for data collection and analysis, with the goal of establishing a base of information to support future clinical guidance. This group proposed "remission" as the most appropriate descriptive term, and HbA1c <6.5% (48 mmol/mol) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion. The group also made suggestions for active observation of individuals experiencing a remission and discussed further questions and unmet needs regarding predictors and outcomes of remission. [ABSTRACT FROM AUTHOR]

Context: A correlation between myopia and insulin resistance has been suggested. Objective: We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Methods: This population-based, retrospective, cohort study comprised 1 329 705 adolescents (579 543 women, 43.6%) aged 16 to 19 years, who were medically examined before mandatory military service during 1993 to 2012, and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right-eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results: There was an interaction between myopia and sex with T2D (P < .001). For women, T2D incidence rates (per 100 000 person-years) were 16.6, 19.2, and 25.1 for those without myopia, and with mild-to-moderate and high myopia, respectively. These corresponded to HRs of 1.29 (95% CI, 1.14-1.45) and 1.63 (1.21-2.18) for women with mildto- moderate and high myopia, respectively, compared to those without myopia, after adjustment for age at study entry, birth year, adolescent body mass index, cognitive performance, socioeconomic status, and immigration status. Results persisted in extensive sensitivity and subgroup analyses. When managed as a continuous variable, every 1-diopter lower spherical equivalent yielded a 6.5% higher adjusted HR for T2D incidence (P = .003). There was no significant association among men. Conclusion: For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to evaluate remission of type 2 diabetes following a short-term intervention with insulin glargine, sitagliptin/metformin, and lifestyle approaches.Research Design and Methods: In this open multicenter trial, 102 patients with type 2 diabetes were randomized to 1) a 12-week intervention with sitagliptin/metformin, insulin glargine, and lifestyle therapy or 2) control group. Participants with HbA1c <7.3% (<56 mmol/mol) at 12 weeks were asked to stop diabetes medications and were followed for evidence of relapse over 52 weeks. Diabetes relapse criteria included HbA1c ≥6.5% (≥48 mmol/mol), ≥50% of capillary glucose readings >10 mmol/L over 1 week, and reinitiation of diabetes medications with or without abnormal fasting plasma glucose (FPG) or 2-h plasma glucose on an oral glucose tolerance test (OGTT). Time-to-relapse analysis was conducted to compare the treatment groups with (primary analysis) and without (supplementary analysis) FPG/OGTT relapse criteria.Results: With the FPG/OGTT relapse criteria included, the hazard ratio (HR) of relapse was 0.72 (95% CI 0.47-1.10) in the intervention group compared with the control group (primary analysis), and the number of participants remaining in remission was not significantly different between treatment groups at 24, 36, 48, and 64 weeks. In the supplementary analyses without these criteria, HR of relapse was 0.60 (95% CI 0.39-0.95), and the number of participants remaining in remission was significantly higher (26 vs. 10%) in the intervention group at 36 weeks.Conclusions: Although our primary outcome was not statistically significant, the tested approach deserves further study with further optimization of its components. [ABSTRACT FROM AUTHOR]

Background: The prevalence of both asthma and early-onset diabetes is on the rise; however, the association between them remains unclear. We examined a possible association of asthma at adolescence with type 2 diabetes in young adulthood.Methods: This is a nationwide, population-based study of 1 718 541 Israeli adolescents (57% males; mean age 17.3 years; range 16-19 years), examined before compulsory military service between 1992 and 2016, with data linked to the Israeli National Diabetes Registry. Asthma diagnosis and severity were determined by a board-certified pulmonologist and based on spirometry tests.Results: Type 2 diabetes developed in 58/9090 (0.64%), 507/97 059 (0.52%), 114/23 332 (0.49%), and 7095/1 589 060 (0.44%) persons with moderate-to-severe, mild, inactive, and no history of asthma, respectively, during a mean follow-up >13 years. The respective odds ratios (ORs) were 1.33 (95% CI, 1.02-1.74), 1.17 (1.06-1.28), and 1.09 (0.9-1.31), considering those without asthma history as the reference, in a model adjusted for birth year, sex, body mass index, and other sociodemographic variables. The association persisted when the analysis accounted for coexisting morbidities, and when persons without asthma, individually matched by age, sex, birth year, and body mass index were the reference. Both mild and moderate-to-severe asthma were associated with type 2 diabetes before age 35 years: ORs 1.18 (1.05-1.34) and 1.44 (1.05-2.00), respectively. The strength of the association was accentuated over time. The effect was unchanged when adjusted for oral and inhaled glucocorticoid use.Conclusion: Adolescents with active asthma have higher risk to develop type 2 diabetes. This seems related to disease severity, independent of adolescent obesity status, apparent before age 35 years, and more pronounced in recent years. [ABSTRACT FROM AUTHOR]

Background: The REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial. Methods: Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model. Results: Although all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively). Conclusions: Treatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952 [ABSTRACT FROM AUTHOR]

Context: Thyroid hormones play a key role in systemic metabolism, yet the relationship between thyroid dysfunction and risk for type 2 diabetes is unclear.Objective: To assess type 2 diabetes risk in adulthood among adolescents with thyroid disorders.Design and Setting: A nationwide, population-based study of Israeli adolescents who were examined before military recruitment during 1988 to 2007 and were followed until December 31, 2016.Participants: 1 382 560 adolescents (mean age 17.3 years).Interventions: The diagnosis of thyroid disorders was based on recent thyroid function tests. Data were linked to the Israeli National Diabetes Registry. Cox proportional hazard models were applied.Main Outcome Measures: Type 2 diabetes incidence.Results: During a mean follow-up of 18.5 years, 1.12% (69 of 6,152) of adolescents with thyroid disorders were diagnosed with type 2 diabetes vs 0.77% of adolescents without thyroid disorders. The hazard ratio (HR) for type 2 diabetes was 2.3 (95% CI, 1.8-2.9) among those with thyroid disorders, after adjustment for sex, birth-year, body mass index, and sociodemographic confounders. The increased diabetes risk was observed in both men and women, with the presence or absence of obesity, and in the absence of other health conditions and was associated with different types of thyroid disorders. It was also similar when the outcome was defined as type 2 diabetes diagnosed at or before the age of 30 years (HR 2.3, 95% CI, 1.5-3.5).Conclusions: Thyroid disorders diagnosed in adolescence are a risk factor for early-onset type 2 diabetes in both men and women. [ABSTRACT FROM AUTHOR]

Aim: To test the hypothesis that the addition of periodic courses of short‐term intensive insulin therapy (IIT) could enhance the effect of metformin (MET) maintenance therapy on preservation of beta‐cell function following induction IIT. Methods: In this multicentre, randomized controlled trial, 108 adults with type 2 diabetes (median 1.3 years' duration; HbA1c 6.6% ± 0.6%) were randomized to 3 weeks of induction IIT (glargine, lispro) followed by MET maintenance, either with or without periodic 2‐week courses of IIT every 3 months for 2 years. Beta‐cell function was assessed by the Insulin Secretion Sensitivity Index‐2 (ISSI‐2) at an oral glucose tolerance test every 3 months. Results: In both arms, induction IIT increased ISSI‐2, improved whole‐body insulin sensitivity and reduced hepatic insulin resistance (all P ≤.0004). The primary outcome of baseline‐adjusted ISSI‐2 at 2 years was not improved by the addition of intermittent IIT (MET + IIT) and was slightly higher in the MET arm (baseline‐adjusted difference −35 [95% CI: −66, –3]), with three additional beta‐cell measures showing no significant differences. Baseline‐adjusted HbA1c at 2 years did not differ between MET and MET + IIT (6.3% ± 0.1% vs. 6.4% ± 0.1%, P =.46), with 32.6% of participants in each arm maintaining HbA1c of 6.0% or less at 2 years. Conclusion: Although initial induction IIT induces metabolic improvement, subsequent repeat courses of IIT every 3 months do not further enhance the effect of MET maintenance therapy on beta‐cell function. [ABSTRACT FROM AUTHOR]

Context: Dulaglutide reduced major adverse cardiovascular events (MACE) in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial. Its efficacy and safety in older vs younger patients have not been explicitly analyzed.Objective: This work aimed to assess efficacy and safety of dulaglutide vs placebo in REWIND by age subgroups (≥ 65 and < 65 years).Methods: A post hoc subgroup analysis of REWIND was conducted at 371 sites in 24 countries. Participants included type 2 diabetes patients aged 50 years or older with established cardiovascular (CV) disease or multiple CV risk factors, and a wide range of glycemic control. Patients were randomly assigned (1:1) to dulaglutide 1.5 mg or placebo as an add-on to country-specific standard of care. Main outcomes measures included MACE (first occurrence of the composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or unknown causes).Results: There were 5256 randomly assigned patients who were 65 years or older (mean = 71.0), and 4645 were younger than 65 years (mean = 60.7). Baseline characteristics were similar in randomized treatment groups. Dulaglutide treatment showed a similar reduction in the incidence (11% vs 13%) of MACE in older vs younger patients. The rate of permanent study drug discontinuation, incidence of all-cause mortality, hospitalizations for heart failure, severe hypoglycemia, severe renal or urinary events, and serious gastrointestinal events were similar between randomized treatment groups within each age subgroup. The incidence rate of serious cardiac conduction disorders was numerically higher in the dulaglutide group compared to placebo within each age subgroup but the difference was not statistically significant.Conclusion: Dulaglutide had similar efficacy and safety in REWIND in patients65 years and older and those younger than 65 years. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association between stuttering in adolescence and incident type 2 diabetes in young adulthood.Methods: This nationwide population-based study included 2 193 855 adolescents of age 16 to 20 years who were assessed for military service between 1980 and 2013. Diagnoses of stuttering in adolescence were confirmed by a speech-language pathologist. Diabetes status for each individual as of December 31, 2016, was determined by linkage to the Israeli National Diabetes Registry. Relationships were analyzed using regression models adjusted for socioeconomic variables, cognitive performance, coexisting morbidities, and adolescent body mass index.Results: Analysis was stratified by sex (Pinteraction = 0.035). Of the 4443 (0.4%) adolescent men with stuttering, 162 (3.7%) developed type 2 diabetes, compared with 25 678 (2.1%) men without stuttering (adjusted odds ratio [OR] 1.3; 95% CI, 1.1-1.6). This relationship persisted when unaffected brothers of men with stuttering were used as the reference group (adjusted OR = 1.5; 95% CI, 1.01-2.2), or when the analysis included only adolescents with unimpaired health at baseline (adjusted OR = 1.4; 95% CI, 1.1-1.7). The association was stronger in later birth cohorts, with an adjusted OR of 2.4 (1.4-4.1) for cases of type 2 diabetes before age 40. Of the 503 (0.1%) adolescent women with stuttering 7 (1.4%) developed type 2 diabetes, compared with 10 139 (1.1%) women without stuttering (OR = 2.03; 95% CI, 0.48-2.20).Conclusions: Adolescent stuttering is associated with an increased risk for early-onset type 2 diabetes among men. [ABSTRACT FROM AUTHOR]

Keywords: Editorials; diabetes complications; diabetes mellitus, type 2; follow-up studies; lifestyle; metformin; prevention EN Editorials diabetes complications diabetes mellitus, type 2 follow-up studies lifestyle metformin prevention 1642 1644 3 05/26/22 20220531 NES 220531 Diabetes can only be diagnosed when an individual is clearly hyperglycemic, as defined by established thresholds of fasting glucose, 2-hour postload glucose, random glucose (with symptoms), and/or HbA1c (hemoglobin A1c) concentrations. The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study). [Extracted from the article]

Aim: The effect of the weekly exendin‐based glucagon‐like peptide‐1 receptor agonist efpeglenatide on cardiovascular (CV) outcomes in high‐risk patients with type 2 diabetes (T2DM) with and without chronic kidney disease (CKD) is unknown. Materials and methods: People with T2DM and glycated haemoglobin >7%, ≥18 years old with previous CV disease, or ≥50 years old with CKD [defined as an estimated glomerular filtration rate (eGFR) of 25–59.9 mL/min/1.73 m2], and one or more additional CV risk factors were recruited. Participants were randomized in a 1:1:1 ratio, stratified by current, intended or neither current nor intended use of a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor to receive weekly injections of efpeglenatide (4 mg or 6 mg) or masked placebo. The primary outcome is a major adverse CV event defined as non‐fatal myocardial infarction, non‐fatal stroke or CV death. Secondary outcomes include a composite kidney outcome (new onset macroalbuminuria with an increase from baseline of ≥30%, sustained 40% decrease in eGFR, renal replacement therapy, or sustained eGFR <15 mL/min/1.73 m2). The trial will continue until ≥330 participants have had a major adverse CV event outcome and the sample size was based on accruing enough outcomes to detect non‐inferiority of efpeglenatide versus placebo. Results: Recruitment of 4076 participants (33% women, mean age 64.5 years) occurred between 11 May 2018 and 25 April 2019 at 344 sites in 28 countries. Mean baseline glycated haemoglobin was 8.9% (1.5), 31.6% had an eGFR <60 mL/min/1.73 m2, 89.5% had previous CV disease and 15.0% were on an SGLT2 inhibitor. Conclusions: The results of the AMPLITUDE O trial will inform the use of exendin‐based glucagon‐like peptide‐1 receptor agonist to people with T2DM and high CV risk, with and without CKD, in the presence and absence of an SGLT2 inhibitor. [ABSTRACT FROM AUTHOR]

Context: The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear.Objective: To assess type 2 diabetes risk among adolescents with NAFLD.Design and Setting: A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997-2011 and were followed until December 31, 2016.Participants: A total of 1 025 796 normoglycemic adolescents were included.Interventions: Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry.Main Outcome Measures: Type 2 diabetes incidence.Results: During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47-4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]).Conclusions: Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years. [ABSTRACT FROM AUTHOR]

Objective: The effects of preventive interventions on cardiovascular autonomic neuropathy (CAN) remain unclear. We examined the effect of intensively treating traditional risk factors for CAN, including hyperglycemia, hypertension, and dyslipidemia, in individuals with type 2 diabetes (T2D) and high cardiovascular risk participating in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.Research Design and Methods: CAN was defined as heart rate variability indices below the fifth percentile of the normal distribution. Of 10,251 ACCORD participants, 71% (n = 7,275) had a CAN evaluation at study entry and at least once after randomization. The effects of intensive interventions on CAN were analyzed among these subjects through generalized linear mixed models.Results: As compared with standard intervention, intensive glucose treatment reduced CAN risk by 16% (odds ratio [OR] 0.84, 95% CI 0.75-0.94, P = 0.003)-an effect driven by individuals without cardiovascular disease (CVD) at baseline (OR 0.73, 95% CI 0.63-0.85, P < 0.0001) rather than those with CVD (OR 1.10, 95% CI 0.91-1.34, P = 0.34) (Pinteraction = 0.001). Intensive blood pressure (BP) intervention decreased CAN risk by 25% (OR 0.75, 95% CI 0.63-0.89, P = 0.001), especially in patients ≥65 years old (OR 0.66, 95% CI 0.49-0.88, P = 0.005) (Pinteraction = 0.05). Fenofibrate did not have a significant effect on CAN (OR 0.91, 95% CI 0.78-1.07, P = 0.26).Conclusions: These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive BP control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention. [ABSTRACT FROM AUTHOR]

Background: Long-term glycemic control reduces retinopathy risk, but transient worsening can occur with glucose control intensification. Glucagon-like peptide 1 receptor agonists (GLP-1RA) lower glucose, but the long-term impact on retinopathy is unknown. GLP-1RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes.Purpose: To examine the associations between retinopathy, HbA1c, systolic blood pressure (SBP), and weight in GLP-1RA CVOTs.Data Sources: Systematic review identified six placebo-controlled GLP-1RA CVOTs reporting prespecified retinopathy outcomes.Study Selection: Published trial reports were used as the primary data sources.Data Extraction: HbA1c, SBP, and weight data throughout follow-up by treatment group were extracted.Data Synthesis: Random-effects model meta-analysis showed no association between GLP-1RA treatment and retinopathy (odds ratio [OR] 1.10; 95% CI 0.93, 1.30), with high heterogeneity between studies (I2 = 52.2%; Q statistic P = 0.063). Univariate meta-regression showed an association between retinopathy and average HbA1c reduction during the overall follow-up (slope = 0.77, P = 0.007), but no relationship for SBP or weight. Sensitivity analyses for HbA1c showed a relationship at 3 months (P = 0.006) and 1 year (P = 0.002). A 0.1% (1.09 mmol/mol) increase in HbA1c reduction was associated with 6%, 14%, or 8% increased Ln(OR) for retinopathy at the 3-month, 1-year, and overall follow-up, respectively.Limitations: CVOTs were not powered to assess retinopathy outcomes and differed in retinopathy-related criteria and methodology. The median follow-up of 3.4 years is short compared with the onset of retinopathy.Conclusions: HbA1c reduction was significantly associated with increased retinopathy risk in meta-regression for GLP-1RA CVOTs. The magnitude of HbA1c reduction was correlated with retinopathy risk in people with diabetes and additional cardiovascular risk factors, but the long-term impact of improved glycemic control on retinopathy was unmeasured in these studies. Retinopathy status should be assessed when intensifying glucose-lowering therapy. [ABSTRACT FROM AUTHOR]

Background: Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial.Methods: REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952.Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018).Interpretation: Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated.Funding: Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes (T2D) is increasingly diagnosed at younger ages. We investigated the association of adolescent obesity with incident T2D at early adulthood.Research Design and Methods: A nationwide, population-based study evaluated 1,462,362 adolescents (59% men, mean age 17.4 years) during 1996-2016. Data were linked to the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied.Results: During 15,810,751 person-years, 2,177 people (69% men) developed T2D (mean age at diagnosis 27 years). There was an interaction among BMI, sex, and incident T2D (Pinteraction = 0.023). In a model adjusted for sociodemographic variables, the hazard ratios for diabetes diagnosis were 1.7 (95% CI 1.4-2.0), 2.8 (2.3-3.5), 5.8 (4.9-6.9), 13.4 (11.5-15.7), and 25.8 (21.0-31.6) among men in the 50th-74th percentile, 75th-84th percentile, overweight, mild obesity, and severe obesity groups, respectively, and 2.2 (1.6-2.9), 3.4 (2.5-4.6), 10.6 (8.3-13.6), 21.1 (16.0-27.8), and 44.7 (32.4-61.5), respectively, in women. An inverse graded relationship was observed between baseline BMI and mean age of T2D diagnosis: 27.8 and 25.9 years among men and women with severe obesity, respectively, and 29.5 and 28.5 years among low-normal BMI (5th-49th percentile; reference), respectively. The projected fractions of adult-onset T2D that were attributed to high BMI (≥85th percentile) at adolescence were 56.9% (53.8-59.9%) and 61.1% (56.8-65.2%) in men and women, respectively.Conclusions: Severe obesity significantly increases the risk for incidence of T2D in early adulthood in both sexes. The rise in adolescent severe obesity is likely to increase diabetes incidence in young adults in coming decades. [ABSTRACT FROM AUTHOR]

Aims: Chronic hyperglycaemia, assessed by elevated glycated haemoglobin (A1C), is a known risk factor for heart failure (HF) and cardiovascular (CV) death among subjects with diabetes. Whether this risk varies with left ventricular ejection fraction (LVEF) is unknown. This study evaluated whether A1C influences a composite outcome of either HF hospitalization or CV death differently along the spectrum of LVEF.Methods and Results: We assessed the relationships of baseline A1C and LVEF with a composite outcome of either CV death or HF hospitalization in the 4091 patients with type 2 diabetes and a recent acute coronary syndrome enrolled in the ELIXA trial who had available LVEF. We assessed for interaction between A1C and LVEF as continuous variables with respect to this outcome. During a median follow-up of 25.7 months, 343 patients (8.4%) had HF hospitalization or died of CV causes. In a multivariable model, A1C and LVEF were each associated with an increased risk of HF hospitalization or CV death [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.21 per 1% higher A1C, and adjusted HR 1.39, 95% CI 1.27-1.51 per 10% lower in LVEF]. Both A1C and LVEF were independently and incrementally associated with risk without evidence of interaction (P for interaction = 0.31). Patients with A1C ≥ 8% and LVEF <40% were at threefold higher risk than those with A1C < 7% and LVEF ≥50% (adjusted HR 3.18, 95% CI 2.03-4.98, P < 0.001).Conclusion: In a contemporary cohort of patients with type 2 diabetes and acute coronary syndrome, baseline chronic hyperglycaemia was associated with an increased risk of HF hospitalization or CV death independently of LVEF. [ABSTRACT FROM AUTHOR]

Objective: To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach.Research Design and Methods: A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200).Results: Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P = 1.79 × 10-7). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P = 8.73 × 10-4). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P = 0.007 for difference).Conclusions: These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers.Research Design and Methods: The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated.Results: During 6.2 years of median follow-up, the median annual change in eGFR was -0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors, as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality.Conclusions: Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia. [ABSTRACT FROM AUTHOR]

Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.Findings: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy.Interpretation: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.Funding: Eli Lilly and Company. [ABSTRACT FROM AUTHOR]

Aim: To examine the generalizability of results from glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population. Materials and methods: Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN‐6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria. Results: No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN‐6, and 12.9% in LEADER. Conclusions: Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP‐1 RA CVOTs. [ABSTRACT FROM AUTHOR]

We compared cardiovascular and other outcomes in patients with dysglycaemia with or without anti‐glutamic acid dehydrogenase (GAD) antibodies participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Of the 12 537 participants, 8162 had anti‐GAD measured at baseline and 267 were anti‐GAD positive. The effects of insulin glargine versus standard care and of n‐3 fatty acids supplements versus placebo were compared by testing the interaction of the treatment effects and anti‐GAD status. The effect of glargine on development of new diabetes was assessed in participants without previous diabetes at baseline. The overall incidence of outcomes did not differ between anti‐GAD positive and anti‐GAD negative subjects. The incidence of the composite of cardiovascular death, non‐fatal myocardial infarction, or non‐fatal stroke did not differ between anti‐GAD positive participants randomized to insulin glargine or to standard care, with a hazard ratio (HR) (95% confidence interval [CI]) of 0.80 (0.44‐1.44) or in anti‐GAD negative participants with a HR of 1.07 (0.96‐1.20) (P for interaction = 0.20). [ABSTRACT FROM AUTHOR]