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Introduction: In the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial, weekly subcutaneous dulaglutide 1.5 mg, a glucagon-like peptide-1 receptor agonist, compared with matched placebo reduced MACE (cardiovascular [CV] death, non-fatal myocardial infarction or non-fatal stroke) (594 versus 663 events) in 9901 participants with type 2 diabetes at moderate CV risk [mean (SD) age 66.2 (6.5) years, 46.3% women, 31% with chronic CV disease and the others with CV risk factors] and followed for a median of 5.4 years. These findings, based on a time to first event analysis, do not reflect total CV event or mortality burden. Objective: To better reflect the burden of disease, the following outcomes were assessed: 1) total number of MACE or fatal events and 2) total number of CV (MACE, unstable angina, heart failure or revascularization) or fatal events in the REWIND participants. Methods: Incidence was estimated per 1000 person-years (py), and hazard ratios (HR) were calculated using conditional time gap and proportional means models. Results: A total of 1972 MACE outcomes or deaths and of 3673 CV outcomes or deaths occurred in the 9901 participants. Of the1128 all-cause deaths, 465 were non-CV. The incidence of total MACE or deaths was 35.8 in the dulaglutide group versus 40.3/1000 py in the placebo group [absolute reduction=4.5/1000 py; conditional time gap HR, 0.90 (95%CI, 0.82-0.98), P =0.020, and proportional means HR, 0.89 (95% CI, 0.80-0.98), P =0.022]. The incidence of total CV or fatal events on dulaglutide was 67.1 and 74.7/1000 py on placebo [absolute reduction=7.6/1000 py; conditional time gap HR, 0.93 (95% CI, 0.87-0.99), P =0.023, and proportional means HR, 0.90 (95% CI 0.82-0.99), P =0.028]. Similar effect sizes were noted for the first occurrence of MACE or deaths such that the absolute risk reduction was 4.1/ 1000 py. Conclusions: These findings suggest that weekly subcutaneous dulaglutide was associated with reduced total MACE, CV or fatal event burden in people with type 2 diabetes and moderate CV risk. This analysis illustrates the clinical relevance of assessing total events in addition to first events in clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique Identifier NCT01394952)

Objectives: 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 persons 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 5th percentile of the normal distribution. Of 10,250 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 to standard intervention, intensive glucose treatment reduced CAN risk by 16% (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 Conclusions: These data confirm a beneficial effect of intensive glycemic therapy and demonstrate, for the first time, a similar benefit of intensive blood pressure control on CAN in T2D. A negative CVD history identifies T2D patients who especially benefit from intensive glycemic control for CAN prevention.

Digital, OBJECTIVE We aimed to compare cardiovascular (CV) events, all-cause mortality, and CV mortality rates among adults with and without diabetes in countries with differing levels of income. RESEARCH DESIGN AND METHODS The Prospective Urban Rural Epidemiology (PURE) study enrolled 143,567 adults aged 35–70 years from 4 high-income countries (HIC), 12 middle-income countries (MIC), and 5 low-income countries (LIC). The mean follow-up was 9.0 6 3.0 years. RESULTS Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1,000 personyears, P < 0.001), all-cause mortality (LIC 13.8, MIC 7.2, HIC 4.2 per 1,000 personyears, P < 0.001), and CV mortality (LIC 5.7, MIC 2.2, HIC 1.0 per 1,000 person-years, P < 0.001) were considerably higher in LIC compared with MIC and HIC. Within LIC, mortality was higher in those in the lowest tertile of wealth index (low 14.7%, middle 10.8%, and high 6.5%). In contrast to HIC and MIC, the increased CV mortality in those with diabetes in LIC remained unchanged even after adjustment for behavioral risk factors and treatments (hazard ratio [95% CI] 1.89 [1.58–2.27] to 1.78 [1.36–2.34]). CONCLUSIONS CVD rates, all-cause mortality, and CV mortality were markedly higher among those with diabetes in LIC compared with MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society., Ciencias Médicas y de la Salud

Metformin is the most commonly prescribed medication for type 2 diabetes, owing to its glucose-lowering effects, which are mediated through the suppression of hepatic glucose production (reviewed in refs. 1-3). However, in addition to its effects on the liver, metformin reduces appetite and in preclinical models exerts beneficial effects on ageing and a number of diverse diseases (for example, cognitive disorders, cancer, cardiovascular disease) through mechanisms that are not fully understood1-3. Given the high concentration of metformin in the liver and its many beneficial effects beyond glycemic control, we reasoned that metformin may increase the secretion of a hepatocyte-derived endocrine factor that communicates with the central nervous system4. Here we show, using unbiased transcriptomics of mouse hepatocytes and analysis of proteins in human serum, that metformin induces expression and secretion of growth differentiating factor 15 (GDF15). In primary mouse hepatocytes, metformin stimulates the secretion of GDF15 by increasing the expression of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP; also known as DDIT3). In wild-type mice fed a high-fat diet, oral administration of metformin increases serum GDF15 and reduces food intake, body mass, fasting insulin and glucose intolerance; these effects are eliminated in GDF15 null mice. An increase in serum GDF15 is also associated with weight loss in patients with type 2 diabetes who take metformin. Although further studies will be required to determine the tissue source(s) of GDF15 produced in response to metformin in vivo, our data indicate that the therapeutic benefits of metformin on appetite, body mass and serum insulin depend on GDF15.

Health coaching for type 2 diabetes (T2DM) represents a promising addition toward efforts to improve clinical health outcomes and quality of life. The purpose of this study was to evaluate the effect of a 12-month telephone diabetes health coaching (DHC) intervention on glycemic control in persons living with T2DM.In this community-based, randomized, controlled trial, adults with T2DM, glycated hemoglobin (A1C) ≥7.5% and telephone access were assigned to either usual diabetes education (DE) or DHC and access to DE. The primary outcome was change in A1C after 1 year, and secondary outcomes included score on the 19-item Audit of Diabetes-Dependent Quality of Life (ADDQoL-19) instrument and self-care behaviours. Safety was assessed in all participants (NCT02128815 at www.clinicaltrials.gov).Three hundred sixty-five participants (50% females; mean age, 57 years; mean A1C, 8.98%) were randomized to control (DE, n=177) or intervention (DHC, n=188) groups. The A1C level decreased by an absolute amount of 1.8% and 1.3% in the intervention and control groups, respectively. DHC plus DE reduced A1C by 0.49% more than DE alone (95% confidence interval, -0.80 to -0.18; p0.01) and improved ADDQoL-19 scores, with between-group differences for the average weighted score of 0.28 (95% confidence interval, 0.04 to 0.52; p=0.02). There were no differences between groups for proportion of participants having an emergency department visit or hospitalization.Providing frequent telephone-based DHC and access to DE to adults living with T2DM for 1 year supports improvements in glycemic control and quality of life.

Objectives: We aimed to compare cardiovascular (CV) events, all-cause and CV mortality rates, among adults with and without diabetes in countries with differing levels of income. Research design and methods: Prospective Urban Rural Epidemiological (PURE) enrolled 143,567 adults aged 35 to 70 years from 4 high income countries (HIC), 12 middle income countries (MIC) and 5 low income countries (LIC). The mean follow-up was 9.0±3.0 years. Results: Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1000 person years, p Conclusions: CVD rates, all-cause and CV mortality were markedly higher among those with diabetes in LIC compared to MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society.

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Background Diabetes is a risk factor for cerebrovascular disease and cognitive impairment. The anatomical basis for this is uncertain. Methods The Canadian Alliance for Healthy Hearts and Minds collected brain and carotid magnetic resonance imaging (MRI) and 2 cognitive tests (the Digit Symbol Substitution Test and the Montreal Cognitive Assessment test) in a cross-sectional sample of men and women. Brain MRIs identified brain infarcts (BI), lacunar BI, high white matter hyperintensity (WMH), vascular brain injury (VBI; BI or high WMH), and small vessel VBI (lacunar BI or high WMH). Carotid MRIs estimated carotid wall volume, a measure of subclinical atherosclerosis. Cognitive scores were standardized to each site’s mean score, and cognitive impairment was identified by 1 or both test scores ≤1 standard deviation below the site’s mean score on that test. Results The 7733 participants included 495 participants (6.4%) with diabetes, of whom 388 were taking diabetes drugs. After age and sex adjustment, diabetes was independently associated with BI (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.05, 2.24), VBI (OR 1.64, 95% CI 1.26, 2.13), small vessel VBI (OR 1.67, 95% CI 1.28, 2.19), and cognitive impairment (OR 1.47, 95% CI 1.20, 1.80). The association between diabetes and small vessel VBI persisted after adjustment for cerebrovascular disease risk factors and nonlacunar infarcts (OR 1.52, 95% CI 1.15, 2.01), and the association with cognitive impairment persisted after adjustment for small vessel VBI (OR 1.27, 95% CI 1.03, 1.56). Conclusion Small vessel disease characterizes much of the relationship between diabetes and VBI. However, additional factors are required to disentangle the relationship between diabetes and cognitive impairment.

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.

OBJECTIVE We examined the impact of acarbose, an alpha-glucosidase inhibitor, on incident diabetes and regression to normoglycemia in 6,522 Acarbose Cardiovascular Evaluation trial participants in China who had impaired glucose tolerance (IGT) and coronary heart disease (CHD). RESEARCH DESIGN AND METHODS Participants were randomly assigned to acarbose or placebo and followed with four-monthly FPGs and annual OGTTs. Incident diabetes was defined as two successive diagnostic FPGs ≥ 7 mmol/L or 2-hr PGs ≥ 11.1 mmol /L while taking study medication, or a masked adjudicated confirmation of this diagnosis. Regression to normoglycemia was defined as FPG 1c, FPG, 2h-PG, BMI eGFR), for IGT alone and for IGT+IFG, and for use of thiazides, ACE inhibitors/angiotensin receptor blockers, beta blockers, calcium channel blockers or statins). RESULTS Incident diabetes was less frequent with acarbose, compared with placebo, being 3.2 and 3.8 per 100 person-years respectively (rate ratio (RR) 0.82, 95%CI 0.71–0.94, p=0.005), with no evidence of differential effects within the predefined subgroups after accounting for multiple testing. Regression to normoglycemia occurred more frequently in those randomized to acarbose, compared with placebo, being 16.3 and 14.1 per 100 person-years respectively (RR 1.16, 95%CI 1.08–1.25, pinteraction=0.0006). The likelihood of remaining in normoglycemic regression did not differ between acarbose and placebo groups (P=0.41). CONCLUSIONS Acarbose reduced the incidence of diabetes and promoted regression to normoglycemia in Chinese people with IGT and CHD.

Digital, 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., Ciencias Médicas y de la Salud

The REWIND trial showed that relative to placebo (PL), once weekly dulaglutide (DU) 1.5 mg reduced the incidence of a major adverse cardiovascular (CV) event (MACE; nonfatal myocardial infarction, nonfatal stroke, or CV death) in patients with T2D with and without established CV disease (hazard ratio (HR) 0.88, 95% CI [0.79, 0.99]; p=0.026). DU also significantly reduced A1C, body weight (BW), and systolic blood pressure (SBP) (Table). In this post-hoc assessment, a mediation analysis was used to estimate the degree to which the effect of DU on these risk factors could statistically account for its effect on MACE. Data were analyzed from 9901 patients who had 1257 first MACE events over 5.4 median yrs of observation. Those risk factors for which the updated mean on follow-up was significantly related to MACE were added to a separate Cox model that included DU allocation, the baseline [BL] value of the measurement and the updated mean of the variable as time dependent covariates. Only A1C satisfied this condition (Table), suggesting that BW and SBP did not mediate the effect of DU on MACE in this study population. The effect size of DU on the MACE outcome was attenuated by 36.1% after accounting for its effect on A1C (Table). In conclusion, the results suggest most of the CV benefit of DU on MACE is not attributable to the A1C, BW, or SBP-lowering effects of DU. Disclosure H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. C. Hasenour: Employee; Self; Eli Lilly and Company. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. K. Branch: Consultant; Self; Bayer AG. Research Support; Self; Bayer AG, Eli Lilly and Company. M. Konig: Employee; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. M. Lakshmanan: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. R. Mody: Employee; Self; Eli Lilly and Company. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi.

The relationship between blood pressure and mortality in T2DM is controversial, with concern for increased risk associated with lower blood pressure. We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline systolic blood pressure (SBP) and mortality in 5852 patients with T2DM who, as required for entry to the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial, had a recent acute coronary syndrome (ACS). Risk of death was assessed in a Cox model that adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, natriuretic peptide (BNP) and urine albumin/creatinine at baseline. Overall there was no significant association between SBP and risk of death (P=0.20), but in 2325 patients with additional CVD (index ACS + at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure) there was a significant association between lower SBP and higher risk of death (hazard ratio per 10 mmHg lower SBP 1.13; 95% CI 1.05 to 1.23) whereas in 3527 patients with only the index ACS no association was observed (hazard ratio per 10 mmHg lower SBP 0.95; 95% CI 0.86 to 1.04, P for interaction Disclosure M.O. Wijkman: None. B. Claggett: None. R. Diaz: None. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. L. Kober: Speaker’s Bureau; Self; AstraZeneca, Novartis AG. Other Relationship; Self; AstraZeneca. E. Lewis: Consultant; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Amgen, Novartis Pharmaceuticals Corporation, Theracos, Inc. A.P. Maggioni: None. E. Wolsk: None. D. Aguilar: None. R. Bentley-Lewis: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc. J.L. Probstfield: None. M.C. Riddle: Consultant; Self; ADOCIA, Dance Biopharm Holdings, Inc., GlaxoSmithKline plc., Sanofi US, Theracos, Inc. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc. J. Tardif: Research Support; Self; Esperion Therapeutics, Inc., Ionis Pharmaceuticals, Inc., REGENXBIO Inc., Sanofi, Servier. Other Relationship; Self; Amarin Corporation, AstraZeneca, DalCor Pharmaceuticals. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. M.A. Pfeffer: Consultant; Self; AstraZeneca, CinCor, Correvio, Corvidia, DalCor Pharmaceuticals, GlaxoSmithKline plc., Innovative Science, Jazz Pharmaceuticals, MyoKardia, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., PharmaScience, Sanofi US, Servier, Takeda Development Center Americas, Inc. Research Support; Self; Novartis Pharmaceuticals Corporation. Funding Sanofi (NCT01147250)

In participants with type 2 diabetes (T2D) in the REWIND trial, dulaglutide (DU) use for median follow-up of 5.4 years was associated with reduced composite renal outcomes, defined as the first occurrence of new macroalbuminuria, sustained decline in estimated glomerular filtration rate (eGFR) of ≥30%, or chronic renal replacement therapy. The objective of this post-hoc analysis was to evaluate the effect of dulaglutide on renal outcomes related to kidney function that are typically used in renal outcomes studies, defined as the composite endpoint of sustained eGFR decline ≥40%, end-stage renal disease (ESRD), or all-cause death. Participants with T2D at cardiovascular (CV) risk were randomized (1:1) to DU 1.5 mg once-weekly or placebo. This post-hoc analysis used Cox proportional hazards modeling for time to first event to determine the risk of renal outcomes. Sensitivity analyses were conducted by replacing the all-cause death component with CV or renal death, or renal death. At baseline, treatment groups had similar eGFR (mean±SD: DU=77.2±22.7; placebo=76.6±22.8). The incidence rate of the composite endpoint was significantly lower for the DU group compared with placebo (Table). Treatment with DU 1.5 mg was associated with a 17% risk reduction in kidney function-related outcomes, suggesting potential delay in progression of diabetic kidney disease in patients with T2D at CV risk. Disclosure J.E. Shaw: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mylan, Sanofi. Research Support; Self; AstraZeneca. Speaker’s Bureau; Self; Eli Lilly and Company, Mylan. F.T. Botros: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. R. Malik: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Atisso: Employee; Self; Eli Lilly and Company. H.M. Colhoun: Advisory Panel; Self; AstraZeneca, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Research Support; Self; AstraZeneca, Eli Lilly and Company, Novo Nordisk Inc., Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi-Aventis. Speaker’s Bureau; Self; Eli Lilly and Company, Regeneron Pharmaceuticals, Sanofi. Stock/Shareholder; Self; Bayer AG, Roche Pharma. Other Relationship; Self; Eli Lilly and Company, Sanofi. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. Funding Eli Lilly and Company

Cardiovascular autonomic neuropathy (CAN) is a common complication that independently predicts cardiovascular (CV) morbidity and mortality in persons with type 2 diabetes (T2D). The effect of preventive interventions on CAN remains unclear. We examined the effects of intensively targeting hyperglycemia, hypertension, and dyslipidemia on CAN, in persons with T2D and high CV risk from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. CAN was defined as heart rate variability indices below the 5th percentile of the normal distribution (standard deviation of all normal-to-normal R-R intervals [SDNN] Disclosure Y. Tang: None. H. Shah: None. C. Bueno Junior: None. X. Sun: None. J. Mitri: Consultant; Spouse/Partner; Janssen Pharmaceuticals, Inc., kymera. Consultant; Self; national dairy council/local dairy council. Research Support; Spouse/Partner; AbbVie Inc., beigene, Janssen Pharmaceuticals, Inc. Research Support; Self; Kowa Pharmaceuticals America, Inc., national dairy council. Research Support; Spouse/Partner; pharma cyclic, TG therapeutics. M. Sambataro: None. L. Sambado: None. H.C. Gerstein: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Consultant; Self; Kowa Pharmaceuticals America, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Sanofi. V. Fonseca: Consultant; Self; Abbott, Asahi Kasei Corporation, AstraZeneca, Bayer Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Stock/Shareholder; Self; Amgen, Bravo4health. A. Doria: Research Support; Self; Sanofi. R. Pop-Busui: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Consultant; Self; Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca. Other Relationship; Self; American Diabetes Association. Funding National Institutes of Health (N01HC95178, N01HC95179, N01HC95180, N01HC95181, N01HC95182, N01HC95183, N01HC95184, IAAY1HC-9035, IAAY1HC1010)

Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes., eLife digest Men experience a gradual decline in their testosterone levels as they grow older. However, the effects of testosterone and the consequences of supplementation on the human body have been unclear. Scientists use so-called randomized controlled trials to establish cause-and-effect and to reduce bias. In these experiments, participants are randomly assigned to a either a treatment group (that receives the intervention being tested) or a control group (that either receives an alternative intervention, a dummy or placebo, or no intervention at all). Randomization ensures that both groups are balanced, and any resulting differences can be attributed to the treatment. However, randomized controlled trials are time-consuming and expensive, so trials of testosterone have had relatively small numbers of participants and short follow-up periods. This makes it difficult to draw conclusions about any potential effects of testosterone administration on less common diseases in men. Now, Paré et al. investigated the effects of naturally produced testosterone using Mendelian randomization, which mimics randomized trials by exploiting the fact that parents randomly pass on their unique genetic variants to their children at conception. This random assignment of genetic variants leads to its informal namesake, “nature’s clinical trial”, and provides the ability to study cause-and-effect for any genetically determined factors, such as testosterone levels. Paré et al. studied the long-term effects of testosterone on 22 diseases previously explored in randomized controlled trials, and hundreds of other traits and diseases that have not been investigated in any randomized controlled trials yet. The Mendelian randomization analysis made it possible to examine the effects of lifelong naturally elevated testosterone levels on 469 traits and diseases. Paré et al. found that testosterone increased the density of bone mineral and decreased body fat. However, it also increased the risks of prostate cancer, high blood pressure, baldness and a condition affecting the spine. It also increased the number of red blood cells and decreased a marker of inflammation, which may be beneficial or detrimental depending on the context. This shows that genetic analyses can be powerful methods to prioritize the allocation of limited resources towards investigating the most pressing clinical questions. The results of this study may help inform physicians and patients about the effects of long-term testosterone use. Ultimately, large randomized controlled trials are needed to conclusively address the cause-and-effect on these diseases.

Background & Objective Both lacunar strokes and diabetes are risk factors for dementia and cognitive dysfunction. Thus, elucidating modifiable risk factors for cognitive dysfunction in people with type 2 diabetes who experienced a lacunar infarct has large public health implications. One such factor may be glycemic status, as measured by glycosylated hemoglobin (A1C). Thus, the aim of this study was to assess the relationship between A1C and cognitive function in people with diabetes after a lacunar stroke. Research Design & Methods The effect of baseline and follow-up A1C on the baseline and the change in Cognitive Assessment Screening Instrument (CASI) score over time among participants with a median of 2 cognitive assessments (range 1-5) was examined in of 942 individuals with diabetes and a lacunar stroke who participated in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial (ClinicalTrials.gov number, NCT00059306). Results Every 1 % higher baseline A1C was associated with a 0.06 lower standardized CASI z-score (95% CI -0.101, -0.018). Higher baseline A1C values were associated with lower CASI z-score over time (p for interaction=0.037). A 1% increase in A1C over time, corresponded with a CASI score decrease of 0.021 (95% CI -0.0043, -0.038) during follow-up. All these remained statistically significant after adjustment for age, sex, education, race, depression, hypertension, hyperlipidemia, BMI, CVD, OSA, diabetic retinopathy, nephropathy insulin use and White Matter Abnormalities. Conclusion This analysis of 942 individuals with diabetes after a lacunar stroke demonstrates a relationship between A1C and change in cognitive scores over time. Intervention studies are needed in order to delineate if better glucose control could slow the rate of cognitive decline in this high risk population.

Background: Dulaglutide (DU) was superior to placebo (PL) in reducing the incidence of Major Adverse Cardiovascular Events in the Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND Study) broad patient population. The safety of DU treatment is also of interest to health care providers who treat an older patient population (≥65 years of age). Aims: The primary objective of this post-hoc analysis was to evaluate DU safety in the REWIND patient subgroup populations categorized by age (≥ 65 and < 65 years) with regards to the occurrence of the composite safety outcome of overall mortality and severe hypoglycemia. One of the key secondary objectives was first occurrence of severe hypoglycemia. Methods: Patients were grouped into two age groups: ≥65 and Results: Of the 9,901 patients randomized in REWIND, a total of 5,256 (DU, 2,619; PL, 2,637) were aged ≥65 years. The incidence of the composite safety outcome for patients aged ≥65 years was 399 of 2619 (15.2%) for DU-treated patients and 425 of 2,637 (16.1%) for PL-treated patients. The incidence of the composite safety outcome for those aged Conclusions: Treatment with DU demonstrated similar safety in REWIND patients aged ≥65 years and those aged

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.

New trials of dementia prevention are needed to test novel strategies and agents. Large, simple, cardiovascular trials have successfully discovered treatments with moderate but worthwhile effects to prevent heart attack and stroke. The design of these trials may hold lessons for the dementia prevention. Here we outline suitable populations, interventions and outcomes for large simple trials in dementia prevention. We consider what features are needed to maximise efficiency. Populations could be selected by age, clinical or genetic risk factors or clinical presentation. Patients and their families prioritise functional and clinical outcomes over cognitive scores and levels of biomarkers. Loss of particular functions or dementia diagnoses therefore are most meaningful to participants and potential patients and can be measured in large trials. The size of the population and duration of follow-up needed for dementia prevention trials will be a major challenge and will need collaboration between many clinical investigators, funders and patient organisations.

Disease risk varies significantly between ethnic groups, however, the clinical significance and implications of these observations are poorly understood. Investigating ethnic differences within the human proteome may shed light on the impact of ancestry on disease risk. We used admixture mapping to explore the impact of genetic ancestry on 237 cardiometabolic biomarkers in 2,216 Latin Americans within the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study. We developed a variance component model in order to determine the proportion of variance explained by inter-ancestry differences, and we applied it to the biomarker panel. Multivariable linear regression was used to identify and localize genetic loci affecting biomarker variability between ethnicities. Variance component analysis revealed that 5% of biomarkers were significantly impacted by genetic admixture (p < 0.05/237), including C-peptide, apolipoprotein-E, and intercellular adhesion molecule 1. We also identified 46 regional associations across 40 different biomarkers (p < 1.13 × 10(−6)). An independent analysis revealed that 34 of these 46 regions were associated at genome-wide significance (p < 5 × 10(−8)) with their respective biomarker in either Europeans or Latin populations. Additional analyses revealed that an admixture mapping signal associated with increased C-peptide levels was also associated with an increase in diabetes risk (odds ratio [OR] = 6.07 per SD, 95% confidence interval [CI] 1.44 to 25.56, p = 0.01) and surrogate measures of insulin resistance. Our results demonstrate the impact of ancestry on biomarker levels, suggesting that some of the observed differences in disease prevalence have a biological basis, and that reference intervals for those biomarkers should be tailored to ancestry. Specifically, our results point to a strong role of ancestry in insulin resistance and diabetes risk.

Background Frailty is associated with higher mortality in individuals at high cardiovascular disease ( CVD ) risk. We hypothesize that frailty is a more important prognostic factor than CVD risk factors and aim to determine the prognostic value of a cumulative deficit frailty index in patients with or at high risk for CVD . Methods and Results We conducted an individual‐level pooled analysis of participants with or at risk for CVD , recruited in 14 multicenter clinical trials. The cumulative deficit index was calculated as the proportion of 26 deficits exhibited. Individuals were categorized as nonfrail, prefrail, or frail if they had indexes of ≤0.1, >0.1 to 0.21, or >0.21, respectively. CVD risk was assessed using the Framingham score. Outcomes included CVD event (new or recurrent myocardial infarction, stroke, or heart failure) and mortality. We studied 154 696 patients (mean age, 70.8 years; 63% men) with median follow‐up of 3.2 years. There were 17 535 CVD events and 15 067 deaths. The frail group (n=13 872) had higher risk of a CVD event (incidence rate ratio, 1.97; 95% CI , 1.85–2.08), all‐cause mortality (hazard ratio, 1.91; 95% CI , 1.79–2.03), and CVD mortality (hazard ratio, 1.91; 95% CI , 1.77–2.05) than the nonfrail group (n=101 343). Associations remained unchanged after adjusting for CVD risk factors. The index statistically outperformed the Framingham score in its ability to discriminate CVD events (C‐statistic, 0.60 [95% CI , 0.60–0.61] versus 0.58 [95% CI , 0.57–0.58], respectively; P Conclusions In individuals with or at high risk of developing CVD , the cumulative deficit index is associated with increased CVD events and mortality, independent of CVD risk factors, and adds incremental prognostic value.

Background: Hypertension is a common modifiable risk factor for cardiovascular disease and mortality. Pathophysiological mechanisms leading to hypertension remain incompletely understood. Mendelian randomization (MR) allows the evaluation of the causal role of markers by minimizing the risk of biases such as reverse causation and confounding. We aimed to identify novel circulating proteins associated with blood pressure through a comprehensive screen of 227 blood biomarkers using MR. Methods: Genetic determinants of 227 biomarkers were identified in ORIGIN (Outcome Reduction With Initial Glargine Intervention; URL: http://www.clinicaltrials.gov . Unique identifier: NCT00069784) participants (N=4147) and combined with genetic effects on systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure from the International Consortium for Blood Pressure (74 064 individuals) using MR. Results were replicated in the UK Biobank (up to 319 103 individuals) and using another biomarker dataset (N=3301). MR analyses with cardiovascular risk factors and outcomes as well as other biomarkers were performed to further evaluate the mechanisms involved. Results: Six biomarkers were associated with blood pressure using MR after adjustment for multiple hypothesis testing. Relationships between NT-proBNP (N-terminal Pro-B-type natriuretic peptide), systolic blood pressure, and diastolic blood pressure confirmed previous reports. Novel circulating proteins associated with blood pressure were also identified. uPA (urokinase-type plasminogen activator) was related to systolic blood pressure; ADM (adrenomedullin) was related to systolic blood pressure and pulse pressure; IL (interleukin) 16 was related to diastolic blood pressure; cFn (cellular fibronectin) and IGFBP3 (insulin-like growth factor-binding protein 3) were related to pulse pressure. With the exception of IL16 and diastolic blood pressure ( P =0.58), these relationships were validated in the UK Biobank ( P Conclusions: We identified novel biomarkers associated with blood pressure using MR. These markers could prove useful for risk assessment and as potential therapeutic targets.

Additional file 1: Table S1. Number of Participants who Experienced Varying Numbers of CV Events. Table S2. Effect of dulaglutide on Total MACE or non-Cardiovascular Death in subgroups. Table S3. Number of Participants who Experienced Varying Numbers of CV Events or on non CV deaths.

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

Supplementary material

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-alpha), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide-significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported White subjects treated with simvastatin and randomized to fenofibrate or placebo in the Action-to-Control-Cardiovascular-Risk-in-Diabetes (ACCORD) Lipid Trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (HR=0.49; 95%C.I. 0.34-0.72) whereas no benefit was observed for other genotypes (p for interaction=3.7x10-4). The “rs6008845-by-fenofibrate” interaction on MACE was replicated in African-Americans from ACCORD (N=585, p=0.02) and in external cohorts (ACCORD-Blood-Pressure, ORIGIN, and TRIUMPH, total N=3059, p=0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11 - a pro-inflammatory and atherogenic chemokine also known as eotaxin (p for rs6008845-by-fenofibrate interaction=0.003). The Genotype-Tissue Expression (GTEx) dataset revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify T2D patients who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Additional file 1. Additional tables and figure.

Supplementary material

Summary Background Data are scarce on the availability and affordability of essential medicines for diabetes. Our aim was to examine the availability and affordability of metformin, sulfonylureas, and insulin across multiple regions of the world and explore the effect of these on medicine use. Methods In the Prospective Urban Rural Epidemiology (PURE) study, participants aged 35–70 years (n=156 625) were recruited from 110 803 households, in 604 communities and 22 countries; availability (presence of any dose of medication in the pharmacy on the day of audit) and medicine cost data were collected from pharmacies with the Environmental Profile of a Community's Health audit tool. Our primary analysis was to describe the availability and affordability of metformin and insulin and also commonly used and prescribed combinations of two medicines for diabetes management (two oral drugs, metformin plus a sulphonylurea [either glibenclamide (also known as glyburide) or gliclazide] and one oral drug plus insulin [metformin plus insulin]). Medicines were defined as affordable if the cost of medicines was less than 20% of capacity-to-pay (the household income minus food expenditure). Our analyses included data collected in pharmacies and data from representative samples of households. Data on availability were ascertained during the pharmacy audit, as were data on cost of medications. These cost data were used to estimate the cost of a month's supply of essential medicines for diabetes. We estimated affordability of medicines using income data from household surveys. Findings Metformin was available in 113 (100%) of 113 pharmacies from high-income countries, 112 (88·2%) of 127 pharmacies in upper-middle-income countries, 179 (86·1%) of 208 pharmacies in lower-middle-income countries, 44 (64·7%) of 68 pharmacies in low-income countries (excluding India), and 88 (100%) of 88 pharmacies in India. Insulin was available in 106 (93·8%) pharmacies in high-income countries, 51 (40·2%) pharmacies in upper-middle-income countries, 61 (29·3%) pharmacies in lower-middle-income countries, seven (10·3%) pharmacies in lower-income countries, and 67 (76·1%) of 88 pharmacies in India. We estimated 0·7% of households in high-income countries and 26·9% of households in low-income countries could not afford metformin and 2·8% of households in high-income countries and 63·0% of households in low-income countries could not afford insulin. Among the 13 569 (8·6% of PURE participants) that reported a diagnosis of diabetes, 1222 (74·0%) participants reported diabetes medicine use in high-income countries compared with 143 (29·6%) participants in low-income countries. In multilevel models, availability and affordability were significantly associated with use of diabetes medicines. Interpretation Availability and affordability of essential diabetes medicines are poor in low-income and middle-income countries. Awareness of these global differences might importantly drive change in access for patients with diabetes. Funding Full funding sources listed at the end of the paper (see Acknowledgments).

Background Myocardial injury after non-cardiac surgery (MINS) is the most common perioperative cardiovascular complication and is independently associated with 30-day mortality. We aimed to assess the association between preoperative glucose concentration and postoperative MINS and mortality. Methods The VISION study is a prospective cohort study done at 12 centres in eight countries. Patients aged 45 years or older who required at least one overnight hospital admission for non-cardiac surgery were enrolled from Aug 6, 2007, to Jan 11, 2011. In the GlucoVISION analysis, we assessed the relations between preoperative casual or fasting glucose concentration and MINS within 3 days after surgery using logistic regression, and 30-day mortality using Cox proportional regression, in people with and without diabetes. Findings 11954 patients were included in this analysis, of whom 2809 (23%) had diabetes. Within the first three postoperative days, MINS occurred in 813 (7%) patients. 249 (2%) patients died by day 30. More patients with diabetes had MINS (odds ratio [OR] 1.98 [95% CI 1.70-2.30]; p

Background Identification of biomarkers that cause coronary artery disease (CAD) has led to important advances in prevention and treatment. Epidemiological analyses have identified many biomarker-CAD relationships; however, these associations may arise from reverse causation and/or confounding and therefore may not represent true causal associations. Mendelian randomization (MR) analyses overcome these limitations. Objectives This study sought to identify causal mediators of CAD through a comprehensive screen of 237 biomarkers using MR. Methods MR was performed by identifying genetic determinants of 227 biomarkers in ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial participants (N = 4,147) and combining these with genetic effects on CAD from the CARDIoGRAM consortium (60,801 cases and 123,504 controls). Blood concentrations of novel biomarkers identified by MR were then tested for association with incident major adverse cardiovascular events in ORIGIN. Results Six biomarkers were found to be causally linked to CAD after adjustment for multiple hypothesis testing. The causal role of 4 of these is well documented, whereas macrophage colony-stimulating factor 1 (CSF1) and stromal cell–derived factor 1 (CXCL12) have not previously been reported, to the best of our knowledge. MR analysis predicted an 18% higher risk of CAD per SD increase in CSF1 (odds ratio: 1.18; 95% confidence interval: 1.08 to 1.30; p = 2.1 × 10−4) and epidemiological analysis identified a 16% higher risk of major adverse cardiovascular events per SD (hazard ratio: 1.16; 95% confidence interval: 1.09 to 1.23; p Conclusions The study identified CSF1 and CXCL12 as causal mediators of CAD in humans. Understanding the mechanism by which these markers mediate CAD will provide novel insights into CAD and could lead to new approaches to prevention. These results support targeting inflammatory processes and macrophages, in particular, to prevent CAD, consistent with the recent CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). (Outcome Reduction With Initial Glargine Intervention [ORIGIN]; NCT00069784)

Epidemiological studies have indicated that the risk of atherothrombotic coronary artery disease (CAD) is higher in patients with diabetes, but these results have not been consistently observed across clinical trials. To address this apparent discrepancy, we can apply the results of genome-wide association studies (GWAS) to provide a better understanding of the shared genetic architecture of diabetes and atherothrombotic CAD. For instance, a large GWAS has identified 16 novel loci that are associated with both diabetes and atherothrombotic CAD. These genetic variants may also be used to assess potential causal relationships reported in observational studies and clinical trials through Mendelian randomization analyses. For example, several Mendelian randomization analyses have shown that diabetes is associated with CAD independent of other risk factors (odds ratio [OR]: 1.63, 95% confidence interval [CI]: 1.23–2.07; P = 0.002). Furthermore, Mendelian randomization analyses can provide more insight into the perceived risk of diabetes among patients without diabetes receiving statin therapy. Here, genetically lower activity of HMG-CoA reductase (HMGCR) was associated with a modest increase in diabetes (OR per allele: 1.02, 95% CI: 1.00–1.05). These results highlight the biological mechanisms that link diabetes with the use of statins. In addition, this work illustrates the great potential value of genetic studies to clarify the mechanistic relationships among atherosclerotic vascular disease, dysglycemia, and diabetes. More research is needed to delineate and subsequently better understand the genetic links between diabetes and atherosclerosis.

Background The Diabetes Quality-of-Life (DQOL) Measure is a 46-item diabetes-specific quality of life instrument. The original English version of the DQOL has been translated into Chinese after cultural adaption, and the Chinese DQOL has been validated in the Chinese diabetic patient population and used in diabetes-related studies. There are two recognized problems with the Chinese DQOL: 1) the instrument is too long, and 2) the non-response rate of certain items is relatively high. This study aimed to develop and validate a short version for the Chinese DQOL. Methods Item reduction was conducted based on the classical test theory (CTT) and item response theory (IRT), each combined with exploratory factor analysis (EFA). The confirmatory factor analysis (CFA) and Spearman correlation coefficient were employed in validating the short versions. Results Both the study sample (n = 2,886) and the validation sample (n = 2,286) were from a longitudinal observation study of Chinese type 2 diabetic patients. The CTT kept 32 items, and the IRT kept 24 items from the original 46-item version. The two short versions were comparable in psychometric properties. Conclusion The 24-item IRT-based short version of the Chinese DQOL was selected as the preferred short version because it imposes a lower burden on patients without compromising the psychometric properties of the instrument. Electronic supplementary material The online version of this article (10.1186/s12955-018-0905-z) contains supplementary material, which is available to authorized users.

Many biomarkers have been epidemiologically linked with CKD; however, the possibility that such associations are due to reverse causation or confounding limits the utility of these biomarkers. To overcome this limitation, we used a Mendelian randomization (MR) approach to identify causal mediators of CKD. We performed MR by first identifying genetic determinants of 227 serum protein biomarkers assayed in 4147 participants of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial who had early or prediabetes, and assessing the effects of these biomarkers on CKD in the CKD genetics consortium (n=117,165; 12,385 cases) using the inverse-variance weighted (fixed-effects) method. We then estimated the relationship between the serum concentration of each biomarker identified and incident CKD in ORIGIN participants. MR identified uromodulin (UMOD) and human EGF receptor 2 (HER2) as novel, causal mediators of CKD (UMOD: odds ratio [OR], 1.30 per SD; 95% confidence interval [95% CI], 1.25 to 1.35; P

As recently as 20 years ago there were no randomized controlled trials of potentially cardiovascular protective therapies in people with type 2 diabetes. The ongoing cardiovascular trials bring needed evidence. Both primary and subsidiary analyses have transformed diabetes from a largely eminence based specialty to one that is firmly evidence based. These studies have provided evidence supporting glucose-lowering drugs for patients with cardiovascular risk factors. Randomized controlled trials such as those described here will continue to challenge assumptions and create new approaches and paradigms that can be pursued to reduce and hopefully eliminate serious cardiovascular and other consequences of diabetes.

Diabetes is defined by hyperglycemia, but whether optimizing glycemic control can reduce its complications was long in doubt. In 1968 Siperstein et al. proposed the hypothesis that microvascular injury accompanying diabetes could be genetically determined (1), and there was concern that, even if the “glucose hypothesis” (2,3) were valid, seeking good control of hyperglycemia was overly risky. Nevertheless, epidemiologic evidence linking hyperglycemia with both microvascular and cardiovascular complications prompted assessment of the effects of intensive glycemic control in the Diabetes Control and Complications Trial (DCCT) for type 1 diabetes (T1D) and the UK Prospective Diabetes Study (UKPDS) for type 2 diabetes (T2D). When the results of the DCCT were reported in Las Vegas on a hot (>110°F) day in June 1993, many people were surprised by the approximately 50% reduction of microvascular changes that was associated with 6.5 years of maintaining hemoglobin A1c (HbA1c) close to 7% (53 mmol/mol) compared with 9% (75 mmol/mol) in the control arm (4). Because the DCCT participants were young, cardiovascular events were too few to analyze and long-term effects on cardiovascular risk remained unknown. Results in T2D from the UKPDS reinforced the message of the DCCT. More intensive glycemic control attaining about a 1% difference in HbA1c in T2D for 10 years led to 25% lower rates of microvascular outcomes (5) and a nonsignificant 16% lower rate of myocardial infarction (5). For more than two decades after these reports the dominant view has been that improving glycemic control reduces eye, nerve, and kidney complications but not cardiovascular risk. Four large randomized clinical trials testing whether seeking HbA1c levels at or below 7% could reduce cardiovascular events showed limited benefits during their periods of active treatment (5–8). Although analysis of data pooled from these four trials …

In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors’ Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association’s Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.

A growing number of single-nucleotide polymorphisms (SNPs) have been associated with body mass index (BMI) and obesity, but whether the effects of these obesity-susceptibility loci are uniform across the BMI distribution remains unclear. We studied the effects of 37 BMI-associated SNPs in 75,230 adults of European ancestry across BMI percentiles by using conditional quantile regression (CQR) and meta-regression (MR) models. The effects of nine SNPs (24%)—rs1421085 ( FTO ; p=8.69 × 10 −15 ), rs6235 ( PCSK1 ; p = 7.11 × 10 −6 ), rs7903146 ( TCF7L2 ; p=9.60 × 10 −6 ), rs11873305 ( MC4R ; p=5.08 × 10 −5 ), rs12617233 ( FANCL ; p=5.30 × 10 −5 ), rs11672660 ( GIPR ; p=1.64 × 10 −4 ), rs997295 ( MAP2K5 ; p=3.25 × 10 −4 ), rs6499653 ( FTO ; p=6.23 × 10 −4 ), and rs3824755 ( NT5C2 ; p=7.90 × 10 −4 )—increased significantly across the sample BMI distribution. We showed that such increases stemmed from unadjusted gene interactions that enhanced the effects of SNPs in persons with a high BMI. When 125 height-associated SNPs were analyzed for comparison, only one ( IGF1 , p=1.80 × 10 −4 ), showed effects that varied significantly across height percentiles. Cumulative gene scores of these SNPs (GS-BMI and GS-height) showed that only GS-BMI had effects that increased significantly across the sample distribution (BMI: p=7.03 × 10 −37 ; height: p=0.499). Overall, these findings underscore the importance of gene-gene and gene-environment interactions in shaping the genetic architecture of BMI and advance a method for detecting such interactions by using only the sample outcome distribution.

Clinical research focuses on the relationship between one or more independent variables and some dependent variable or outcome chosen to reflect some underlying process. For categorical variables, the research may either be focused on a specific end point such as myocardial infarction (MI) or on an underlying construct such as vascular disease (with MI as just one exemplar). In the latter instance, a composite index such as major adverse cardiovascular event (MACE), defined as either a nonfatal stroke, nonfatal MI, or cardiovascular death, may be used. Composite categorical outcomes such as MACE optimize power by ensuring a high event rate, and the results they yield are generalizable to diseases that are consistent with the underlying construct. It is therefore surprising that there is no widely used method to combine continuous variables into composite continuous outcomes. Nevertheless, there is a clear need for such a methodology when the underlying construct cannot be easily captured by one measurement. Glucose control is an example of a construct that can be assessed in many ways, including fasting or postprandial plasma glucose, HbA1c, fructosamine, or “time in target.” A composite of two or more of these could provide a better reflection of glucose control than any one alone. Whereas sophisticated statistical techniques such as structural equation modeling (1) can be used to model some underlying construct or latent variable from two or more measurements, a simpler way of combining them into an index that reflects the underlying construct could provide a powerful tool for both researchers and clinicians. Such an approach is described below. When the same measurements are made using the …

Aims In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial (Clinicaltrials.gov: NCT000069784), titrated doses of basal insulin glargine targeting fasting normoglycaemia had a neutral effect on cardiovascular outcomes. The dose of insulin required to achieve normoglycaemia provides a unique measurement of each individual's resistance to insulin's action, and was therefore used to examine the link between insulin resistance and cardiovascular outcomes. Materials and Methods Self-titration of insulin doses targeting a fasting plasma glucose ≤5.3 mmoL/L (95 mg/dL) was promoted at every visit and cardiovascular and other serious health outcomes were ascertained. All analyses were restricted to participants allocated to insulin glargine, who added it to lifestyle or 1 glucose-lowering oral agent at randomization. Normoglycaemia was defined as a fasting plasma glucose

To quantify whether insulin therapy, and concomitant weight gain, affects recreational physical activity and TV viewing time using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial.12,537 insulin-naïve individuals with dysglycaemia were randomised to receive either basal insulin glargine or standard care and followed for a median of 6.2years. Complete recreational physical activity and TV viewing time questionnaires across baseline, 2year follow-up and study end were available for 8954 participants. Differences between groups at follow-up were assessed by analysis of covariance.At follow-up, there was no difference in physical activity or TV viewing time between those taking insulin glargine and those receiving standard care, despite body weight increasing by 1.66 (7.56) kg in the insulin glargine group and reducing by -0.65 (7.90) kg in the standard care group (P0.001). The dose of insulin glargine was not associated with changes in physical activity.Despite modest weight gain, insulin glargine did not adversely impact recreational physical activity levels within an international cohort with dysglyaemia. ORIGIN ClinicalTrials.gov number: NCT00069784.

The discovery of brown adipose tissue (BAT) in adults has sparked interest in its role as a therapeutic target in metabolic disorders. Infrared thermography is a promising way to quantify BAT; however, a standardized methodology has not been established. This study aims to establish a standardized and reproducible protocol to measure thermal response to cold in the supraclavicular area using thermographic imaging. In Phase 1, we compared the thermal response to 12 °C cold after acclimation at either 32 °C or room temperature using thermographic imaging. Repeatability of the 32 °C acclimation trial was studied in a second group in Phase 2. Phase 1 included 28 men (mean age 23.9 ± 5.9 y; mean BMI 25.2 ± 3.9 kg/m2) and Phase 2 included 14 men (mean age 20.9 ± 2.4 y; mean BMI 23.6 ± 3.1 kg/m2). The thermal response was greater after 32 °C than after room temperature acclimation (0.22 ± 0.19 vs 0.13 ± 0.17 °C, p = 0.05), was not related to outdoor temperature (r = −0.35, p = 0.07), did not correlate with supraclavicular fat (r = −0.26, p = 0.21) measured with dual-energy x-ray absorptiometry and was repeatable [ICC 0.69 (0.14–0.72)]. Acclimation at 32 °C followed by cold generates a reproducible change in supraclavicular skin temperature measurable by thermal imaging that may be indicative of BAT metabolic activity.

Background: The reasons for the increased risk of gestational diabetes among South Asian women are not well understood. We sought to identify the determinants of gestational diabetes and its impact on newborn health in a prospective birth cohort of South Asian women and their babies. Methods: As part of the South Asian Birth Cohort (START) prospective birth cohort study in Ontario, we recruited 1012 South Asian women with singleton pregnancies in the second trimester of pregnancy between July 11, 2011, and Nov. 10, 2015. We collected health information and physical measurements and administered an oral glucose tolerance test. Birth weight and skinfold thickness measurements were obtained from their newborns, and cord blood glucose and insulin levels were measured. Results: The incidence of gestational diabetes was 36.3% (95% confidence interval [CI] 33.3%-39.3%); the age-standardized rate was 40.7%. Factors associated with gestational diabetes included maternal age (odds ratio [OR] 1.08 [95% CI 1.04-1.12]), family history of diabetes (OR 1.65 [95% CI 1.26-2.17]), prepregnancy weight (OR 1.025 [95% CI 1.01-1.04]) and low diet quality (OR 1.57 [95% CI 1.16-2.12]). Maternal height was protective against gestational diabetes (OR 0.97 [95% CI 0.95-0.99]). The population attributable risk due to prepregnancy body mass index and low diet quality was 37.3%. Compared to newborns of women without gestational diabetes, those of women with gestational diabetes had a significantly higher birth weight (3267 [standard error (SE) 23] g v. 3181 [SE 17] g, p = 0.005), greater skinfold thickness (11.7 [SE 0.1] mm v. 11.2 [SE 0.1] mm, p = 0.007) and lower insulin sensitivity (glucose/insulin ratio 0.092 [SE 0.009] mmol/pmol v. 0.129 [SE 0.006] mmol/pmol, p = 0.001). Interpretation: The modifiable risk factors of prepregnancy weight and low diet quality accounted for 37% of the population attributable risk of gestational diabetes in our cohort. Intervention studies to lower prepregnancy weight and to prevent gestational diabetes among South Asian women in high-income countries are needed.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Aims Diabetes puts many individuals at risk for developing diabetic retinopathy (DR). Non-mydriatic (NM) retinal photography without pharmacological pupil dilation can be used to detect DR, however, its value in a general clinical setting has not been established. The objective of this review is to evaluate the validity of NM retinal photos, as compared to the reference standard of seven standard stereoscopic 30 degree field photographs (7SF), for their use of detecting DR in community-dwelling adults. Methods English articles were identified through MEDLINE (1992–2016), EMBASE (1992–2016), Center for Disease Control and Prevention, Food and Drug Administration, Health Canada, and Google Scholar (1992–2016). Only studies that examined the validity of NM retinal photos, without pharmacological pupil dilation, as compared to 7SF, used in a community-dwelling adult population were included. Risk of bias was assessed using the QUADAS-2. Results Of the 368 articles identified in the search, 6 articles met eligibility requirements. Sensitivities ranged from 64 to 97.9% and specificities ranged from 65.6 to 98%. Studies that used multiple field images to detect DR in a younger population generally produced higher quality photos and more valid results. Conclusions The strongest validity indicators were reported in studies capturing multiple field images.

Introduction: Fibrinolytic factors, plasminogen activator inhibitor-1, tissue plasminogen activator, tissue plasminogen activator/plasminogen activator-complex and the haemostatic factor von Willebrand factor are known markers of cardiovascular disease. Their plasma levels are adversely affected in patients with dysglycaemia, and glucose normalization with insulin glargine might improve the levels of these factors. Methods: Prespecified Swedish substudy of the Outcome Reduction with an Initial Glargine Intervention trial (ClinicalTrials.gov number, NCT00069784). Tissue plasminogen activator activity, tissue plasminogen activator antigen, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex and von Willebrand factor were analysed at study start, after 2 years and at the end of the study (median follow-up of 6.2 years). Results: Of 129 patients (mean age of 64 ± 7 years, females: 19%), 68 (53%) and 61 (47%) were randomized to the insulin glargine and standard care group, respectively. Allocation to insulin glargine did not significantly affect the studied fibrinolytic markers or von Willebrand factor compared to standard care. Likewise, there were no significant differences in plasminogen activator inhibitor-1, tissue plasminogen activator antigen and von Willebrand factor. During the whole study period, the within-group analysis revealed a curvilinear pattern and significant changes for tissue plasminogen activator/plasminogen activator inhibitor-1 complex, tissue plasminogen activator antigen and von Willebrand factor in the insulin glargine but not in the standard care group. Conclusion: In people with dysglycaemia and other cardiovascular risk factors, basal insulin does not improve the levels of markers of fibrinolysis or von Willebrand factor compared to standard glucose-lowering treatments.