Search

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648 , hazard ratio [HR] 1.23, P = 3.6 × 10−9), rs77142250 (near HS3ST1 , HR 1.89, P = 9.9 × 10−9), and rs335407 (near TFB1M/NOX3 , HR 1.25, P = 1.5 × 10−8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison–adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10−16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate whether the sex disparities in type 2 diabetes–associated cardiovascular disease (CVD) risks may be related to early-onset hypertension that could benefit from intensive blood pressure (BP) control. RESEARCH DESIGN AND METHODS: We analyzed intensive versus standard BP control in relation to incident CVD events in women and men with type 2 diabetes, based on their age of hypertension diagnosis. RESULTS: Among 3,792 adults with type 2 diabetes (49% women), multivariable-adjusted CVD risk was increased per decade earlier age at hypertension diagnosis (hazard ratio 1.11 [1.03–1.21], P = 0.006). Excess risk associated with early-diagnosed hypertension was attenuated in the presence of intensive versus standard antihypertensive therapy in women (P = 0.036) but not men (P = 0.76). CONCLUSIONS: Women with type 2 diabetes and early-onset hypertension may represent a higher-risk subpopulation that not only contributes to the excess in diabetes-related CVD risk for women but may benefit from intensive BP control. [ABSTRACT FROM AUTHOR]

In high-income countries, rates of atherosclerotic complications in type 2 diabetes have declined markedly over time due to better management of traditional risk factors including lipids, blood pressure, and glycemia levels. Population-wide reductions in smoking have also helped lower atherosclerotic complications and so reduce premature mortality in type 2 diabetes. However, as excess adiposity is a stronger driver for heart failure (HF), and obesity levels have remained largely unchanged, HF risks have not declined as much and may even be rising in the increasing number of people developing type 2 diabetes at younger ages. Excess weight is also an underrecognized risk factor for chronic kidney disease (CKD). Based on evidence from a range of sources, we explain how excess adiposity must be influencing most risks well before diabetes develops, particularly in younger-onset diabetes, which is linked to greater excess adiposity. We also review potential mechanisms linking excess adiposity to HF and CKD and speculate on how some of the responsible pathways—e.g., hemodynamic, cellular overnutrition, and inflammatory—could be favorably influenced by intentional weight loss (via lifestyle or drugs). On the basis of available evidence, we suggest that the cardiorenal outcome benefits seen with sodium–glucose cotransporter 2 inhibitors may partially derive from their interference of some of these same pathways. We also note that many other complications common in diabetes (e.g., hepatic, joint disease, perhaps mental health) are also variably linked to excess adiposity, the aggregated exposure to which has now increased in type 2 diabetes. All such observations suggest a greater need to tackle excess adiposity earlier in type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Breastfeeding duration is inversely associated with risks of cardiovascular disease (CVD) and type 2 diabetes in parous women. However, the association among women at high risk, including women with type 2 diabetes or gestational diabetes mellitus (GDM) is unclear. RESEARCH DESIGN AND METHODS: We included 15,146 parous women with type 2 diabetes from the Nurses' Health Study I and II (NHS, NHS II) and 4,537 women with a history of GDM from NHS II. Participants reported history of breastfeeding via follow-up questionnaires. Incident CVD by 2017 comprised stroke or coronary heart disease (CHD) (myocardial infarction, coronary revascularization). Adjusted hazard ratios (aHRs) and 95% CIs were estimated using Cox models. RESULTS: We documented 1,159 incident CVD cases among women with type 2 diabetes in both cohorts during 188,874 person-years of follow-up and 132 incident CVD cases among women with a GDM history during 100,218 person-years of follow-up. Longer lifetime duration of breastfeeding was significantly associated with lower CVD risk among women with type 2 diabetes, with pooled aHR of 0.68 (95% CI 0.54–0.85) for >18 months versus 0 months and 0.94 (0.91–0.98) per 6-month increment in breastfeeding. Similar associations were observed with CHD (pooled aHR 0.93 [0.88–0.97]) but not with stroke (0.96 [0.91–1.02]) per 6-month increment in breastfeeding. Among women with GDM history, >18 months versus 0 months of breastfeeding was associated with an aHR of 0.49 (0.28–0.86) for total CVD. CONCLUSIONS: Longer duration of breastfeeding was associated with lower risk of CVD in women with type 2 diabetes or GDM. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the associations among mannose, indexes of insulin resistance (IR) and secretion, and long-term cardiovascular outcomes. RESEARCH DESIGN AND METHODS: Fasting mannose was assayed in 1,403 participants, one-half of which had a first myocardial infarction (MI) with either normal glucose tolerance (n = 1,045) or newly detected dysglycemia (i.e., impaired glucose tolerance or type 2 diabetes; n = 358). Regression models were used to explore mannose associations with surrogate indexes of IR/insulin secretion. Multivariate Cox models were used to investigate the independent association between high (higher quartile) versus low (lower three quartiles) mannose and major adverse cardiac events (MACE) (n = 163) during the 10-year follow-up. RESULTS: Mannose was independently associated with IR indexes (all P ≤ 0.001). High versus low mannose was independently associated with MACE (hazard ratio 1.54, 95% CI 1.07–2.20) in the overall population. CONCLUSIONS: Mannose might represent a new biomarker able to track early, potentially detrimental glucometabolic alterations independently of glycemic state. [ABSTRACT FROM AUTHOR]

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. [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]

OBJECTIVE: We investigated genetic risk of cardiovascular disease (CVD) by age at type 2 diabetes (T2D) diagnosis. RESEARCH DESIGN AND METHODS: We compared incident CVD events by age at T2D diagnosis using UK Biobank (N = 12,321) and the Seoul National University Hospital (SNUH) cohort (N = 1,165). Genetic risk was quantified using polygenic risk score (PRS). RESULTS: Individuals with earlier T2D diagnosis had higher CVD risk. In UK Biobank, the effect size of coronary artery disease (CAD) PRS on incident CAD was largest in individuals diagnosed with T2D at ages 30–39 years (hazard ratio 2.25; 95% CI 1.56–3.26) and decreased as age at diagnosis increased: ages 40–49 (1.51; 1.30–1.75), 50–59 (1.36; 1.24–1.50), and 60–69 years (1.30; 1.14–1.48) (Pinteraction = 0.0031). A similar trend was observed in the SNUH cohort. This increased genetic risk associated with earlier T2D diagnosis was largely mitigated by a healthy lifestyle. CONCLUSIONS: Individuals with an earlier T2D diagnosis have a higher genetic risk of CAD, and this information could be used to tailor lifestyle interventions. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We investigated the relationship between hs-CRP, a marker of low-grade inflammation, alone or in combination with C-peptide, a marker of hyperinsulinemia/insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We computed adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS: During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07–1.96]) and with even greater risk of all-cause mortality (2.47 [1.88–3.25]). Compared with patients with low hs-CRP (≤3 mg/L) and low C-peptide (<1,470 pmol/L), those with high levels of both biomarkers had the highest CVE (1.61 [1.10–2.34]) and all-cause mortality risk (2.36 [1.73–3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. CONCLUSIONS: The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker supports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the effects of intensive systolic blood pressure (SBP) lowering on the risk of major adverse kidney outcomes in people with type 2 diabetes mellitus (T2DM) and/or prediabetes and cardiovascular risk factors. RESEARCH DESIGN AND METHODS: This post hoc ACCORD-BP subgroup analysis included participants in the standard glucose-lowering arm with cardiovascular risk factors required for SPRINT eligibility. Cox proportional hazards regression models compared the hazard for the composite of dialysis, kidney transplant, sustained estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2, serum creatinine >3.3 mg/dL, or a sustained eGFR decline ≥57% between the intensive (<120 mmHg) and standard (<140 mmHg) SBP-lowering arms. RESULTS: The study cohort included 1,966 SPRINT-eligible ACCORD-BP participants (40% women) with a mean age of 63 years. The mean SBP achieved after randomization was 120 ± 14 and 134 ± 15 mmHg in the intensive and standard arms, respectively. The kidney composite outcome occurred at a rate of 9.5 and 7.2 events per 1,000 person-years in the intensive and standard BP arms (hazard ratio [HR] 1.35 [95% CI 0.85–2.14]; P = 0.20). Intensive SBP lowering did not affect the risk of moderately (HR 0.96 [95% CI 0.76–1.20]) or severely (HR 0.92 [95% CI 0.66–1.28]) increased albuminuria. Including SPRINT participants with prediabetes in the cohort did not change the overall results. CONCLUSIONS: This post hoc subgroup analysis suggests that intensive SBP lowering does not increase the risk of major adverse kidney events in individuals with T2DM and cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. [ABSTRACT FROM AUTHOR]

OBJECTIVE: A plant-based dietary pattern, the Portfolio Diet, has been shown to lower LDL cholesterol and other cardiovascular disease risk factors. However, no study has evaluated the association of this diet with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: This analysis included 145,299 postmenopausal women free of diabetes at baseline in the Women's Health Initiative (WHI) Clinical Trials and Observational Study from 1993 to 2021. Adherence to the diet was assessed with a score based on six components (high in plant protein [soy and pulses], nuts, viscous fiber, plant sterols, and monounsaturated fat and low in saturated fat and cholesterol) determined from a validated food-frequency questionnaire. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% CIs of the association of the Portfolio Diet, alongside the Dietary Approaches to Stop Hypertension (DASH) and Mediterranean diets, with incident type 2 diabetes, with adjustment for potential confounders. RESULTS: Over a mean follow-up of 16.0 years, 13,943 cases of incident type 2 diabetes were identified. In comparisons of the highest with the lowest quintiles of adherence, the HRs for risk of incident type 2 diabetes were 0.77 (95% CI 0.72, 0.82) for the Portfolio Diet, 0.69 (0.64, 0.73) for the DASH diet, and 0.78 (0.74, 0.83) for the Mediterranean diet. These findings were attenuated by 10% after additional adjustment for BMI. CONCLUSIONS: Greater adherence to the plant-predominant Portfolio, DASH, and Mediterranean diets was prospectively associated with lower risk of type 2 diabetes in postmenopausal women. [ABSTRACT FROM AUTHOR]

The article presents the discussion on worldwide pandemic of type 2 diabetes (T2D) and obesity. Topics include duodenal-jejunal bypass liner being developed to mimic the proposed small-bowel mechanisms of Roux-en-Y gastric bypass; and decrease in medication dosages and/or discontinuation of antidiabetes medication such as insulin being a recognized benefit of EndoBarrier treatment .

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. [ABSTRACT FROM AUTHOR]

Objective: In the Italian Diabetes and Exercise Study_2 (IDES_2), behavioral counseling promoted a sustained increase in physical activity (PA) volume (+3.3 MET h ⋅ week-1), moderate- to vigorous-intensity PA (MVPA) (+6.4 min ⋅ day-1), and light-intensity PA (LPA) (+0.8 h ⋅ day-1) and decrease in sedentary time (SED-time) (-0.8 h ⋅ day-1). Here, we investigated the relationships of changes in PA/SED-time with changes in physical fitness and cardiometabolic risk profile in individuals with type 2 diabetes.Research Design and Methods: In this 3-year randomized clinical trial, 300 physically inactive and sedentary patients were randomized 1:1 to receive 1-month theoretical and practical counseling once a year or standard care. Changes in physical fitness and cardiovascular risk factors/scores according to quartiles of accelerometer-measured changes in PA/SED-time were assessed, together with univariate and multivariable associations between these parameters, in the whole cohort and by study arm.Results: Physical fitness increased and HbA1c and coronary heart disease 10-year risk scores decreased with quartiles of MVPA and SED-time change. In quartile IV of MVPA increase and SED-time decrease, cardiorespiratory fitness increased by 5.23 and 4.49 mL ⋅ min-1 ⋅ kg-1 and HbA1c decreased by 0.73 and 0.85%, respectively. Univariate correlations confirmed these relationships, and mean changes in both MPVA and SED-time predicted changes in physical fitness and cardiovascular risk factors/scores independently of one another and of other confounders. Similar findings were observed with LPA and PA volume and in each group separately.Conclusions: Even modest increments in MVPA may have a clinically meaningful impact, and reallocating SED-time to LPA may also contribute to improved outcomes, possibly by increasing total energy expenditure. [ABSTRACT FROM AUTHOR]

Objective: To assess the risk of major adverse cardiovascular events (MACE), all-cause mortality, and initiation of medical treatment in subjects with prediabetes according to first-time measured HbA1c.Research Design and Methods: Through registry databases, we identified 326,305 Danish patients with a first HbA1c between 40 and 51 mmol/mol (5.8-6.8%) from 2011 to 2017. After exclusion of patients with prior disease, 84,678 patients were followed 12 months after first HbA1c measurement. Cox regression models were used to estimate hazard ratios (HRs) of MACE and standardized absolute risks. Cumulative incidences were used to analyze initiation of glucose-lowering, antihypertensive, cholesterol-lowering, and antithrombotic medication.Results: The 12-month risk of MACE and all-cause mortality increased gradually with increasing HbA1c until 47 mmol/mol (6.5%). In comparisons of subjects with HbA1c 40-41 mmol/mol (5.8-5.9%), subjects with HbA1c 46-47 mmol/mol (6.4-6.5%) had a 0.79% (95% CI 0.33-1.24) higher standardized absolute risk and an HR of 2.21 (95% CI 1.67-2.92) of MACE. Patients with HbA1c 48-49 mmol/mol (6.5-6.6%) had a 0.09% (95% CI -0.35 to 0.52) lower absolute risk and an HR of 1.33 (95% CI 0.87-2.05) of MACE. Initiation of medication was significantly lower among patients with HbA1c of 46-47 mmol/mol (6.4-6.5%) than among patients with HbA1c of 48-49 mmol/mol (6.5-6.6%).Conclusions: In the Danish population screened for diabetes with HbA1c, the highest risk of MACE and all-cause mortality was found in subjects with HbA1c just below the diagnostic threshold for diabetes. Our results highlight the need for increased focus on the treatment of cardiovascular risk factors for subjects with prediabetes. [ABSTRACT FROM AUTHOR]

Objective: Early menopause may be associated with higher cardiovascular disease (CVD) risk. Type 2 diabetes mellitus (T2DM), coupled with early menopause, may result in even greater CVD risk in women. We examined CVD risk in women with early compared with normal-age menopause, with and without T2DM overall, and by race/ethnicity.Research Design and Methods: We pooled data from the Atherosclerosis Risk in Communities study, the Multi-Ethnic Study of Atherosclerosis, and the Jackson Heart Study. We included women with data on menopausal status, menopausal age, and T2DM, excluding pre- or perimenopausal women and those with prevalent CVD. Outcomes included incident coronary heart disease (CHD), stroke, heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD) (CHD or stroke). We estimated the risk associated with early (<45 years) compared with normal-age menopause using Cox proportional hazards models. Covariates included age, race/ethnicity, education, BMI, blood pressure, cholesterol, smoking, alcohol consumption, antihypertensive medication, lipid-lowering medication, hormone therapy use, and pregnancy history.Results: We included 9,374 postmenopausal women for a median follow-up of 15 years. We observed 1,068 CHD, 659 stroke, 1,412 HF, and 1,567 ASCVD events. T2DM significantly modified the effect of early menopause on CVD risk. Adjusted hazard ratios for early menopause and the outcomes were greater in women with T2DM versus those without (CHD 1.15 [95% CI 1.00, 1.33] vs. 1.09 [1.03, 1.15]; stroke 1.21 [1.04, 1.40] vs. 1.10 [1.04, 1.16]; ASCVD 1.29 [1.09, 1.51] vs. 1.10 [1.04, 1.17]; HF 1.18 [1.00, 1.39] vs. 1.09 [1.03, 1.16]). The modifying effect of T2DM on the association between early menopause and ASCVD was only statistically significant in Black compared with White women.Conclusions: Early menopause was associated with an increased risk for CVD in postmenopausal women. T2DM may further augment the risk, particularly in Black women. [ABSTRACT FROM AUTHOR]

Objective: Natriuretic peptide (NP) concentrations are increased in cardiovascular diseases (CVDs) but are associated with a lower diabetes risk. We investigated associations of N-terminal pro-B-type NP (NT-proBNP) and midregional proatrial NP (MR-proANP) with incident type 2 diabetes stratified by the presence of CVD.Research Design and Methods: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium, we included 45,477 participants with NT-proBNP measurements (1,707 developed type 2 diabetes over 6.5 years of median follow-up; among these, 209 had CVD at baseline) and 11,537 participants with MR-proANP measurements (857 developed type 2 diabetes over 13.8 years of median follow-up; among these, 106 had CVD at baseline). The associations were estimated using multivariable Cox regression models.Results: Both NPs were inversely associated with incident type 2 diabetes (hazard ratios [95% CI] per 1-SD increase of log NP: 0.84 [0.79; 0.89] for NT-proBNP and 0.77 [0.71; 0.83] for MR-proANP). The inverse association between NT-proBNP and type 2 diabetes was significant in individuals without CVD but not in individuals with CVD (0.81 [0.76; 0.86] vs. 1.04 [0.90; 1.19]; P multiplicative interaction = 0.001). There was no significant difference in the association of MR-proANP with type 2 diabetes between individuals without and with CVD (0.75 [0.69; 0.82] vs. 0.81 [0.66; 0.99]; P multiplicative interaction = 0.236).Conclusions: NT-proBNP and MR-proANP are inversely associated with incident type 2 diabetes. However, the inverse association of NT-proBNP seems to be modified by the presence of CVD. Further investigations are warranted to confirm our findings and to investigate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To examine if the association between higher A1C and risk of cardiovascular disease (CVD) among adults with and without diabetes is modified by racial residential segregation.Research Design and Methods: The study used a case-cohort design, which included a random sample of 2,136 participants at baseline and 1,248 participants with incident CVD (i.e., stroke, coronary heart disease [CHD], and fatal CHD during 7-year follow-up) selected from 30,239 REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants originally assessed between 2003 and 2007. The relationship of A1C with incident CVD, stratified by baseline diabetes status, was assessed using Cox proportional hazards models adjusting for demographics, CVD risk factors, and socioeconomic status. Effect modification by census tract-level residential segregation indices (dissimilarity, interaction, and isolation) was assessed using interaction terms.Results: The mean age of participants in the random sample was 64.2 years, with 44% African American, 59% female, and 19% with diabetes. In multivariable models, A1C was not associated with CVD risk among those without diabetes (hazard ratio [HR] per 1% [11 mmol/mol] increase, 0.94 [95% CI 0.76-1.16]). However, A1C was associated with an increased risk of CVD (HR per 1% increase, 1.23 [95% CI 1.08-1.40]) among those with diabetes. This A1C-CVD association was modified by the dissimilarity (P < 0.001) and interaction (P = 0.001) indices. The risk of CVD was increased at A1C levels between 7 and 9% (53-75 mmol/mol) for those in areas with higher residential segregation (i.e., lower interaction index). In race-stratified analyses, there was a more pronounced modifying effect of residential segregation among African American participants with diabetes.Conclusions: Higher A1C was associated with increased CVD risk among individuals with diabetes, and this relationship was more pronounced at higher levels of residential segregation among African American adults. Additional research on how structural determinants like segregation may modify health effects is needed. [ABSTRACT FROM AUTHOR]

Objective: Depression is highly frequent in older adults with type 2 diabetes and is associated with cognitive impairment, yet little is known about how various depression dimensions differentially affect cognition. We investigated longitudinal associations of specific depression dimensions with cognitive decline.Research Design and Methods: Participants (N = 1,002) were from the Israel Diabetes and Cognitive Decline study, were ≥65 years of age, had type 2 diabetes, and were not experiencing dementia at baseline. Participants underwent a comprehensive neuropsychological battery at baseline and every 18 months thereafter, including domains of episodic memory, attention/working memory, semantic categorization/language, and executive function, and Z-scores of each domain were averaged and further normalized to calculate global cognition. Depression items from the 15-item Geriatric Depression Scale were measured at each visit and subcategorized into five dimensions: dysphoric mood, withdrawal-apathy-vigor (entitled apathy), anxiety, hopelessness, and memory complaint. Random coefficients models examined the association of depression dimensions with baseline and longitudinal cognitive functioning, adjusting for sociodemographics and baseline characteristics, including cardiovascular risk factors, physical activity, and use of diabetes medications.Results: In the fully adjusted model at baseline, all dimensions of depression, except for anxiety, were associated with some aspect of cognition (P values from 0.01 to <0.001). Longitudinally, greater apathy scores were associated with faster decline in executive function (P = 0.004), a result that withstood adjustment for multiple comparisons. Associations of other depression dimensions with cognitive decline were not significant (P > 0.01).Conclusions: Apathy was associated with a faster cognitive decline in executive function. These findings highlight the heterogeneity of depression as a clinical construct rather than as a single entity and point to apathy as a specific risk factor for cognitive decline among older adults with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that vitamin C supplementation could be a potential therapy in type 2 diabetes. However, its effectiveness and evidence quality require further evaluation.Purpose: To investigate the efficacy of oral vitamin C supplementation in improving glycemic control, cardiovascular risk factors, and oxidative stress in people with type 2 diabetes.Data Sources: Databases (PubMed, Embase, Scopus, Cochrane Library) and clinical trial registries were searched for randomized controlled trials up to 8 September 2020.Study Selection: Trials in adults with type 2 diabetes were included. Trials were excluded if supplements were not exclusive to vitamin C and if <2 weeks in duration.Data Extraction: Primary outcomes were HbA1c, glucose, cholesterol, triglycerides, and blood pressure (BP). Data were extracted for changes in outcomes between vitamin C and control groups. Evidence certainty was assessed using Grading of Recommendations, Assessment, Development, and Evaluation methods.Data Synthesis: Twenty-eight studies (N = 1,574 participants) were included in the review. Outcomes that changed to a statistically and clinically significant extent with vitamin C were systolic BP (mean difference -6.27 [95% CI -9.60, -2.96] mmHg; P = 0.0002), with moderate evidence certainty, and HbA1c (-0.54% [-0.90, -0.17]; P = 0.004) and diastolic BP (-3.77 [-6.13, -1.42] mmHg; P = 0.002) with very low evidence certainty.Limitations: Studies were predominantly short term (<6 months) with a small number of participants (n < 100).Conclusions: While evidence from short-term studies suggests that vitamin C supplementation may improve glycemic control and BP in people with type 2 diabetes, vitamin C supplementation cannot currently be recommended as a therapy until larger, long-term, and high-quality trials confirm these findings. [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]

The article presents the discussion on the effect of Dapagliflozin on Hematocrit in patients with type 2 diabetes at high cardiovascular risk. Topics include expanding beyond patients with type 2 diabetes (T2D) to patients with heart failure and chronic kidney disease regardless of T2D status; and evidence suggesting a relationship between SGLT2 inhibitors and increasing hematocrit (Hct) hemoglobiin.

Objective: Weight loss diets may reduce serum urate (SU) by lowering insulin resistance while providing cardiometabolic benefits, something urate-lowering drugs have not shown in trials. We aimed to examine the effects of weight loss diets on SU and cardiometabolic risk factors.Research Design and Methods: This secondary study of the Dietary Intervention Randomized Controlled Trial (DIRECT) used stored samples from 235 participants with moderate obesity randomly assigned to low-fat, restricted-calorie (n = 85); Mediterranean, restricted-calorie (n = 76); or low-carbohydrate, non-restricted-calorie (n = 74) diets. We examined SU changes at 6 and 24 months overall and among those with hyperuricemia (SU ≥416 μmol/L), a relevant subgroup at risk for gout.Results: Among all participants, average SU decreases were 48 μmol/L at 6 months and 18 μmol/L at 24 months, with no differences between diets (P > 0.05). Body weight, HDL cholesterol (HDL-C), total cholesterol:HDL-C ratio, triglycerides, and insulin concentrations also improved in all three groups (P < 0.05 at 6 months). Adjusting for covariates, changes in weight and fasting plasma insulin concentrations remained associated with SU changes (P < 0.05). SU reductions among those with hyperuricemia were 113, 119, and 143 μmol/L at 6 months for low-fat, Mediterranean, and low-carbohydrate diets (all P for within-group comparison < 0.001; P > 0.05 for between-group comparisons) and 65, 77, and 83 μmol/L, respectively, at 24 months (all P for within-group comparison < 0.01; P > 0.05 for between-group comparisons).Conclusions: Nonpurine-focused weight loss diets may simultaneously improve SU and cardiovascular risk factors likely mediated by reducing adiposity and insulin resistance. These dietary options could provide personalized pathways to suit patient comorbidity and preferences for adherence. [ABSTRACT FROM AUTHOR]

Objective: Women who develop gestational diabetes mellitus (GDM) have an elevated lifetime risk of cardiovascular disease, which has been attributed to an adverse cardiovascular risk factor profile that is apparent even within the first year postpartum. Given its presence in the early postpartum, we hypothesized that this adverse cardiovascular risk factor profile may develop over time in the years before pregnancy.Research Design and Methods: With population-based administrative databases, we identified all nulliparous women in Ontario, Canada, who had singleton pregnancies between January 2011 and December 2016 and two or more measurements of the following analytes between 2007 and the start of pregnancy: A1C, fasting glucose, random glucose, lipids, and transaminases. This population consisted of 8,047 women who developed GDM and 93,114 women who did not.Results: The two most recent pregravid tests were performed at a median of 0.61 years and 1.86 years before pregnancy, respectively. Women who went on to develop GDM had higher pregravid A1C, fasting glucose, random glucose, LDL cholesterol, triglycerides, and ALT and lower HDL cholesterol than their peers (all P < 0.0001). Notably, in the years before pregnancy, women who went on to develop GDM had higher annual increases than their peers in A1C (1.9-fold higher) (difference 0.0089%/year [95% CI 0.0043-0.0135]) and random glucose (4.3-fold), greater annual decrease in HDL cholesterol (5.5-fold), and lesser annual decline in LDL cholesterol (0.4-fold) (all P ≤ 0.0002). During this time, fasting glucose and triglycerides increased in women who developed GDM but decreased in their peers (both P < 0.0001).Conclusions: The adverse cardiovascular risk factor profile of women with GDM evolves over time in the years before pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Type 1 diabetes is accompanied by a significant burden of cardiovascular disease (CVD), which is poorly explained by traditional risk factors. We therefore aimed to explore whether arterial stiffness estimated by the augmentation index (AIx) predicts mortality in individuals with type 1 diabetes.Research Design and Methods: After baseline examination comprising pulse wave analysis by applanation tonometry alongside assessment of traditional cardiovascular risk factors, 906 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study were followed up for a median of 8.2 years (interquartile range 5.7-9.7). Associations between baseline hemodynamics, including AIx, and all-cause mortality as well as a composite of cardiovascular and/or diabetes-related mortality were investigated using multivariable Cox regression models.Results: The 67 individuals who died during follow-up had higher baseline AIx (median 28% [interquartile range 21-33] vs. 19% [9-27]; P < 0.001) compared with those alive. This association was independent of conventional risk factors (age, sex, BMI, HbA1c, estimated glomerular filtration rate [eGFR], and previous CVD event) in Cox regression analysis (standardized hazard ratio 1.71 [95% CI 1.10-2.65]; P = 0.017) and sustained in a subanalysis of individuals with chronic kidney disease. Similarly, higher AIx was associated with the composite secondary end point of cardiovascular and diabetes-related death (N = 53) after adjustments for sex, BMI, eGFR, previous CVD event, and height (standardized hazard ratio 2.30 [1.38-3.83]; P = 0.001).Conclusions: AIx predicts all-cause mortality as well as a composite cardiovascular and/or diabetes-related cause of death in individuals with type 1 diabetes, independent of established cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Objective: The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events.Research Design and Methods: CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes.Results: Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]).Conclusions: Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained. [ABSTRACT FROM AUTHOR]

Objective: HbA1c levels are increasingly measured in screening for diabetes; we investigated whether HbA1c may simultaneously improve cardiovascular disease (CVD) risk assessment, using QRISK3, American College of Cardiology/American Heart Association (ACC/AHA), and Systematic COronary Risk Evaluation (SCORE) scoring systems.Research Design and Methods: UK Biobank participants without baseline CVD or known diabetes (n = 357,833) were included. Associations of HbA1c with CVD was assessed using Cox models adjusting for classical risk factors. Predictive utility was determined by the C-index and net reclassification index (NRI). A separate analysis was conducted in 16,596 participants with known baseline diabetes.Results: Incident fatal or nonfatal CVD, as defined in the QRISK3 prediction model, occurred in 12,877 participants over 8.9 years. Of participants, 3.3% (n = 11,665) had prediabetes (42.0-47.9 mmol/mol [6.0-6.4%]) and 0.7% (n = 2,573) had undiagnosed diabetes (≥48.0 mmol/mol [≥6.5%]). In unadjusted models, compared with the reference group (<42.0 mmol/mol [<6.0%]), those with prediabetes and undiagnosed diabetes were at higher CVD risk: hazard ratio (HR) 1.83 (95% CI 1.69-1.97) and 2.26 (95% CI 1.96-2.60), respectively. After adjustment for classical risk factors, these attenuated to HR 1.11 (95% CI 1.03-1.20) and 1.20 (1.04-1.38), respectively. Adding HbA1c to the QRISK3 CVD risk prediction model (C-index 0.7392) yielded a small improvement in discrimination (C-index increase of 0.0004 [95% CI 0.0001-0.0007]). The NRI showed no improvement. Results were similar for models based on the ACC/AHA and SCORE risk models.Conclusions: The near twofold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors. While HbA1c adds minimally to cardiovascular risk prediction, those with prediabetes should have their conventional cardiovascular risk factors appropriately measured and managed. [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]

Objective: Diabetes in older age is heterogeneous, and the treatment approach varies by patient characteristics. We characterized the short-term all-cause and cardiovascular mortality risk associated with hyperglycemia in older age.Research Design and Methods: We included 5,791 older adults in the Atherosclerosis Risk in Communities Study who attended visit 5 (2011-2013; ages 66-90 years). We compared prediabetes (HbA1c 5.7% to <6.5%), newly diagnosed diabetes (HbA1c ≥6.5%, prior diagnosis <1 year, or taking antihyperglycemic medications <1 year), short-duration diabetes (duration ≥1 year but <10 years [median]), and long-standing diabetes (duration ≥10 years). Outcomes were all-cause and cardiovascular mortality (median follow-up of 5.6 years).Results: Participants were 58% female, and 24% had prevalent cardiovascular disease. All-cause mortality rates, per 1,000 person-years, were 21.2 (95% CI 18.7, 24.1) among those without diabetes, 23.7 (95% CI 20.8, 27.1) for those with prediabetes, 33.8 (95% CI 25.2, 45.5) among those with recently diagnosed diabetes, 29.6 (95% CI 25.0, 35.1) for those with diabetes of short duration, and 48.6 (95% CI 42.4, 55.7) for those with long-standing diabetes. Cardiovascular mortality rates, per 1,000 person-years, were 5.8 (95% CI 4.6, 7.4) among those without diabetes, 6.6 (95% CI 5.2, 8.5) for those with prediabetes, 11.5 (95% CI 7.0, 19.1) among those with recently diagnosed diabetes, 8.2 (95% CI 5.9, 11.3) for those with diabetes of short duration, and 17.3 (95% CI 13.8, 21.7) for those with long-standing diabetes. After adjustment for other cardiovascular risk factors, prediabetes and newly diagnosed diabetes were not significantly associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.03 [95% CI 0.85, 1.23] and HR 1.31 [95% CI 0.94, 1.82], respectively) or cardiovascular mortality (HR 1.00 [95% CI 0.70, 1.43] and HR 1.35 [95% CI 0.74, 2.49], respectively). Excess mortality risk was primarily concentrated among those with long-standing diabetes (all-cause: HR 1.71 [95% CI 1.40, 2.10]; cardiovascular: HR 1.72 [95% CI 1.18, 2.51]).Conclusions: In older adults, long-standing diabetes has a substantial and independent effect on short-term mortality. Older individuals with prediabetes remained at low mortality risk over a median 5.6 years of follow-up. [ABSTRACT FROM AUTHOR]

The article offers information related to cardiovascular disease and risk management presented in American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" 2020. Topics discussed include information on cardiovascular biomarkers for risk stratification of secondary prevention patients; use of 24-hour ambulatory blood pressure monitoring to provide evidence of white coat hypertension; and suggestion to measure Blood pressure at every routine clinical visit.

The article presents a study which examined the influence of sexual dimorphism and sex steroids on cardiovascular autonomic neuropathy in patients with type 1 diabetes. Topics discussed include features of study participants, the assessment of cardiovascular autonomic function using Ewing tests, and group of women with more cardiovascular risk factors than the other study subgroups.

Objective: Trimethylamine N-oxide (TMAO) is suggested as an independent gut microbiota-derived risk factor for cardiovascular and renal disease. We investigated associations between plasma TMAO concentrations and cardio-renal outcomes in a prospective study of individuals with type 1 diabetes.Research Design and Methods: Plasma TMAO was measured at baseline in 1,159 individuals with type 1 diabetes (58% male, mean ± SD age 46 ± 13 years). End points were all-cause and cardiovascular mortality, cardiovascular disease (CVD), and renal events tracked from national registries. Associations between TMAO and end points were tested using Cox regression models.Results: After 15.0 (6.7-19.3) (median [interquartile range]) years of follow-up, we recorded all-cause and cardiovascular mortality (n = 363 and 120, respectively), combined CVD (n = 406), coronary outcome (myocardial infarction and coronary intervention) (n = 163), stroke (n = 115), hospitalization for heart failure (n = 81), and end-stage renal disease (n = 144). In univariate analyses, higher TMAO concentrations were associated with all end points (P ≤ 0.005). Except for stroke and heart failure, all end points remained significantly associated with higher TMAO concentrations after adjustment for conventional cardiovascular risk factors (P ≤ 0.003). After further adjustment for baseline estimated glomerular filtration rate (eGFR), results became insignificant for all end points. TMAO was inversely associated with baseline eGFR (R2 = 0.29; P < 0.001).Conclusions: In individuals with type 1 diabetes, higher concentrations of plasma TMAO were associated with mortality, CVD events, and poor renal outcome, independent of conventional risk factors. However, the association became insignificant after further adjustment for baseline eGFR. This could reflect TMAO as a renal function marker or a risk factor for micro- and macrovascular complications mediated through impaired renal function. [ABSTRACT FROM AUTHOR]

The article discusses the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with diabetes. Topics mentioned include the morbidity and mortality for individuals with diabetes, the rates of incident heart failure hospitalization in patients with diabetes and the increase of blood pressure in patients with diabetes.

Objective: It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents.Research Design and Methods: Data were available for 3,497 children and adolescents aged 6-17 years from five population-based cross-sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as "healthy" [no risk factors] or "unhealthy" [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT ≥90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center.Results: In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58-3.32) for metabolically healthy overweight and 3.91 (2.46-6.21) for MHO. ORs for high cIMT were 1.44 (1.03-2.02) for unhealthy normal weight, 3.49 (2.51-4.85) for unhealthy overweight, and 6.96 (5.05-9.61) for unhealthy obesity.Conclusions: Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status. [ABSTRACT FROM AUTHOR]

Objective: We aimed to study whether visit-to-visit variability of glycated hemoglobin A1c (HbA1c) is associated with incident major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes in people without diabetes.Research Design and Methods: We included primary care patients with no history of diabetes or cardiovascular disease and with three annual HbA1c measurements within normal range (<6.5% [48 mmol/mol]). For each individual, we measured the HbA1c variability as the SD of the residuals obtained from a linear regression on the three HbA1c measurements. From the linear regression, we also obtained the estimated index HbA1c (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA1c variability and outcome were analyzed using Cox regression, adjusted for traditional risk factors, intercept, and trend and reported as hazard ratio per SD increase in variability (HRSD).Results: In total, 6,756 individuals were included. During a median follow-up time of 6.3 years, 996 developed MACE, 856 died, and 1,267 developed type 2 diabetes. We found a significant association between increasing HbA1c variability and incident MACE (HRSD 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HRSD 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HRSD 1.00 [95% CI 0.95-1.05]). We calculated 5-year absolute risks of MACE and all-cause mortality and found clinically relevant differences across several age, sex, comorbidity, and HbA1c variability-defined subgroups.Conclusions: In a primary care population free of diabetes and cardiovascular disease, high HbA1c variability was associated with increased risks of MACE and all-cause mortality. [ABSTRACT FROM AUTHOR]

Objective: To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT).Research Design and Methods: This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control.Results: The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012).Conclusions: Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia. [ABSTRACT FROM AUTHOR]

Objective: Epidemiological studies have reported a relationship between severe hypoglycemia, cognitive dysfunction, and dementia in middle-aged and older people with type 2 diabetes. However, whether severe or nonsevere hypoglycemia precedes cognitive dysfunction is unclear. Thus, the aim of this study was to analyze the relationship between hypoglycemia and incident cognitive dysfunction in a group of carefully followed patients using prospectively collected data in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial.Research Design and Methods: This prospective cohort analysis of data from a randomized controlled trial included individuals with dysglycemia who had additional cardiovascular risk factors and a Mini-Mental State Examination (MMSE) score ≥24 (N = 11,495). Severe and nonsevere hypoglycemic events were collected prospectively during a median follow-up time of 6.2 years. Incident cognitive dysfunction was defined as either reported dementia or an MMSE score of <24. The hazard of at least one episode of severe or nonsevere hypoglycemia for incident cognitive dysfunction (i.e., the dependent variable) from the time of randomization was estimated using a Cox proportional hazards model after adjusting for baseline cardiovascular disease, diabetes status, treatment allocation, and a propensity score for either form of hypoglycemia.Results: This analysis did not demonstrate an association between severe hypoglycemia and incident cognitive impairment either before (hazard ratio [HR] 1.16; 95% CI 0.89, 1.52) or after (HR 1.00; 95% CI 0.76, 1.31) adjusting for the severe hypoglycemia propensities. Conversely, nonsevere hypoglycemia was inversely related to incident cognitive impairment both before (HR 0.59; 95% CI 0.52, 0.68) and after (HR 0.58; 95% CI 0.51, 0.67) adjustment.Conclusions: Hypoglycemia did not increase the risk of incident cognitive dysfunction in 11,495 middle-aged individuals with dysglycemia. [ABSTRACT FROM AUTHOR]

Objective: It is well established that diabetic nephropathy increases the risk of cardiovascular disease (CVD), but how severe diabetic retinopathy (SDR) impacts this risk has yet to be determined.Research Design and Methods: The cumulative incidence of various CVD events, including coronary heart disease (CHD), peripheral artery disease (PAD), and stroke, retrieved from registries, was evaluated in 1,683 individuals with at least a 30-year duration of type 1 diabetes drawn from the Finnish Diabetic Nephropathy Study (FinnDiane). The individuals were divided into four groups according to the presence of diabetic kidney disease (DKD) and/or SDR (+DKD/+SDR, +DKD/-SDR, -DKD/+SDR, and -DKD/-SDR) at baseline visit. Furthermore, age-specific incidences were compared with 4,016 control subjects without diabetes. SDR was defined as laser photocoagulation and DKD as estimated glomerular filtration rate <60 mL/min/1.73 m2.Results: During 12,872 person-years of follow-up, 416 incident CVD events occurred. Even in the absence of DKD, SDR increased the risk of any CVD (hazard ratio 1.46 [95% CI 1.11-1.92]; P < 0.01), after adjustment for diabetes duration, age at diabetes onset, sex, smoking, blood pressure, waist-to-hip ratio, history of hypoglycemia, and serum lipids. In particular, SDR alone was associated with the risk of PAD (1.90 [1.13-3.17]; P < 0.05) and CHD (1.50 [1.09-2.07; P < 0.05) but not with any stroke. Moreover, DKD increased the CVD risk further (2.85 [2.13-3.81]; P < 0.001). However, the risk was above that of the control subjects without diabetes also in patients without microvascular complications, until the patients reached their seventies.Conclusions: SDR alone, even without DKD, increases cardiovascular risk, particularly for PAD, independently of common cardiovascular risk factors in long-standing type 1 diabetes. More remains to be done to fully understand the link between SDR and CVD. This knowledge could help combat the enhanced cardiovascular risk beyond currently available regimens. [ABSTRACT FROM AUTHOR]

Objective: We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk.Research Design and Methods: A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression.Results: The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, P = 4 × 10-10, and HR per SD 1.35, 95% CI 1.16-1.58, P = 2 × 10-4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10-4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years.Conclusions: When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We assessed whether changes in metabolic syndrome (MetS) severity during the treatment of prediabetes are associated with reduced risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We analyzed data from the Diabetes Prevention Program (DPP) for 2,476 adults in 1996-1999 with prediabetes randomized to receive treatment with lifestyle modification, metformin, or placebo for 2-3 years and followed through 2014 for T2DM and CVD outcomes. We calculated effect sizes from baseline in a MetS severity z score (MetS-Z) and the individual MetS components, and assessed relationships between 1-year effect size and incident T2DM and CVD using hazard ratios (HRs) and mediation analysis. RESULTS: Baseline MetS-Z and its components were associated with risk of incident T2DM and CVD. During year 1 of intervention, MetS-Z and its components decreased most with lifestyle modification, followed by treatment with metformin and placebo. Risk of T2DM within 1-5 years was most strongly associated with 1-year changes in MetS-Z and waist circumference (both HRs for a 1 SD increase = 1.80), whereas the risk of CVD was associated with a 1-year change in MetS-Z, glucose, and systolic blood pressure. In mediation analyses, the effect of lifestyle modification on T2DM risk was mediated by 1-year changes in MetS-Z, waist circumference, glucose, and triglycerides, whereas the effect of metformin was mediated by MetS-Z and glucose. CONCLUSIONS: Changes in these risk indicators of MetS severity during intervention in the DPP reflect altered disease risk and may help in tracking earlier responses to treatment and in motivating patients. [ABSTRACT FROM AUTHOR]

The article focuses on new therapeutics for cardiovascular disease (CVD) prevention in diabetes being costly, highlighting the need for better risk stratification so that interventions may be targeted to those at the highest risk. Topics include the high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) being measures of subclinical cardiac damage associated with cardiovascular risk in the general population, and the troponins appear differentially has associated with diabetes.

The article discusses the burden of complications in U.S. adults with young onset type 2 or type 1 diabetes. Topics include the National Health Interview Survey (NHIS) is the representative U.S. study that collects self-reported information on types of diabetes; participants reported whether they ever being diagnosed with diabetes other than during pregnancy; and young-onset type 2 diabetes as being diagnosed before age 40.

Objective: Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown.Research Design and Methods: We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl.Results: A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11-1.42]) and fatal (1.49 [1.30-1.71]) CVD and with all-cause mortality (1.25 [1.11-1.40]), myocardial infarction (1.22 [1.02-1.45]), and amputations (1.36 [1.05-1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79-1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00-1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes.Conclusions: Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to compare the incidence of cardiovascular disease (CVD) among patients with type 2 diabetes mellitus (T2DM) with treated hypertension who achieved systolic blood pressures (SBPs) of <120, <130, and <140 mmHg after an increase in their antihypertensive regimen.Research Design and Methods: A retrospective cohort study was conducted on 28,014 primary care adult patients with T2DM with no prior diagnosis of CVD and who achieved SBP readings <140 mmHg after an increase in the number of antihypertensive medications prescribed. Using an extension of propensity score matching, a total of 2,079, 10,851, and 15,084 matched patients with achieved SBP measurements of <120, <130, and <140 mmHg were identified. The association between achieved SBP and incident CVD were evaluated using Cox regressions. Subgroup analyses were conducted by stratifying patients' baseline characteristics.Results: Over a median follow-up period of 4.8 years, the incidence of CVD in patients with achieved SBP measures of <120, <130, and <140 mmHg were 318 (15.3%; incidence rate [IR] 34.3/1,000 person-years [PY]), 992 (9.1%; IR 20.4/1,000 PY), and 1,635 (10.8%; IR 21.4/1,000 PY). Achieved SBP <120 mmHg was associated with a higher risk of CVD compared with achieved SBP <130 mmHg (hazard ratio [HR] 1.75 [95% CI 1.53, 2.00]) and achieved SBP <140 mmHg (HR 1.67 [95% CI 1.46, 1.90]). There was a significant reduction in CVD risk in patients <65 years (HR 0.81 [95% CI 0.69, 0.96]) but no difference for other patients, including patients ≥65 years, who achieved SBP <130 mmHg when compared with the group that achieved SBP <140 mmHg.Conclusions: Our findings support a SBP treatment target of 140 mmHg and suspect no risk reduction attenuation on CVD for lower SBP targets (<120 or <130 mmHg) for most patients with uncomplicated T2DM. A randomized control trial is still needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Objective: Identifying patients who may experience decreased or increased mortality risk from intensive glycemic therapy for type 2 diabetes remains an important clinical challenge. We sought to identify characteristics of patients at high cardiovascular risk with decreased or increased mortality risk from glycemic therapy for type 2 diabetes using new methods to identify complex combinations of treatment effect modifiers.Research Design and Methods: The machine learning method of gradient forest analysis was applied to understand the variation in all-cause mortality within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (N = 10,251), whose participants were 40-79 years old with type 2 diabetes, hemoglobin A1c (HbA1c) ≥7.5% (58 mmol/mol), cardiovascular disease (CVD) or multiple CVD risk factors, and randomized to target HbA1c <6.0% (42 mmol/mol; intensive) or 7.0-7.9% (53-63 mmol/mol; standard). Covariates included demographics, BMI, hemoglobin glycosylation index (HGI; observed minus expected HbA1c derived from prerandomization fasting plasma glucose), other biomarkers, history, and medications.Results: The analysis identified four groups defined by age, BMI, and HGI with varied risk for mortality under intensive glycemic therapy. The lowest risk group (HGI <0.44, BMI <30 kg/m2, age <61 years) had an absolute mortality risk decrease of 2.3% attributable to intensive therapy (95% CI 0.2 to 4.5, P = 0.038; number needed to treat: 43), whereas the highest risk group (HGI ≥0.44) had an absolute mortality risk increase of 3.7% attributable to intensive therapy (95% CI 1.5 to 6.0; P < 0.001; number needed to harm: 27).Conclusions: Age, BMI, and HGI may help individualize prediction of the benefit and harm from intensive glycemic therapy. [ABSTRACT FROM AUTHOR]

Objective: Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk.Research Design and Methods: Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years.Results: SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust.Conclusions: These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Improved risk assessment for patients with type 2 diabetes and elevated cardiovascular (CV) risk is needed. The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P) predicts a gradient of risk in patients with prior myocardial infarction (MI) but has not been evaluated in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: CV event rates were compared by baseline TRS 2°P in 16,488 patients enrolled in SAVORTIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53)with type 2 diabetes and high CV risk or established CV disease. Calibration was tested in the diabetes cohort from the REACH (REduction of Atherothrombosis for Continued Health) Registry. RESULTS: TRS 2°P revealed a robust risk gradient for the composite of CV death, MI, and ischemic stroke in the full trial population, with 2-year event rates of 0.9% in the lowestand 19.8% in the highest-risk groups (Ptrend < 0.001). A clear risk gradient was present within the subgroups of all coronary artery disease (CAD), CAD without prior MI, CAD with priorMI, peripheral artery disease, and prior stroke (Ptrend < 0.001 for each), with consistent risk relationships across subgroups. The C-statistic (0.71 for CV death and 0.66 for the composite end point) was consistent in each subgroup. There was close calibration with the type 2 diabetes cohort from the REACH Registry (goodness-of-fit P = 0.78). CONCLUSIONS: The expanded TRS 2°P provides a practical and well-calibrated risk prediction tool for patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]