Background It is unclear how metabolic syndrome (MetS) and diabetes affect Gal‐3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal‐3, and their joint associations with incident HF. Methods and Results We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996–1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross‐sectional associations of metabolic risk categories with high Gal‐3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal‐3 quartiles with HF. In cross‐sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10–1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32–1.92]) were associated with elevated Gal‐3. Over a median follow‐up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal‐3 in the lowest quartile, the combination of MetS with diabetes and Gal‐3 ≥75th percentile was associated with a 4‐fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30–5.73]). Gal‐3 provided HF prognostic information above and beyond MetS, NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity cardiac troponin T, and CRP (C‐reactive protein) (ΔC statistic for models with versus without Gal‐3: 0.003; P =0.004). Conclusions MetS and diabetes are associated with elevated Gal‐3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal‐3.

Introduction: Limited data exist on links between glycemic markers and cardiac autonomic neuropathy (CAN) across the dysglycemia spectrum (including prediabetes and diabetes). We assessed associations of multiple glycemic markers with heart rate (HR) and CAN, measured via heart rate variability (HRV). Methods: This cross-sectional analysis included 2,266 participants who attended a 14-year follow up DPPOS visit. We evaluated associations of glycemic markers (fasting glucose, HbA1c and HOMA-IR) with HR and HRV (standard deviation of all normal-to-normal intervals [SDNN], root mean square of successive differences between normal-to-normal intervals [rMSSD] and QT index [QTI]) measures, using linear regression. Similarly, the relations between glycemic markers and CAN (SDNN ≤17.13 ms, rMSSD ≤24.94 ms or QTI ≥112) were assessed using logistic regression. Results: Participants had 65 years old on average, 68.2% were women, 53.4% were White, and 57.3% had diabetes. Glycemic measures were positively associated with HR and negatively associated with SDNN and rMSSD (Figure 1). Greater HbA1C, FPG and HOMA IR were associated with greater odds of CAN (OR [95% CI] per SD change: 1.34 [1.14, 1.62], 1.27 [1.08, 1.53] and 1.19 [1.02, 1.39], P<0.05). Conclusions: Glucose metabolism is associated with heart rate and risk of cardiac autonomic dysfunction across the spectrum of dysglycemia. Disclosure J. Echouffo Tcheugui: None. X. Liu: None. R.B. Goldberg: None. M. Budoff: Speaker's Bureau; Boehringer-Ingelheim, Lilly Diabetes, AstraZeneca. S. Dagogo-Jack: Consultant; Merck Sharp & Dohme Corp., Medtronic, Bayer Inc. Stock/Shareholder; Aerami. S. Golden: None. U.N. Ibebuogu: None. W.C. Knowler: None. N. White: None. M. Temprosa: None. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)

Objective: To assess associations between distal symmetric polyneuropathy (DSPN) and Diabetes Prevention Program (DPP) treatment groups, diabetes status or duration, and cumulative glycemic exposure approximately 21 years after DPP randomization. Research Design and Methods: In DPP, 3,234 adults ≥25 years old at high risk for diabetes were randomized to intensive lifestyle (ILS), metformin, or placebo interventions to prevent diabetes. After DPP, 2,779 joined the DPP Outcomes Study (DPPOS). Open label metformin was continued, placebo was discontinued, ILS was provided as semi-annual group-based classes, and all were offered quarterly lifestyle classes. Symptoms and signs of DSPN were assessed in 1,792 participants at DPPOS Year 17. Multivariable logistic regression models evaluated DSPN associations with treatment group, diabetes status/duration, and cumulative glycemic exposure. Results: Twenty-one years after DPP randomization, 66% had diabetes. DSPN prevalence did not differ by initial DPP treatment assignment (ILS 21.5%, metformin 21.5%, and placebo 21.9%). There was a significant interaction between treatment assignment to ILS and age (p<0.05) on DSPN. At DPPOS Year 17, the OR for DSPN comparing ILS to Placebo was 17.4% (95% CI 3.0% - 29.3%) lower with increasing 5-year age intervals. DSPN prevalence was slightly lower for those at risk for diabetes (19.6%) versus those with diabetes (22.7%) and was associated with longer diabetes duration and time-weighted HbA1c (p-values<0.001). Conclusions: The likelihood of DSPN was similar across DPP treatment groups, while higher for those with diabetes, longer diabetes duration, and higher cumulative glycemic exposure. ILS may have long-term benefits on DSPN for older adults.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.

Osteopontin is a proinflammatory cytokine associated with systemic vascular, inflammatory, and autoimmune diseases. It has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that plasma osteopontin is a deleterious neuroinflammatory marker increased in people with dementia and cerebral small vessel disease (CSVD). We conducted a pilot study in participants in the longitudinal multi-ethnic Northern Manhattan Study (NOMAS). Three groups were selected based on their dementia status and evidence of subclinical CSVD, and chosen to be similar in age, sex, and education attainment: No Dementia/No CSVD (n = 19), Dementia/No CSVD (n = 22), and Dementia+CSVD (n = 21). Dementia (any type) was diagnosed by consensus adjudication following a series of comprehensive neuropsychological assessments and a review of medical history. CSVD was indicated by silent brain infarcts, perivascular spaces, cerebral microbleeds, and white matter hyperintensity volumes on MRI. Osteopontin was measured by quantitative solid-phase ELISA. Multinomial logistic regression was used to examine the difference in osteopontin levels across groups, adjusting for key determinants of CSVD and neurodegeneration in NOMAS, including age, race/ethnicity, BMI, and brain volume. Osteopontin levels were substantially elevated in the Dementia+ CSVD group (mean = 70.69±39.00 ng/ml) and only slightly increased in the Dementia/No CSVD group (mean = 45.46±19.11) compared to the No dementia/No CSVD group (mean = 36.43±15.72). Osteopontin was associated with dementia+CSVD (Odds Ratio (OR) per ng/ml = 1.06, 95%CI 1.02-1.11) in unadjusted analysis, and this remained consistent and significant after adjusting for covariates, including brain volume. Osteopontin was strongly correlated with WMHV (Pearson r = 0.46, p = 0.0001), but not with other components of CSVD. In this pilot study, we observed a significant relationship between increased levels of osteopontin and dementia. This link is predominately driven by vascular contributions to dementia through the presence of CSVD, specifically through the burden of white matter lesions on MRI. Brain volume, a marker of neurodegeneration, does not seem to influence this relationship. Our study provides further evidence to suggest that underlying white matter disease and CSVD are likely targets of deleterious osteopontin expression in dementia.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini‐Mental State Exam. We examined cross‐sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5‐year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Objective: To evaluate how DSPN differs across the randomized DPP treatment groups and is associated with diabetes (DM) status, DM duration, and cumulative glycemic exposure. Methods: In the DPP, adults ≥25 years of age at high risk for DM (n=3234) were randomized to determine the effects of intensive lifestyle modification (ILS) or metformin (MET) compared to placebo (PLA) on incident diabetes. After DPP ended, participants were invited to join the DPPOS during which metformin was continued in those randomized to receive it. DSPN was rigorously assessed in 1,792 participants at DPPOS year 17 based on both symptoms and signs (pinprick, vibration, and monofilament). Multivariable logistic regression models were used to determine whether DSPN was associated with randomized treatment group, DM status and duration, and cumulative glycemic exposure. Results: At 21 years following DPP randomization, 66% had developed DM with median duration of 15 years. The prevalence of DSPN did not differ by DPP treatment group (21.5%, 21.5% and 21.9% in ILS, MET and PLA, respectively), but was slightly lower for those at risk for DM (19.6%) vs. those with DM (22.7%). There was a significant effect modification by age of the association between DPP treatment group and DSPN (p<0.05): the odds ratio (OR) for DSPN with ILS vs PLA decreased by 3.7% (95% CI 0.6-6.7) with each 1 year increase in age. MET vs. PLA was not associated with DSPN and age did not influence the null association. In models adjusted for treatment group, demographics, cardiometabolic risks, and low vitamin B12 or B12 supplement use, DSPN was associated with DM status (OR 1.40, p<0.001 vs. no DM), greater DM duration (OR 1.04 per 1 year, p<0.001), and higher time-weighted HbA1c (OR 1.85 per 1% increase, p<0.001). Conclusions: The likelihood of DSPN was higher for those with DM, longer DM duration, and higher cumulative glycemic exposure. Although ILS did not prevent DSPN overall, there were ILS benefits with increasing age. Disclosure C.Lee: Employee; Pfizer Inc. N.White: None. W.H.Herman: Advisory Panel; National Committee for Quality Assurance, Consultant; Merck Sharp & Dohme Corp., Other Relationship; National Institutes of Health, American Diabetes Association. D.Research group: None. A.Ciarleglio: None. S.Edelstein: None. J.P.Crandall: Research Support; Abbott Diabetes. D.Dabelea: None. R.B.Goldberg: None. S.E.Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc., Other Relationship; Novo Nordisk. W.C.Knowler: None. M.Ma: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)

BACKGROUND:Osteopontin (OPN) is a proinflammatory cytokine that has been recently implicated in neuroinflammation and neurodegeneration. We hypothesized that an increase in plasma OPN is a deleterious neuroinflammatory marker in people with dementia and cerebral small vessel disease (CSVD). METHODS:A pilot study was conducted on participants in the Northern Manhattan Study (NOMAS). Three groups were selected based on their dementia status and evidence of subclinical CSVD and chosen to be similar in age, sex, and education attainment: No dementia/No CSVD (n = 19), Dementia/No CSVD (n = 22), and Dementia + CSVD (n = 21). Dementia (any type) was diagnosed by consensus adjudication following a series of comprehensive neuropsychological assessments and a review of the medical history. CSVD was indicated by silent brain infarcts, enlarged perivascular spaces, cerebral microbleeds, and white matter hyperintensity volumes (WMHV) on MRI. Multinomial logistic regression was used to examine the difference in OPN levels across groups, adjusting for key determinants of CSVD and neurodegeneration. RESULTS:Plasma OPN levels were elevated in the Dementia+CSVD group (mean = 70.69 ± 39.00 ng/mL) but not in the Dementia/No CSVD group (mean = 45.46 ± 19.11 ng/mL) compared to the No Dementia/No CSVD group (mean = 36.43 ± 15.72 ng/mL). OPN was associated with Dementia+CSVD (Odds Ratio [OR] per ng/mL = 1.06, 95% CI 1.02-1.11) after adjusting for covariates, including brain volume. OPN was strongly correlated with WMHV (Spearman's rank correlation ρ = 0.46, p = 0.0001) but not with other components of CSVD. CONCLUSION:In this pilot, greater levels of plasma OPN were associated with dementia with evidence of CSVD. This link was predominately driven by the contribution of OPN to dementia through the burden of white matter lesions.

Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of morbidity and mortality in diabetes, and diabetes increases ASCVD risk two-fold compared with those without diabetes.1 Dyslipidemia is a risk factor for ASCVD in diabetes and a therapeutic target for risk reduction. Despite a decrease in the absolute rate of ASCVD in the past 2 decades, which may be attributable in part to the success of cardioprevention management strategies,2 uncertainties remain on when and how to treat diabetic dyslipidemia. There are several reasons for this, including gaps in the understanding of the nature and atherogenicity of dyslipidemia in diabetes, greater recognition of the heterogeneity of cardiovascular risk in the population with diabetes together with insufficient information in lower-risk younger as well as aging individuals, and recognition of the limitations in benefits of some available lipid-lowering agents. This review provides an up-to-date assessment of the nature of dyslipidemia in diabetes, evaluation of ASCVD risk, evidence for clinical benefit from lipid lowering, and current approaches to pharmacologic management.

Background: Cardiac autonomic neuropathy (CAN) is a complication of diabetes mellitus (DM) that is associated with increased mortality. Exercise-based assessment of autonomic function has identified diminished parasympathetic reactivation after exercise in type 2 DM. It is postulated herein, that this would be more prominent among those with type 1 DM. Methods: Sixteen subjects with type 1 DM (age 32.9 ± 10.1 years), 18 subjects with type 2 DM (55.4 ± 8.0 years) and 30 controls (44.0 ± 11.6 years) underwent exercise-based assessment of autonomic function. Two 16-min submaximal bicycle tests were performed followed by 45 min of recovery. On the second test, atropine (0.04 mg/kg) was administered near end-exercise so that all of the recovery occurred under parasympathetic blockade. Plasma epinephrine and norepinephrine levels were measured at rest, during exercise, and during recovery. Results: There were no differences in resting or end-exercise heart rates in the three groups. Parasympathetic effect on RR-intervals during recovery (p < 0.03) and heart rate recovery (p = 0.02) were blunted in type 2 DM. Type 1 DM had higher baseline epinephrine and norepinephrine levels (p < 0.03), and exhibited persistent sympathoexcitation during recovery. Conclusions: Despite a longer duration of DM in the study patients with type 1 versus type 2 DM, diminished parasympathetic reactivation was not noted in type 1 DM. Instead, elevation in resting plasma catecholamines was noted compared to type 2 DM and controls. The variable pathophysiology for exercise-induced autonomic abnormalities in type 1 versus type 2 DM may impact prognosis.

Objective This study investigated associations of adiposity and adiposity-related biomarkers with incident type 2 diabetes (T2D) among parous women. Methods Among women in the Diabetes Prevention Program (DPP) who reported a previous live birth, circulating biomarkers (leptin, adiponectin, sex hormone-binding globulin, and alanine aminotransferase; n = 1,711) were measured at enrollment (average: 12 years post partum). Visceral (VAT) and subcutaneous adipose tissue areas at the L2-L3 region and the L3-L4 region were quantified by computed tomography (n = 477). Overall and stratified (by history of gestational diabetes mellitus [GDM]) adjusted Cox proportional hazards models were fit. Results Alanine aminotransferase, L2-L3 VAT, and L3-L4 VAT were positively associated (hazard ratio [HR] for 1-SD increases: 1.073, p = 0.024; 1.251, p = 0.009; 1.272, p = 0.004, respectively), and adiponectin concentration was inversely associated with T2D (HR 0.762, p < 0.001). Whereas leptin concentration was not associated with T2D overall, in GDM-stratified models, a 1-SD higher leptin was positively associated with risk of T2D in women without GDM (HR: 1.126, p = 0.016) and inversely in women with a history of GDM (HR: 0.776, p = 0.013, interaction p = 0.002). Conclusions Among parous women, alanine aminotransferase and VAT are positively associated with incident T2D, whereas adiponectin is inversely associated. Leptin is associated with higher risk of T2D in women with a history of GDM but a lower risk in women without a history of GDM.

OBJECTIVE: To determine whether interventions that slow or prevent the development of type 2 diabetes mellitus in those at risk reduce the subsequent prevalence of diabetic retinopathy. RESEARCH DESIGN AND METHODS: The Diabetes Prevention Program (DPP) randomized subjects at risk for developing type 2 diabetes because of overweight/obesity and dysglycemia to either metformin (MET), intensive lifestyle intervention (ILS) or placebo (PLB) to assess the prevention of diabetes. During the DPP and DPP Outcome Study (DPPOS), we performed fundus photography over time on study participants, regardless of their diabetes status. Fundus photographs were graded using the ETDRS grading system with diabetic retinopathy defined as typical lesions of diabetic retinopathy (microaneurysms, exudates or hemorrhage, or worse) in either eye. RESULTS: Despite reduced progression to diabetes in the ILS and MET groups compared to PLB, there was no difference in the prevalence of diabetic retinopathy between treatment groups after 1, 5, 11 or 16 years of follow up. No treatment group differences in retinopathy were found within prespecified subgroups (baseline age, sex, race/ethnicity, baseline BMI). In addition, there was no difference in the prevalence of diabetic retinopathy between those exposed to metformin and those not exposed to metformin regardless of treatment group assignment. CONCLUSION: Interventions that delay or prevent the onset of type 2 diabetes in overweight/obese subjects with dysglycemia who are at risk for diabetes do not reduce the development of diabetic retinopathy for up to 20 years.

AIMS:To determine the prevalence of mild, moderate and severe hypertriglyceridemia (HTG) in a large, diverse healthcare system cohort with type 2 diabetes (T2D) and to study associations between triglyceride levels and demographic factors, glycemic control, body weight and to investigate whether triglyceride levels associate with markers of fatty liver and renal disease. METHODS:19,086 individuals with T2D were studied between 2015 and 2020. We compared groups with normotriglyceridemia (<150 mg/dl [<1.7 mmol/l]), mild (150-199 mg/dl [1.7-2.25 mmol/l]), moderate (200-499 mg/dl [2.26-5.64 mmol/l]) or severe HTG (>499 mg/dl [>5.64 mmol/l]). We also performed univariate and multivariate correlational analyses with triglyceride level as a continuous variable. RESULTS:39 % had triglyceride levels ≥150 mg/dl (<1.7 mmol/l), 19 % had moderate and 2 % had severe HTG. There was a lower proportion of Blacks in all HTG categories compared to Whites. There was no overall gender difference in prevalence except that severe HTG was more common in men and as HTG severity worsened mean age fell. Triglycerides correlated with HbA1c and associated with BMI, LDL-C, diastolic BP, transaminases and urine albumin/creatinine ratio, independent of HbA1c. CONCLUSION:This study fills gaps in our knowledge of the distribution and clinical associations of HTG in T2D and characterizes the features of the small but important group with severe HTG. We demonstrate the influence of age, sex and race, confirm the moderate effects of glycemic control and obesity on triglyceride level, and provide evidence that triglyceride levels may be a marker for fatty liver and nephropathy independent of glycemic control.

There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood. (C) 2022 by the American College of Cardiology Foundation.

OBJECTIVE: To determine glycemic and non-glycemic risk factors that contribute to the presence of diabetic retinopathy (DR) before and after the onset of type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: During the Diabetes Prevention Program (DPP) and DPP Outcome Study (DPPOS), we performed fundus photography over time on adults at high risk to develop T2D, including after they developed diabetes. Fundus photographs were graded using the ETDRS grading system with DR defined as typical lesions of DR (microaneurysms, exudates or hemorrhage, or worse) in either eye. RESULTS: By DPPOS year 16 (approximately 20 years after randomization into DPP), 24% of 1,614 who had developed T2D and 14% of 885 who remained non-diabetic had DR. In univariate analyses, utilizing results from across the entire duration of follow-up, American Indian race was associated with less frequent DR compared to Non-Hispanic Whites (NHW), and higher HbA1c, fasting and 2-hour plasma glucose levels during an oral glucose tolerance test, weight, and history of hypertension, dyslipidemia and smoking, but not treatment group assignment, were associated with more frequent DR. On multivariate analysis, American Indian race was associated with less DR compared to NHW (OR = 0.36; 95% CI: 0.20-0.66) and average HbA1c was associated with more DR (OR = 1.92; 95% CI: 1.46-1.74 per SD [0.7%] increase in HbA1c). CONCLUSION: DR may occur in adults with prediabetes and early in the course of T2D. HbA1c was an important risk factor for the development of DR across the entire glycemic range from prediabetes to T2D.

BACKGROUND:Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. We studied diabetes duration and subclinical myocardial injury, as reflected by high-sensitivity cardiac troponin (hs-cTnT).METHODS:We analyzed 9052 participants without heart failure or coronary heart disease (mean age 63 years, 58% female, 21% Black, 15% with diabetes) at The Atherosclerosis Risk in Communities Study (ARIC) Visit 4 (1996 to 1998). Diabetes duration was calculated based on diabetes status at Visits 1 (1987 to 1989) through 4, or using self-reported age of diabetes diagnosis prior to Visit 1. We used multinomial logistic regression to determine the association of diabetes duration with increased (≥14 ng/L) or detectable (≥6 ng/L) Visit 4 hs-cTnT, relative to undetectable hs-cTnT, adjusted for demographics and cardiovascular risk factors.RESULTS:The prevalence of increased Visit 4 hs-cTnT was higher in persons with longer diabetes duration, from 12% for those with diabetes 0 to <5 years up to 31% among those with diabetes for ≥15 years (P for trend <0.0001). New onset diabetes at Visit 4 was associated with 1.92× higher relative risk (95% CI, 1.27-2.91) of increased hs-cTnT than no diabetes. Longer diabetes duration was associated with greater myocardial injury, with duration ≥15 years associated with 9.29× higher risk (95% CI, 5.65-15.29) for increased hs-cTnT and 2.07× (95% CI, 1.24-3.16) for detectable hs-cTnT, compared to no diabetes.CONCLUSIONS:Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether the prevention and delay of diabetes onset can mitigate early myocardial damage.

Objective: This study investigated associations of adiposity and adiposity-related biomarkers with incident type 2 diabetes (T2D) among parous women. Methods: Among women in the Diabetes Prevention Program (DPP) who reported a previous live birth, circulating biomarkers (leptin, adiponectin, sex hormone-binding globulin, and alanine aminotransferase; n = 1,711) were measured at enrollment (average: 12 years post partum). Visceral (VAT) and subcutaneous adipose tissue areas at the L2-L3 region and the L3-L4 region were quantified by computed tomography (n = 477). Overall and stratified (by history of gestational diabetes mellitus [GDM]) adjusted Cox proportional hazards models were fit. Results: Alanine aminotransferase, L2-L3 VAT, and L3-L4 VAT were positively associated (hazard ratio [HR] for 1-SD increases: 1.073, p = 0.024; 1.251, p = 0.009; 1.272, p = 0.004, respectively), and adiponectin concentration was inversely associated with T2D (HR 0.762, p < 0.001). Whereas leptin concentration was not associated with T2D overall, in GDM-stratified models, a 1-SD higher leptin was positively associated with risk of T2D in women without GDM (HR: 1.126, p = 0.016) and inversely in women with a history of GDM (HR: 0.776, p = 0.013, interaction p = 0.002). Conclusions: Among parous women, alanine aminotransferase and VAT are positively associated with incident T2D, whereas adiponectin is inversely associated. Leptin is associated with higher risk of T2D in women with a history of GDM but a lower risk in women without a history of GDM.

There is a need to identify high-risk features that predict early-onset atherosclerotic cardiovascular disease (ASCVD). The authors provide insights to help clinicians identify and address high-risk conditions in the 20- to 39-year age range (young adults). These include tobacco use, elevated blood pressure/hypertension, family history of premature ASCVD, primary severe hypercholesterolemia such as familial hypercholesterolemia, diabetes with diabetes-specific risk-enhancing factors, or the presence of multiple other risk-enhancing factors, including in females, a history of pre-eclampsia or menopause under age 40. The authors update current thinking on lipid risk factors such as triglycerides, non-high-density lipoprotein cholesterol, apolipoprotein B, or lipoprotein (a) that are useful in understanding an individual's long-term ASCVD risk. The authors review emerging strategies, such as coronary artery calcium and polygenic risk scores in this age group, that have potential clinical utility, but whose best use remains uncertain. Finally, the authors discuss both the obstacles and opportunities for addressing prevention in early adulthood.

Background: Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study). Methods: During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. Results: Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78–1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87–1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. Conclusions: Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions. Registration: URL: https://www.clinicaltrials.gov ; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

Subclinical markers of atherosclerosis, including CAC, are less favorable in adults with IGT. In previous adult studies, higher PA has been associated with lower CAC with findings varying by age and sex. PA and CAC were examined by age and sex in the diverse Diabetes Prevention Program Outcomes Study (DPPOS) cohort with IGT who were randomized at baseline to lifestyle intervention, metformin, or placebo groups for a mean of 3.2 years, and subsequently observed in DPPOS for follow-up. PA was measured via questionnaire (annually); accelerometry once at 11-13yrs and CAC Agatston score (AS) using chest computed tomography at 13-15 yrs from randomization. The relationship between PA and CAC was examined using Tobit regression models in 1434 participants with valid PA and CAC data (mean age 63±9.5 yrs; 70% female; 54% with diabetes) adjusted for treatment group, age, sex, race/ethnicity, lipid medication use, diabetes status, and cumulative metformin exposure; pairwise and three-way interactions were examined. Accelerometry-assessed median (IQR) daily step counts and moderate+ PA (MVPA) minutes were 5302 (3576, 7104) and 21 (9, 41), respectively. Median (IQR) AS was 9 (0, 151). In fully adjusted models, each 1000 steps /day was associated with lower CAC (p=0.024). Results were examined by sex and age subgroups (<65 and ≥65 yrs) with significant inverse associations found in women (<65 and ≥65 yrs; both p<0.001) but not in men (<65 and ≥65 yrs; both p>0.05). Similarly, significant inverse associations between MVPA minutes and CAC AS were found in women (<65 yrs p=0.003; ≥65 yrs p=0.012) but not in men (<65 yrs p=0.91 and ≥65 yrs p=0.056). Questionnaire-measured PA and CAC associations showed similar trends. In contrast, minutes of sedentary and light PA were not significantly associated with CAC. Suggested sex differences in the PA-CAC association in adults with initial glucose intolerance was found and should be investigated in other studies. Disclosure B. Rockette-wagner: None. E. Horton: None. M. A. Hoskin: None. U. N. Ibebuogu: None. M. Schlögl: None. R. B. Goldberg: None. D. Research group: None. A. Kriska: None. N. Younes: None. S. Edelstein: None. T. J. Orchard: None. M. Armstrong: None. A. L. Brown: Research Support; Self; Medtronic, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases. D. Dabelea: None. K. M. Gadde: Other Relationship; Self; AstraZeneca, Research Support; Self; BioKier, National Institute of Diabetes and Digestive and Kidney Diseases. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)