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We evaluated the importance of body composition, amount of subcutaneous and visceral fat, liver and heart ectopic fat, adipose tissue distribution and cell size as predictors of cardio-metabolic risk in 53 non-obese male individuals. Known family history of type 2 diabetes was identified in 25 individuals. The participants also underwent extensive phenotyping together with measuring different biomarkers and non-targeted serum metabolomics. We used ensemble learning and other machine learning approaches to identify predictors with considerable relative importance and their intricate interactions. Visceral fat and age were strong individual predictors of ectopic fat accumulation in liver and heart along with markers of lipid oxidation and reduced glucose tolerance. Subcutaneous adipose cell size was the strongest individual predictor of whole-body insulin sensitivity and also a marker of visceral and ectopic fat accumulation. The metabolite 3-MOB along with related branched-chain amino acids demonstrated strong predictability for family history of type 2 diabetes.

Objective: Low weight has been associated with increased mortality risks in type 1 diabetes. We aimed to investigate the importance of weight and weight gain/loss in the Swedish population diagnosed with type 1 diabetes., Research Design and Methods: Patients with type 1 diabetes ( n = 26,125; mean age 33.3 years; 45% women) registered in the Swedish National Diabetes Registry from 1998 to 2012 were followed from the first day of study entry. Cox regression was used to calculate risk of death from cardiovascular disease (CVD), major CVD events, hospitalizations for heart failure (HF), and total deaths., Results: Population mean BMI in patients with type 1 diabetes increased from 24.7 to 25.7 kg/m 2 from 1998 to 2012. Over a median follow-up of 10.9 years, there were 1,031 deaths (33.2% from CVD), 1,460 major CVD events, and 580 hospitalizations for HF. After exclusion of smokers, patients with poor metabolic control, and patients with a short follow-up time, there was no increased risk for mortality in those with BMI <25 kg/m 2 , while BMI >25 kg/m 2 was associated with a minor increase in risk of mortality, major CVD, and HF. In women, associations with BMI were largely absent. Weight gain implied an increased risk of mortality and HF, while weight loss was not associated with higher risk., Conclusions: Risk of major CVD, HF, CVD death, and mortality increased with increasing BMI, with associations more apparent in men than in women. After exclusion of factors associated with reverse causality, there was no evidence of an obesity paradox., (© 2019 by the American Diabetes Association.)

Background: Risk of cardiovascular disease (CVD) and mortality for patients with versus without type 2 diabetes mellitus (T2DM) appears to vary by the age at T2DM diagnosis, but few population studies have analyzed mortality and CVD outcomes associations across the full age range., Methods: With use of the Swedish National Diabetes Registry, everyone with T2DM registered in the Registry between 1998 and 2012 was included. Controls were randomly selected from the general population matched for age, sex, and county. The analysis cohort comprised 318 083 patients with T2DM matched with just <1.6 million controls. Participants were followed from 1998 to 2013 for CVD outcomes and to 2014 for mortality. Outcomes of interest were total mortality, cardiovascular mortality, noncardiovascular mortality, coronary heart disease, acute myocardial infarction, stroke, heart failure, and atrial fibrillation. We also examined life expectancy by age at diagnosis. We conducted the primary analyses using Cox proportional hazards models in those with no previous CVD and repeated the work in the entire cohort., Results: Over a median follow-up period of 5.63 years, patients with T2DM diagnosed at ≤40 years had the highest excess risk for most outcomes relative to controls with adjusted hazard ratio (95% CI) of 2.05 (1.81-2.33) for total mortality, 2.72 (2.13-3.48) for cardiovascular-related mortality, 1.95 (1.68-2.25) for noncardiovascular mortality, 4.77 (3.86-5.89) for heart failure, and 4.33 (3.82-4.91) for coronary heart disease. All risks attenuated progressively with each increasing decade at diagnostic age; by the time T2DM was diagnosed at >80 years, the adjusted hazard ratios for CVD and non-CVD mortality were <1, with excess risks for other CVD outcomes substantially attenuated. Moreover, survival in those diagnosed beyond 80 was the same as controls, whereas it was more than a decade less when T2DM was diagnosed in adolescence. Finally, hazard ratios for most outcomes were numerically greater in younger women with T2DM., Conclusions: Age at diagnosis of T2DM is prognostically important for survival and cardiovascular risks, with implications for determining the timing and intensity of risk factor interventions for clinical decision making and for guideline-directed care. These observations amplify support for preventing/delaying T2DM onset in younger individuals.

Background: Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated., Methods: In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes., Results: The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death., Conclusions: Patients with type 2 diabetes who had five risk-factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population. (Funded by the Swedish Association of Local Authorities and Regions and others.).

Background: People with type 1 diabetes are at elevated risk of mortality and cardiovascular disease, yet current guidelines do not consider age of onset as an important risk stratifier. We aimed to examine how age at diagnosis of type 1 diabetes relates to excess mortality and cardiovascular risk., Methods: We did a nationwide, register-based cohort study of individuals with type 1 diabetes in the Swedish National Diabetes Register and matched controls from the general population. We included patients with at least one registration between Jan 1, 1998, and Dec 31, 2012. Using Cox regression, and with adjustment for diabetes duration, we estimated the excess risk of all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, acute myocardial infarction, stroke, cardiovascular disease (a composite of acute myocardial infarction and stroke), coronary heart disease, heart failure, and atrial fibrillation. Individuals with type 1 diabetes were categorised into five groups, according to age at diagnosis: 0-10 years, 11-15 years, 16-20 years, 21-25 years, and 26-30 years., Findings: 27 195 individuals with type 1 diabetes and 135 178 matched controls were selected for this study. 959 individuals with type 1 diabetes and 1501 controls died during follow-up (median follow-up was 10 years). Patients who developed type 1 diabetes at 0-10 years of age had hazard ratios of 4·11 (95% CI 3·24-5·22) for all-cause mortality, 7·38 (3·65-14·94) for cardiovascular mortality, 3·96 (3·06-5·11) for non-cardiovascular mortality, 11·44 (7·95-16·44) for cardiovascular disease, 30·50 (19·98-46·57) for coronary heart disease, 30·95 (17·59-54·45) for acute myocardial infarction, 6·45 (4·04-10·31) for stroke, 12·90 (7·39-22·51) for heart failure, and 1·17 (0·62-2·20) for atrial fibrillation. Corresponding hazard ratios for individuals who developed type 1 diabetes aged 26-30 years were 2·83 (95% CI 2·38-3·37) for all-cause mortality, 3·64 (2·34-5·66) for cardiovascular mortality, 2·78 (2·29-3·38) for non-cardiovascular mortality, 3·85 (3·05-4·87) for cardiovascular disease, 6·08 (4·71-7·84) for coronary heart disease, 5·77 (4·08-8·16) for acute myocardial infarction, 3·22 (2·35-4·42) for stroke, 5·07 (3·55-7·22) for heart failure, and 1·18 (0·79-1·77) for atrial fibrillation; hence the excess risk differed by up to five times across the diagnosis age groups. The highest overall incidence rate, noted for all-cause mortality, was 1·9 (95% CI 1·71-2·11) per 100 000 person-years for people with type 1 diabetes. Development of type 1 diabetes before 10 years of age resulted in a loss of 17·7 life-years (95% CI 14·5-20·4) for women and 14·2 life-years (12·1-18·2) for men., Interpretation: Age at onset of type 1 diabetes is an important determinant of survival, as well as all cardiovascular outcomes, with highest excess risk in women. Greater focus on cardioprotection might be warranted in people with early-onset type 1 diabetes., Funding: Swedish Heart and Lung Foundation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effect of lipid-lowering therapy (LLT) in primary prevention on cardiovascular disease (CVD) and death in type 1 diabetes., Research Design and Methods: We used the Swedish National Diabetes Register (NDR) to perform a propensity score-based study. Propensity scores for treatment with LLT were calculated from 32 baseline clinical and socioeconomic variables. The propensity score was used to estimate the effect of LLT in the overall cohort (by stratification). We estimated risk of acute myocardial infarction, stroke, coronary heart disease, and cardiovascular and all-cause mortality in individuals with and without LLT using Cox regression. A total of 24,230 individuals included in 2006-2008 NDR with type 1 diabetes without a history of CVD were followed until 31 December 2012; 18,843 were untreated and 5,387 treated with LLT (97% statins). The mean follow-up was 6.0 years., Results: The propensity score allowed balancing of all 32 covariates, with no differences between treated and untreated after accounting for propensity score. Hazard ratios (HRs) for treated versus untreated were as follows: cardiovascular death 0.60 (95% CI 0.50-0.72), all-cause death 0.56 (0.48-0.64), fatal/nonfatal stroke 0.56 (0.46-0.70), fatal/nonfatal acute myocardial infarction 0.78 (0.66-0.92), fatal/nonfatal coronary heart disease 0.85 (0.74-0.97), and fatal/nonfatal CVD 0.77 (0.69-0.87)., Conclusions: This observational study shows that LLT is associated with 22-44% reduction in the risk of CVD and cardiovascular death among individuals with type 1 diabetes without history of CVD and underlines the importance of primary prevention with LLT to reduce cardiovascular risk in type 1 diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To investigate the long term effects of continuous subcutaneous insulin infusion (insulin pump therapy) on cardiovascular diseases and mortality in people with type 1 diabetes., Design: Observational study., Setting: Swedish National Diabetes Register, Sweden 2005-12., Participants: 18,168 people with type 1 diabetes, 2441 using insulin pump therapy and 15,727 using multiple daily insulin injections., Main Outcome Measures: Cox regression analysis was used to estimate hazard ratios for the outcomes, with stratification of propensity scores including clinical characteristics, risk factors for cardiovascular disease, treatments, and previous diseases., Results: Follow-up was for a mean of 6.8 years until December 2012, with 114,135 person years. With multiple daily injections as reference, the adjusted hazard ratios for insulin pump treatment were significantly lower: 0.55 (95% confidence interval 0.36 to 0.83) for fatal coronary heart disease, 0.58 (0.40 to 0.85) for fatal cardiovascular disease (coronary heart disease or stroke), and 0.73 (0.58 to 0.92) for all cause mortality. Hazard ratios were lower, but not significantly so, for fatal or non-fatal coronary heart disease and fatal or non-fatal cardiovascular disease. Unadjusted absolute differences were 3.0 events of fatal coronary heart disease per 1000 person years; corresponding figures were 3.3 for fatal cardiovascular disease and 5.7 for all cause mortality. When lower body mass index and previous cardiovascular diseases were excluded, results of subgroup analyses were similar to the results from complete data. A sensitivity analysis of unmeasured confounders in all individuals showed that an unmeasured confounders with hazard ratio of 1.3 would have to be present in >80% of the individuals treated with multiple daily injections versus not presence in those treated with pump therapy to invalidate the significantly lower hazard ratios for fatal cardiovascular disease. Data on patient education and frequency of blood glucose monitoring were missing, which might have influenced the observed association., Conclusion: Among people with type 1 diabetes use of insulin pump therapy is associated with lower cardiovascular mortality than treatment with multiple daily insulin injections., (© Steineck et al 2015.)