Obesity in diabetes. Cardiovascular outcomes and risk factor trajectories

Sammanfattning: Introduction: The association between body mass index (BMI) and mortality in diabetes is complex and sparsely investigated for cardiovascular (CVD) outcomes. We aimed to investigate these relationships among patients with type 1 and type 2 diabetes using data from the Swedish national diabetes registry (NDR), with focus on potential reverse causality. Considering recent fi ndings of marked excess risks among patients with early onset of type 1 diabetes we aimed to investigate risk factor trajectories based on age at onset. Methods: The thesis is based on data from the Swedish national diabetes registry (Study I-IV) and matched controls taken from the general population (Study I and III), using statistical methods such as Cox regression, linear regression, mixed models and machine learning. Results: Study I, the short-term risk of death (<5 years from baseline) in patients with type 2 diabetes was slightly lower among obese patients than in age- and sex matched controls, with a nadir among obese patients varying between 30-<40 kg/m2, depending on age. Long-term mortality (≥5 years from baseline) exhibited a stepwise increase from BMI 25-<30 kg/m2, where patients with BMI ≥40 kg/m2 had a 2-fold risk of death compared to the general population, with similar fi ndings for CVD death. In Study II, we found a slight increase in the risk of death, CVD death, major CVD (stroke or acute myocardial infarction [AMI]) and heart failure (HF) with rising BMI in patients with type 1 diabetes, but no increase in risk in patients with normal weight after exclusion of individuals with poor metabolic control, smokers and patients with follow-up shorter than 10 years. In Study III, the association between BMI and the risk of AMI was essentially fl at but worsened with poor glycemic control, while, in contrast, there was a markedly increasing risk for HF with rising BMI with a nadir as low as ~18.5 kg/m2. The risk of HF was further exaggerated by poor glycemic control with an 8-fold excess risk of HF among patients with BMI ≥40 kg/m2 and hemoglobin A1c (HbA1c) ≥70 mmol/mole. In Study IV, patients with an onset of type 1 diabetes ≤15 years had a high mean HbA1c of ~70 mmol/mole in early adulthood, whereas patients with a later onset (16-30 years) displayed a gradual increase in HbA1c up to a mean at ~65 mmol/mole, common for all groups regardless of age at onset. Machine learning models showed that baseline HbA1c (duration of diabetes >1 year) was linked to age, educational level and CVD risk factors. Conclusions: Among patients with type 1 and type 2 diabetes our analyses provided no support for an obesity paradox for the outcomes of death (type 1 diabetes) and CVD complications including HF after considering the infl uence of reverse causality. The strong relationship between obesity and HF which was worsened by poor glycemic control, was absent for AMI, indicating different pathophysiological mechanisms behind these two outcomes. The age at onset of type 1 diabetes seems to be an important predictor of glycemic control during the fi rst years of adulthood, as well as for the prevalence of albuminuria leading to a more rapid decline in eGFR from an early age. Our study also stresses the importance of early optimization of CVD risk factors, in particular glycemic control, in patients with type 1 diabetes.