Prospective Study On Progression From Different Blood Glucose States To Cardiovascular Disease Based On Cohort Population

Objectives:The study aimed to explore the impact of blood glucose levels on the incidence and survival of cardiovascular disease.Further,we explored the natural history from normoglycaemia to prediabetes,subsequently to diabetes,cardiovascular disease,and death,to clarify the transition probability,effective intervention nodes,and the influencing factors at different stages during the disease progression.This study was designed to provide scientific support for realizing the prevention and treatment of diabetes,reducing the disease burden,and controlling the occurrence of adverse outcomes.Methods:1.Based on the Jinchang cohort platform,we adopted a prospective cohort study design,participants whose identification codes were fully matched from baseline and follow-up from 2014 to 2019 were selected as the study subjects.Individuals with absence of relevant indicators at baseline,coronary heart disease（CHD）,and stroke at baseline were excluded.Outcomes of CHD and stroke in this population were followed up.The Cox proportional risk model was used to explore the association between diabetes,fasting plasma glucose（FPG）and the risk of CHD and stroke.The dose-response relationship between FPG and the risk of CHD and stroke was fitted using the restricted cubic spline method,and the Kaplan-Meier survival analysis was used to assess the effects of diabetes and FPG on the survival of CHD and stroke.2.We adopted a prospective cohort study design,participants whose identification codes were fully matched from baseline and follow-up from 2014 to 2019 were selected as the study subjects,excluding those with missing fasting plasma glucose at baseline,CHD,stroke,malignancies,and absence of relevant indicators at baseline.Resulting a total of 42,585 participants were included in this study.Clinical records and epidemiology surveys of the study population at both baseline and three phases of follow-ups were acquired.According to the development process of diabetes and its major complications,the baseline and follow-up population were divided into 7 states:normoglycaemia,prediabetes,diabetes,CHD,stroke,comorbid CHD and stroke,and death.We aimed to quantify the dynamic progression trajectories from different blood glucose states to cardiovascular disease and death.The multi-state model was applied to explore the inter-state transition intensities and transition probabilities,the mean sojourn time of the different states,and influencing factors at different transition stages.Results:1.In the total population,the incidence density of CHD and stroke in the diabetes group were 13.73/1000 person-years and 9.92/1000 person-years,respectively,higher than the incidence density of 4.16/1000 person-years and 3.06/1000 person-years in the normoglycaemia group.The risk of CHD and stroke in the diabetes group were 1.61 times（HR=1.61,95%CI:1.40-1.86）and 1.71 times（HR=1.71,95%CI:1.45-2.02）that of the normoglycaemia group,respectively.The risk of CHD and stroke in the prediabetes group were 1.38 times（HR=1.38,95%CI:1.22-1.57）and 1.28 times（HR=1.28,95%CI:1.10-1.48）that of the normoglycaemia group,respectively.Both diabetes and prediabetes were independently associated with the incidence of CHD and stroke in men,and diabetes was independently associated with the incidence of CHD and stroke in women,no association was observed between prediabetes and stroke incidence（HR=1.17,95%CI:0.87-1.56）in women.2.The risk of CHD and stroke were significantly increased from FPG≥5.6mmol/L.The incidence density and incidence risk of CHD and stroke increased progressively with increasing baseline FPG（P for trend<0.001）.In the total population,compared with the 3.9mmol/L≤FPG<5.6mmol/L group,in the 5.6mmol/L≤FPG<6.1mmol/L,6.1mmol/L≤FPG<7.0mmol/L and the FPG≥7.0 mmol/L groups the incidence risk of CHD were increased by 29%（HR=1.29,95%CI:1.11-1.49）,59%（HR=1.59,95%CI:1.36-1.87）and 52%（HR=1.52,95%CI:1.30-1.77）,the incidence risk of stroke were increased by 22%（HR=1.22,95%CI:1.03-1.45）,43%（HR=1.43,95%CI:1.17-1.73）and 64%（HR=1.64,95%CI:1.37-1.96）,respectively.There was a non-linear dose-response relationship between FPG and risk of CHD and stroke in the total population and men(P_overall<0.001,P_non-linear<0.05).In women,there was a non-linear dose-response relationship(P_overall<0.001,P_non-linear<0.001)between FPG and the risk of developing CHD,and a linear dose-response relationship(P_overall<0.05,P_non-linear>0.05)between FPG and the risk of stroke.3.During the median follow-up of 7 years,7,498 participants developed prediabetes,2,307 developed diabetes,1,367 developed CHD,1,051 developed stroke,81 developed comorbid CHD and stroke,and 324 died.Among 15 postulated transitions,the transition from CVD to death had a higher rate than other transitions.The progression rates to death were 157.21/1000 person-years from comorbid CHD and stroke,69.31/1000 person-years from stroke,and 40.14/1000 person-years from CHD.Among transitions to CHD and stroke,the transition from diabetes had the highest rate（12.21/1000 and 12.16/1000 person-years）,followed by transition from prediabetes（6.81/1000 and 4.93/1000 person-years）,and normoglycaemia（3.28/1000 and2.39/1000 person-years）.The rate of recovery from prediabetes to normoglycaemia state was 46.51/1000 person-years.Participants<65 years（51.56/1000 person-years）had a recovery rate 3.13 times higher compared to participants≥65 years(16.48/1000person-years.Men（52.23/1000 person-years）had a recovery rate 1.52 times higher than women（34.35/1000 person-years）.4.In the total population,men and women,the transition intensity of the reversal from prediabetes to normoglycaemia were 1.30,1.36,and 1.10 times that of the transition to diabetes,CHD,and stroke,respectively;the transition intensity from diabetes to CHD were 4.33,3.86,and 5.40 times that of normoglycaemia,respectively,and the transition intensity from diabetes to stroke were 6.25,6.00,and 5.00 times that of normoglycaemia,respectively.Men and those aged 65 years and older had a greater chance of progressing to more severe disease states compared to women and those aged under 65 years.5.Individuals with normoglycaemia or prediabetes had a higher probability of maintaining their current state or improving during follow-up,with 7.43%,17.85%,and24.05%probability of a reversal from prediabetes to normoglycaemia and 3.95%,9.89%,and 13.91%probability of progression to diabetes at 1,3,and 5 years,respectively.Among transitions to CHD and stroke,transition from diabetes had the highest 5-year probability（9.36%,8.19%）,followed by transition from prediabetes（4.71%,3.24%）,and normoglycaemia（2.84%,1.90%）.The more severe state individuals were in,the more likely they were to deteriorate over time.At 1,3,and 5years,the probabilities of death in patients with comorbid CHD and stroke were 21.43%,51.50%,and 70.06%,respectively,with the probabilities of death from stroke（11.02%,30.34%and 46.10%）being higher than from CHD（7.74%,21.97%and 34.44%）,and the mortality risk for both was higher in men than in women.6.In the cohort population,the mean sojourn time for prediabetes,diabetes,CHD,stroke,comorbid CHD and stroke were 6.77,18.43,10.41,6.64,and 4.15 years,respectively.7.Multivariate analysis showed that age and hypertension were common risk factors for different stages of disease progression.Male,alcohol consumption,age,overweight or obesity,hypertriglyceridemia,hypertension,and hyper-LDL cholesterolemia were risk factors for the transition from normoglycaemia to prediabetes,with higher education level as a protective factor.Women,age,hypertension,overweight or obesity,hypertriglyceridemia,and hyperuricemia decreased the chance from prediabetes to normoglycaemia.Overweight or obesity,hypo-HDL cholesterolemia,smoking,women,hypertension,hyperuricaemia,hyper-LDL cholesterolemia,age,and hypertriglyceridemia were risk factors for the onset of diabetes.Age,smoking,hyper-LDL cholesterolemia,and hypertension were risk factors for the transition from normoglycaemia to CHD,with higher education level as a protective factor.Age,smoking,hyper-LDL cholesterolemia,hypo-HDL cholesterolemia,and hypertension were risk factors for the transition from prediabetes to CHD.Age and hypertension were risk factors for the transition from normoglycaemia to stroke,with higher education level as a protective factor.Age,hypertension,and smoking were risk factors for the transition from prediabetes to stroke.Age and hypertension were common risk factors for the transitions from diabetes to CHD and stroke.Conclusions:1.Diabetes was an independent risk factor for the onset of CVD,with a 5-year probability of progression to CHD and stroke of 9.36%and 8.19%respectively.Age and hypertension accelerated the progression.2.The probability of transition to death from CVD was high,and the average sojourn time was short.The risk of death from stroke was higher than that from CHD,and the risk of death from both was higher in men than in women.3.The mean sojourn time for prediabetes was 6.77 years,with a 1-year and 5-year probability of reversal to normoglycaemia of 7.43%and 24.05%respectively,making it the optimal intervention stage in the disease trajectory.Weight management,control of lipids,blood pressure,and uric acid in the normal range during this period may promote reversion to normoglycaemia.4.Age and hypertension were associated with an accelerated rate for most transitions,education level,smoking,overweight or obesity,dyslipidemia and hyperuricemia played crucial but different roles in transitions,which could provide a theoretical basis for phased and targeted prevention and delay of diabetes development and the formulation of interventions.