Triangulation study on the causal effect of fasting serum glucose on atherosclerotic cardiovascular disease

Abstract

Background: Diabetes is a known risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD), but previous observational studies have not been able to establish a causal relationship between dysglycemia-related markers and the incidence of cardiovascular disease. However, in recent epidemiological research, triangulation has been proposed as a scientific research method that can improve the limitations of causal inference. The purpose of this study is to confirm the causal relationship between fasting serum glucose (FSG) and ASCVD using triangulation. Methods: In this study, triangulation was analyzed using meta-analysis of clinical trials, cohort analysis, and Mendelian randomization (MR) analysis. The meta-analysis was performed on clinical trials (RCTs) and observational cohort studies, respectively. The cohort analysis used data from the Korean Cancer Prevention Study(KCPS)-II. KCPS-II subjects were 159,844 people who visited 18 comprehensive health checkup centers across the country, including Seoul and Gyeonggi Province, from 2004 to 2013. A blood-based prospective cohort study was established by obtaining consent forms for research participation. am. Mendelian randomization (MR) analysis used data from the Korean Genome Epidemiology Study (KOGES) biobank for fasting blood sugar, and data confirmed in the Korean cancer prevention study was used to determine the occurrence of atherosclerotic cardiovascular disease. Additionally, the Biobank of Japan (BBJ) was also used for atherosclerotic cardiovascular disease data. Mendelian randomization (MR) analysis was performed using standard (one-sample) MR within the Korean Cancer Prevention Study-II, two-sample MR using KOGES and KCPS-II biobanks, and genetic variables of systolic blood pressure and LDL cholesterol. Controlled multivariate MR (MVMR) was analyzed separately. In this study, fasting blood sugar was affected by every 10 mg/dL increase. Results: All studies have shown that FSG has an effect on ASCVD. First, in a meta-analysis using cohort studies, the risk of ASCVD increased by 3.7% for every 10 mg/dL increase in fasting blood sugar (HR=1.037, 95% CI=1.022-1.053). Second, a cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4.9% (HR=1.049, 95% CI=1.039-1.059). Third, the results of the standard MR study also showed that for evert 10 mg/dL increase in FSG influenced the risk of ASCVD (HR=1.134, 95%CI=1.038-1.238). Fourth, the results of the two-sample MR study also showed that for evert 10 mg/dL increase in FSG influenced the risk of ASCVD (HR=1.110, 95%CI=1.040-1.180). Lastly, the results of the multivariable MR study showed that the OR per 10 mg/dL increase in FSG in ASCVD was 1.138, which was statistically significant (95% CI=1.068-1.214, p-value=<0.001). This study showed similar results for a 10 mg/dL increase in FSG and ischemic heart disease, but did not show a significant relationship with stroke. Conclusion: FSG has been shown to have a causal relationship with the occurrence of ASCVD in Koreans. Therefore, the results of this study suggest that glycemic control has the potential to substantially reduce the lifetime risk of cardiovascular disease.