Genetic evidence strongly supports managing weight and blood pressure in addition to glycemic control in preventing vascular complications in people with type 2 diabetes

Objective:

To investigate the causal association of type 2 diabetes and its components on the risk of vascular complications independent of shared risk factors obesity and hypertension, and to identify the main driver of this risk. 

Study design and method

We conducted Mendelian randomization using independent genetic variants previously associated with type 2 diabetes, fasting glucose, HbA1c, fasting insulin, BMI, and systolic blood pressure as instrumental variables. We obtained summary-level data for 18 vascular diseases (15 for type 2 diabetes) from FinnGen and publicly available genome-wide association studies as our outcomes. We conducted univariable and multivariable Mendelian randomization, in addition to sensitivity tests to detect and minimize pleiotropic effects.

Results

Univariable Mendelian randomization analysis showed that type 2 diabetes was associated with 9 of 15 outcomes, BMI and systolic blood pressure with 13 and 15 of 18 vascular outcomes, fasting insulin with 4, and fasting glucose with 2. No robust association was found for HbA1c instruments. Adjusting for correlated traits in the multivariable test, BMI and systolic blood pressure maintained consistent causal effects, while five associations with type 2 diabetes (chronic kidney disease, ischemic heart disease, heart failure, subarachnoid haemorrhage, and intracerebral haemorrhage) were attenuated to null. 

Conclusion

Our findings add strong evidence to support the importance of BMI and systolic blood pressure in the development of vascular complications in people with type 2 diabetes. Such findings strongly support the need for better weight and blood pressure management in type 2 diabetes, independent of glucose lowering, to limit important complications.