The Causal Effect of Systolic Blood Pressure Lowering on Vascular Outcomes in Diabetes: A Mendelian Randomization Study

Context: The effect of lowering systolic blood pressure (SBP) on clinical outcomes in diabetic patients is controversial. Objective: We used 2-sample mendelian randomization (MR) to study the causal effect of decreasing SBP on the risk of macrovascular and microvascular outcomes in diabetic patients. Methods: We used 362 SBP-related genetic variants from a large genome-wide association study (n = 299 024) and UK Biobank (n = 375 256) as exposure. We evaluated 5 macrovascular and microvascular complications up to 60 742 cases as outcomes in diabetes, including coronary artery disease (CAD), peripheral artery disease (PAD), nephropathy, retinopathy, and composite complications. All cases were diagnosed together with diabetes. We performed follow-up analyses by conducting 7 sensitivity analyses and comparing the present MR with results in general population, and clinical trials. Results: Genetic predisposition of each 10-mm Hg SBP decrease was significantly associated with a 28% decreased risk of CAD (odds ratio [OR]: 0.72; 95% CI, 0.59-0.89; P = .002), a 34% decreased risk of nephropathy (OR: 0.66; 95% CI, 0.54-0.81; P < .001), and a 34% decreased risk of the composite complications (OR: 0.66; 95% CI, 0.58-0.76; P < .001), and was nominally associated with a decreased risk of PAD (OR: 0.69; 95% CI, 0.48-0.99) and retinopathy (OR: 0.90; 95% CI, 0.81-0.99). The MR results in diabetes were similar with that in the general population and clinical trials. Conclusion: SBP lowering was causally associated with an attenuated risk of diabetic CAD and nephropathy. It provides genetic evidence for the beneficial effect of lifelong SBP control in preventing diabetes-related vascular outcomes.