Blood pressure management in type 2 diabetes: integrating clinical trials and genetic data

Background: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. On the other hand, controversy exists as to whether the threshold of blood pressure for initiation of antihypertensive therapy should differ between people with and without type 2 diabetes. I aimed to integrate individual participant data from major randomised controlled trials and genetic data to fill these knowledge gaps.
Objectives: This thesis sought to examine three main objectives: to investigate the effect of pharmacological blood pressure-lowering on the risk of new-onset type 2 diabetes; to investigate the separate effects of blood pressure-lowering drug classes on the risk of new-onset type 2 diabetes; to investigate the effect of pharmacological blood pressure-lowering treatment for the prevention of major cardiovascular disease in persons with and without type 2 diabetes.
Methods: For the first and second objectives, I conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC). Analyses were complemented with Mendelian randomisation studies using naturally randomised genetic variants associated with systolic blood pressure and genetic variants in the gene that encodes the therapeutic targets of each drug class. For the third objective, I used one-stage individual participant-level data meta-analysis using the BPLTTC dataset. I expressed the treatment effect per 5 mmHg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mmHg increments from <120 mmHg to ≥170 mmHg).
Results: For the first and second objectives, blood pressure-lowering treatment was found to reduce the risk of diabetes by 11% (hazard ratio per 5 mmHg lower systolic blood pressure 0.89 [95% confidence interval [CI] 0.84 to 0.95]). Similarly, in the Mendelian randomisation study, each 5 mmHg genetically influenced lower systolic blood pressure was associated with an 11% lower risk of diabetes (odds ratio 0.89 [95% CI 0.86 to 0.93]). Evidence from genetic data and trials was also consistent in that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduced the risk of diabetes, and beta-blockers increased this risk. There was no effect for calcium channel blockers and findings for thiazide diuretics were inconsistent. For the third objective, over 4.2 years median follow-up (IQR 3.0 to 5.0), a 5 mmHg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0.94 [95% CI 0.91 to 0.98]) compared with those without type 2 diabetes (0.89 [0.87 to 0.92]; p for interaction=0.001). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes (absolute risk reduction -1.54 [95% CI -2.04 to -1.04] in people with diabetes and -1.61 [-1.86 to -1.36] in people without diabetes, p for interaction =1). We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group.
Conclusions: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. Additionally, although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted.

Keywords: blood pressure
type 2 diabetes
Mendelian randomisation
individual patient data meta analysis
IPD meta-analysis
diabetes
hypertension
antihypertensive drugs
triangulation of evidence
Advisor: Bennett, D
Rahimi, K
Canoy, D
Dehghan, A