EBM Focus: A Sweet Side Effect of Treating Hypertension with ACEIs and ARBs


Prescribed medicine on counter in pharmacy

How do you prevent a stroke? Control blood pressure. How do you prevent type 2 diabetes? Also control blood pressure? Observational data suggest that hypertension is associated with an increased risk of developing type 2 diabetes. While controlling blood pressure improves clinical outcomes in patients with diabetes, it is not (yet) a conventional approach for diabetes prevention. A recent individual participant data meta-analysis sought to evaluate whether high blood pressure is a modifiable risk factor for the development of type 2 diabetes and parse out how five different classes of antihypertensives might affect that risk.

Researchers collected individual participant level data from the Blood Pressure Lowering Treatment Trialists’ Collaboration, including 22 randomized trials comparing specific antihypertensives with placebos or other antihypertensives for cardiovascular prevention. Participants were sorted into intervention and comparator treatment arms. People with preexisting diabetes and studies in which diabetes was common were both excluded. A stratified Cox proportional hazards model was used for the individual participant data meta-analysis and logistic regression models were used in the network meta-analysis.

A one-stage individual participant data meta-analysis included 145,939 people from 19 of the 22 randomized trials. Over a median follow-up of 4.5 years there were 9,883 new cases of type 2 diabetes. In this analysis, a five mm Hg drop in systolic blood pressure decreased the risk of developing type 2 diabetes by 11 percent overall (hazard ratio 0.89). Effects were more pronounced in participants with BMI over 30. In a separate network meta-analysis of all 22 trials, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decreased the risk of type 2 diabetes compared to placebo (absolute risk reduction [ARR] -1.2% for ACEIs and -0.56% for ARBs). Beta-blockers and thiazide diuretics increased the risk (ARR +2.1% and +0.6%, respectively). Calcium channel blockers had no effect.

In the hierarchy of evidence, a meta-analysis of individual participant data is at the top of the pyramid; it uses raw individual level data (as opposed to aggregate data) from multiple studies to answer a particular clinical question. Despite being at the top of the evidence pyramid, individual participant data meta-analyses are not free from threats to validity. In this case, the results are limited by the fact that the development of diabetes was a secondary, not a primary, outcome of the included trials. In addition, there was significant statistical (and likely clinical) heterogeneity amongst the trials. Still, these data provide stronger evidence than we had before that elevated blood pressure is a risk factor for the development of type 2 diabetes, and maybe more importantly, that lowering blood pressure (specifically with ACEIs and ARBs) may reduce that risk. The class-specific effects (both positive and negative) of antihypertensives on the development of diabetes need more evaluation prospectively. For now, when individualizing antihypertensive therapy, consider using ACEIs and ARBs as first-line agents in patients at increased risk for diabetes.