Hamilton, Ontario—Which antihypertensive is prescribed makes a difference in the risk of developing type 2 diabetes (T2D), according to a new study, which suggests that this concept should be incorporated into clinical guidelines.

A presentation at this year’s Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain, reports that using angiotensin-converting enzyme (ACE) inhibitors with lower blood pressure is linked to a 24% reduced risk of developing T2D compared with placebo.

McMaster University–led researchers also determined that natural genetic variations associated with ACE concentrations in the body are also related to T2D risk.

Three large randomized control trials—HOPE, PEACE, SOLVD—suggested that ACE inhibitors might prevent T2D compared with placebo in people at high risk for cardiovascular outcomes, according to the report. Noting that the causal relation between ACE inhibition and prevention of the disease remains questionable, the authors posited that ACE concentration-lowering genetic variants could be used to infer the pharmacological effect of ACE inhibitors on T2D risk.

To do that, researchers used a “Mendelian Randomization” approach, i.e., assessing individual risk of developing T2D based on natural genetic variations that influence the concentration of the ACE enzyme in the blood, and used this to infer the causal effects that ACE inhibitors would have on T2D risk.

As a first step, the study team assessed the association between T2D prevalence and ACE serum concentration in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial, which had more than 8,000 participants. Then, researchers investigated whether 17 genetic variants linked to lower ACE concentrations in the ORIGIN study, involving about 4,000 subjects, were also linked to lower prevalence of T2D in the DIAbetes Genetics Replication And Meta-analysis consortium, which involved nearly 27,000 cases and more than 132,000 controls.

Creating an ACE concentration–lowering genetic risk score (GRS), they then tested it for association with T2D prevalence in the nearly 345,000-participant United Kingdom Biobank cohort. As a final step, the researchers compared the genetically determined effect of lower ACE concentrations on T2D risk to the pharmacological inhibition of ACE versus placebo, employing a meta-analysis of randomized clinical trials, involving a total of about 31,200 patients.

The authors report that the MR analysis revealed that a lower genetically determined ACE serum concentration predicted a lower risk of T2D, while the meta-analysis of six RCTs estimated that ACE inhibitors reduced T2D risk by 24% compared with placebo.

“These results support the protective effect of long-term ACE inhibition on type 2 diabetes risk,” according to the researchers. “Although future research is needed to more accurately clarify the metabolic actions of ACE inhibitors, current evidence supports that targeting ACE may protect a person from developing type 2 diabetes. Furthermore, considering a patient’s risk of developing type 2 diabetes may be recommended when prescribing blood-pressure lowering drugs—if at high risk of type 2 diabetes, an ACE inhibitor could be considered.”

The authors also called for a review of standard practices, adding, “Current guidelines do not take account of the protective effect of ACE inhibitors on T2D risk and this is something that could be considered.”

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