ACE inhibitors may have potential uses in diabetes, aside from lowering blood pressure.
Diabetes prevalence has doubled in the past 25 years, necessitating a way to slow its incidence. Commonly, diet and lifestyle changes are used to delay the onset of type 2 diabetes, as are glucose-lowering drugs. Some studies have suggested that angiotensin–converting enzyme (ACE) inhibitors may reduce the risk of developing type 2 diabetes in people with a high risk of cardiovascular outcomes. Another study found that there was a nonsignificant decrease in type 2 diabetes incidence in those with low risks for cardiovascular disease. As such, the data supporting the use of ACE inhibitors in preventing type 2 diabetes is mixed. The authors used Mendelian randomization, a statistical method that uses genetic associations that will allow the inference of causality while reducing bias, to see if ACE inhibitors would protect against developing type 2 diabetes.
The authors hoped to use the variation of ACE levels to provide evidence for or against the use of ACE inhibitors in the prevention of developing type 2 diabetes. During the first step of this study, genetic variants associated with ACE concentrations near the ACE locus were identified using the ORIGIN (Outcome Reduction with Initial Glargine INtervention) trial. Then, the authors conducted a Mendelian Randomization analysis to assess the association between these variants and the risk of developing type 2 diabetes. Next, estimation of type 2 diabetes obtained from the randomization as compared to the estimates obtained from a previous randomized control trial meta-analysis of ACE inhibitors versus placebos, after standardization for blood pressure changes. This study looked at data from 341,872 participants, of which 16,320 had type 2 diabetes. The primary outcome was the prevalence of type 2 diabetes at baseline. The two-sample Mendelian regression analysis of ACE concentration change on type 2 diabetes looked at the effect of the ACE concentration-lowering single nucleotide polymorphisms (SNPs) (found in the ORIGIN trial), and the impact of those on the risk of developing type 2 diabetes from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. After sorting through all that data, the authors identified 17 independent SNPs that were significantly associated with ACE concentrations in the ORIGIN trial. These explained 39% of the variance in ACE concentrations, supporting their use in subsequent analyses. Finally, the authors looked at six randomized controlled trials where an ACE inhibitor was used against a placebo, totaling 31,200 participants, with 1,312 new-onset diabetes cases in those receiving ACE inhibitors and 1,506 cases in the control group.
Through a two-sample Mendelian regression analysis, the authors found that lower ACE concentrations were associated with a lower risk of type 2 diabetes (OR per SD 0.92 [95% CI 0.89-0.95]) when using the data from DIAGRAM. When the authors looked at data from the UK Biobank, they estimated that a single standard deviation ACE concentration-lowering genetic risk score resulted in a 3% lower risk of type 2 diabetes (OR per SD 0.97 [95% CI 0.96-0.99]). They found no interaction between ACE inhibitor usage and ACE concentration-lowering genetic risk score on type 2 diabetes risk (P interaction = 0.99). A single standard deviation decrease in the ACE concentration-lowering genetic risk score saw a 0.02 mmol/mol lower HbA1c (P = 0.022). In their investigation of the six randomized controlled trials, those on an ACE inhibitor had a decreased incidence of type 2 diabetes of 24% (OR 0.76 [95% CI 0.60-0.97]). Those receiving an ACE inhibitor saw a MAP reduction of 2.4 mmHg during treatment. The ACE concentration-lowering genetic risk score was associated with an 81% decrease in type 2 diabetes risk per 2.4 mmHg reduction of MAP (0.19 [0.07-0.51]; P = 0.007 for difference). Furthermore, the authors found a causal association between lower ACE concentrations and lower BMIs (P = 0.000742).
The authors found that genetic variations of ACE concentrations were associated with a lower prevalence of type 2 diabetes. While most of their focus was examining the genetic differences that cause changes in ACE concentrations, they managed to find some surprising information. They provided information that reinforces the protective effects of ACE inhibitors on type 2 diabetes. Their findings suggest a cumulative effect over time, though they believe this reduction of risk is due to a decrease in BMI. While one previous study did not find that ACE inhibitors significantly reduced the risk of developing type 2 diabetes, this study’s finding suggests that they may. As always, more studies are needed to confirm the effects that ACE inhibitors may have in preventing type 2 diabetes.
- This study saw a decrease in the incidence of type 2 diabetes by 24%, based on an analysis of six previous randomized controlled studies.
- ACE inhibitors may be a way to help prevent type 2 diabetes, especially in those with a history of high blood pressure.
- This study adds to previous studies that support the use of ACE inhibitors in the prevention of type 2 diabetes.
Pigeyre, Marie, et al. “ACE and Type 2 Diabetes Risk: A Mendelian Randomization Study.” Diabetes Care, American Diabetes Association, Feb. 2020, care.diabetesjournals.org/content/early/2020/01/30/dc19-1973.
George McConnell, PharmD. Candidate, LECOM School of Pharmacy