Lowering blood pressure can effectively prevent new-onset type 2 diabetes, according to large meta-analyses of the differing effects of five classes of antihypertensive drugs. Angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers were most effective in reducing risk of type 2 diabetes, while β blockers and thiazide diuretics increased this risk and calcium channel blockers had no effects.
The findings are published in The Lancet.
“This is the first study that integrated large scale clinical trial data with genetic analysis to provide solid evidence for the preventive effect of blood pressure lowering on risk of diabetes. Using randomized evidence from major pharmacological blood pressure lowering trials and complementary genetic analysis, this study has shown consistent evidence for the preventive effect of blood pressure reduction on type 2 diabetes risk,” Kazem Rahimi, FRCP, DM, MSc, FESC, of the Nuffield Department of Women’s and Reproductive Health, University of Oxford, U.K., told BreakingMED in an email correspondence.
“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events. The relative magnitude of reduction per 5 mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events, which will strengthen the case for blood pressure reduction through lifestyle interventions known to reduce blood pressure, and blood pressure-lowering treatments with drugs, and possibly device therapies. The differing effects of some drug classes also support decision making for drug choice according to an individual’s risk profile. In particular, ACE-Is and ARBs were found to clearly reduce the risk of diabetes,” he added.
In this individual participant data network meta-analysis, Rahimi and colleagues sought to assess the effects of five major classes of antihypertensive agents on the risk of new-onset type 2 diabetes.
They included data from 22 studies conducted between 1973 and 2008, including all trials—primary and secondary prevention—in which researchers assessed specific classes of antihypertensive medications compared with placebo or other BP lowering medications with at least 1,000 person-years of follow-up. Trials in patients with diabetes were excluded.
In all, data from 19 randomized, controlled trials were included in the one-stage individual participant data meta-analysis, with 145,939 patients (60.6% men), and 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4.5 years, new-onset type 2 diabetes was diagnosed in 9,883 patients.
Rahimi and colleagues found that reductions of 5 mmHg in systolic blood pressure reduced the risk of type 2 diabetes across all trials by 11% (HR: 0.89; 95% CI: 0.84-0.95).
Compared with placebo, two of the five major classes of antihypertensives reduced the risk of new-onset type 2 diabetes: ACEIs (RR: 0.84; 95% CI: 0.76-0.93) and ARBs (RR: 0.84; 95% CI: 0.76-0.92). Risks for new-onset type 2 diabetes were increased by the use of β blockers (RR: 1.48; 95% CI: 1.27-172) and thiazide diuretics (RR: 1.20; 95% CI: 1.07-1.35). Calcium channel blockers had no effects on risks (RR: 1.02; 95% CI: 0.92-1.13).
Should these results change clinical practice?
“The evidence that blood pressure reduction is linked to diabetes presents clinicians and health policy makers with an opportunity to modify disease risk, for instance, either through the use of appropriate antihypertensive medications or by promoting lifestyle behaviors known to reduce blood pressure such as by maintaining a healthy weight through physical activity and a balanced diet. These findings have important implications also in the context of the generally disappointing pharmacological interventions through glucose-modifying pathways and the observed increase in risk of type 2 diabetes with lipid-lowering treatments as another major strategy for prevention of cardiovascular disease,” said Rahimi.
“This evidence also supports the indication for selected classes of antihypertensive drugs for the prevention of type 2 diabetes, which could further refine the selection of drug choice according to an individual’s risk profile. In particular, ACE-I and ARBs should be the preferred drug when clinical risk of diabetes is a concern. We did not assess the effect of combinations of drugs with opposing or synergistic effects on type 2 diabetes risk because of the limited information available. However, we believe that understanding the effect of a single class of drug is still of major clinical importance, even for selecting the most appropriate combinations of treatment,” he concluded.
In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, both of the University of North Carolina at Chapel Hill, noted the importance of preventing type 2 diabetes and of these results.
“Based on the accumulated evidence, including the results of these analyses, blood pressure control, particularly with RAS inhibition, should be considered as a possible strategy to reduce the risk of developing diabetes,” they wrote. “The absolute risk reduction found in this meta-analysis is modest; however, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension. It remains unknown to what extent the reduction in diabetes risk is due to blood pressure reduction per se versus RAS inhibition specifically.”
Cavender and Wirka also highlighted the supplementary mendelian randomization study of genetic variants the affect blood pressure conducted by these researchers. Using data from the International Consortium for Blood Pressure genome-wide association study and the U.K. Biobank, Rahimi et al found that genetic variants that affect the renin-angiotensin system (RAS) pathway associated with lower BP were also associated with a reduced risk of diabetes.
Researchers also found an association between BP lowering variants in the β adrenergic pathway and an increased risk of type 2 diabetes, while the calcium channel blocker variants had a neutral effect. Associations with thiazide variants were not conclusive.
In interpreting these results, Cavender and Wirka stressed that limitations in ascertaining new-onset diabetes should be considered. Nevertheless, they concluded, these results are salient and valuable.
“Despite its limitations, this meta-analysis provides additional evidence supporting the hypothesis that blood pressure control with specific medications can reduce the risk of diabetes. This study supports the possibility that earlier, more aggressive lowering of blood pressure, with an emphasis on RAS inhibitors, can decrease the incidence of diabetes. Perhaps these data are enough to encourage the writers of the hypertension guidelines in the USA to follow the lead of the European Society of Cardiology to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” concluded Cavender and Wirka.
Other study limitations included the absence of an analysis of the effect of combination of drugs with opposing or synergistic effects, incomplete data on dosages and post-randomization treatment, and that the diagnosis of diabetes was not a primary endpoint in the trials they included.
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According to results of individual patient and network meta-analyses, lowering systolic BP results in significant reductions in the risk of developing type 2 diabetes.
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ACE inhibitors and ARBs were most effective in reducing the risks of type 2 diabetes, while β blockers and thiazide diuretics only increased risks, and calcium channel blockers did nothing.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This study was funded by the British Heart Foundation, the National Institute for Health Research, and Oxford Martin School.
Rahimi reports personal fees from the journals Heart and PLoS Medicine, outside the submitted work.
Cavender declares research support (non-salary) from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis (for the PARADISE MI trial, which evaluated valsartan and sacubutril in patients with acute myocardial infarction and heart failure) and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo-Nordisk, none of which are relevant to specific therapies for the treatment of hypertension.
Wirka declared no competing interests.
Cat ID: 446
Topic ID: 74,446,730,446,6,13,192,925
