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Lowering blood pressure — known to prevent the vascular complications of type 2 diabetes — can also stop the onset of diabetes itself, although the effects vary according to antihypertensive drug class, results from a new meta-analysis show.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) — so-called renin-angiotensin system (RAS) blockers — showed the strongest association with preventive effects, while conversely, beta-blocker and thiazide diuretic antihypertensives were linked to an increased risk of new-onset diabetes.

“This study suggests that blood pressure lowering can help prevent diabetes in addition to its well-established beneficial effects in reducing cardiovascular events,” write Milad Nazarzadeh and colleagues with the Blood Pressure Lowering Treatment Trialists’ Collaboration in their article published in The Lancet.

“The differing effects of the drug classes support decision-making for antihypertensive drug choice according to an individual’s risk profile,” note Nazarzadeh, of Deep Medicine, Oxford Martin School, University of Oxford, beipackzettel ciprofloxacin 500 UK, and colleagues.

“In particular, [RAS inhibitors], ACE inhibitors and ARBs, should become the drugs of choice when clinical risk of diabetes is of concern, whereas beta blockers and thiazide diuretics should be avoided where possible,” they add.

In an accompanying editorial, Matthew A. Cavender, MD, MPH, and Robert C. Wirka, MD, of the University of North Carolina at Chapel Hill, agree that the new findings, along with the bulk of previous evidence, point to an important role of RAS-inhibiting drugs in diabetes prevention.

“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 write.

They note that, while “the absolute risk reduction found in this meta-analysis is modest, interventions with small benefits can have an outsized effect when applied to conditions as common as hypertension.”

And commenting on the findings to the UK Science & Media Centre, Marc George, MBChB, PhD, blood pressure clinical lead for University College London Hospital, UK, said: “Lowering blood pressure prevents heart attacks, strokes, and kidney failure, and this new large and comprehensive study published in The Lancet also shows that it lowers the risk of developing diabetes. Until now this effect was not clear.”

Kevin McConway, PhD, emeritus professor of applied statistics, The Open University, UK, similarly concurs: “Though there is good evidence that lowering people’s blood pressure, if it is too high, can have important health benefits in reducing the risk of heart attacks and strokes, it hasn’t been clear whether lowering blood pressure can reduce the chance of developing type 2 diabetes in the future. This is an impressive study.”

RAS Blockers Associated With Lower Diabetes Risk

The findings are from an individual data meta-analysis of 19 randomized, placebo-controlled trials conducted between 1973 and 2008 and involving five major classes of antihypertensive drugs: ACE inhibitors, ARBs, beta-blockers, thiazide diuretics, and calcium channel blockers.

Overall, the studies included 145,939 participants, of whom 60.6% were men.

Over a median follow-up of 4.5 years, 9883 of the study participants developed new-onset type 2 diabetes.

Those treated with ACE inhibitors or ARBs had a reduced relative risk of new-onset diabetes that was nearly identical (risk reduction [RR] 0.84 for both) versus placebo.

However, treatment with beta-blockers or thiazide diuretics was associated with an increased risk of type 2 diabetes (RR, 1.48 and 1.20, respectively), consistent with previous evidence that, specifically, second-line thiazide diuretics and third-line beta blockers increase the risk of diabetes.

No significant reduction or increase in risk was observed with calcium channel blockers (RR, 1.02).

For the reductions with ACE inhibitors and ARBs, each reduction in systolic blood pressure of 5-mm Hg was associated with an 11% reduced risk of developing diabetes.

“The relative magnitude of reduction per 5-mm Hg systolic blood pressure lowering was similar to those reported for prevention of major cardiovascular events,” the authors say.

“[This] 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,” they say.

In the opposite direction, research has suggested that each 20-mm Hg increase in systolic blood pressure is associated with as much as a 77% increased risk of type 2 diabetes, however, the causality of that association is uncertain, the authors note.

Results Fill Gap in Evidence for Guidelines

The meta-analysis findings were further validated in a supplemental mendelian randomization analysis, which used data from the International Consortium for Blood Pressure genome-wide association study and the UK Biobank. The analysis showed that people with genetic variants that have a similar effect on the RAS pathway as ACE inhibitors and ARBs also had a reduced risk of diabetes.

On this point, Dipender Gill, BMBCh, PhD, lecturer in clinical pharmacology and therapeutics at St George’s, University of London, told the UK Science and Media Centre: “This is a comprehensive study triangulating clinical trial and genetic data to find support for effects of blood pressure reduction through particular pharmacological targets on glycemic control and risk of type 2 diabetes.” 

Nazarzadeh and colleagues say that uncertainty regarding whether the reduction in diabetes risk is caused by blood pressure lowering itself, or by some other effect of the antihypertensive drugs, has meant that guideline recommendations on the role of antihypertensive drugs have been lacking.

However, the authors assert that “our study fills this gap in evidence using individual participant data from randomized controlled trials and assessing effects for a standardized fixed degree of blood pressure reduction.”

“With consistent results from both randomized controlled trials and genetic analyses, we have shown that elevated blood pressure is indeed a modifiable risk factor for new-onset type 2 diabetes in people without a diagnosis of diabetes, with a relative effect size similar to those seen for the prevention of major cardiovascular disease,” they state.

Authors of US Hypertension Guidelines Should Follow Lead of ESC

Under the European Society of Cardiology (ESC) guidelines, RAS inhibitors (in combination with a calcium channel blocker or thiazide diuretic) have a class 1 recommendation for the treatment of hypertension, however, diabetes and cardiology societies in the United States only recommend a preference for a RAS inhibitor over other agents among those with concomitant albuminuria.

But with an estimated 13% of Americans having diabetes and a striking 34.5% having prediabetes, the need for more measures to tackle the problem is urgent, say Cavender and Wirka in their editorial.

“Perhaps these data are enough to encourage the writers of the hypertension guidelines in the US to follow the lead of the ESC to make RAS inhibitors the first-line hypertension treatment for all patients and not just in those with albuminuria,” they state.

Cavender has reported receiving research support from Amgen, AstraZeneca, Boehringer-Ingelheim, CSL Behring, and Novartis, and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Boston Scientific, Edwards Lifesciences, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article. Wirka and George have reported no relevant financial relationships. McConway is a trustee of the SMC and member of its advisory committee. Gill is employed part-time by Novo Nordisk.

Lancet. 2021;398:1778-1779, 1803-1810. Full text, Abstract

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