. 2021 Nov 13;398(10313):1803-1810.

doi: 10.1016/S0140-6736(21)01920-6.

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

Milad Nazarzadeh¹, Zeinab Bidel¹, Dexter Canoy², Emma Copland¹, Malgorzata Wamil³, Jeannette Majert¹, Karl Smith Byrne⁴, Johan Sundström⁵, Koon Teo⁶, Barry R Davis⁷, John Chalmers⁸, Carl J Pepine⁹, Abbas Dehghan¹⁰, Derrick A Bennett¹¹, George Davey Smith¹², Kazem Rahimi¹³; Blood Pressure Lowering Treatment Trialists’ Collaboration

Affiliations

¹ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK.
² Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
³ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK.
⁴ International Agency for Research on Cancer/WHO, Genomic Epidemiology Branch, Lyon, France.
⁵ Clinical Epidemiology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁷ The University of Texas School of Public Health, Houston, TX, USA.
⁸ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁹ Department of Medicine, University of Florida, Gainesville, FL, USA.
¹⁰ Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, London, UK.
¹¹ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹² MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹³ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address: kazem.rahimi@wrh.ox.ac.uk.

PMID: 34774144
PMCID: PMC8585669
DOI: 10.1016/S0140-6736(21)01920-6

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

Milad Nazarzadeh et al. Lancet. 2021.

. 2021 Nov 13;398(10313):1803-1810.

doi: 10.1016/S0140-6736(21)01920-6.

Authors

Affiliations

¹ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK.
² Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
³ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK.
⁴ International Agency for Research on Cancer/WHO, Genomic Epidemiology Branch, Lyon, France.
⁵ Clinical Epidemiology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁶ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁷ The University of Texas School of Public Health, Houston, TX, USA.
⁸ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁹ Department of Medicine, University of Florida, Gainesville, FL, USA.
¹⁰ Department of Biostatistics and Epidemiology, School of Public Health, Imperial College London, London, UK.
¹¹ Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
¹² MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
¹³ Deep Medicine, Oxford Martin School, University of Oxford, Oxford, UK; Nuffield Department of Women's and Reproductive Health, Medical Science Division, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Electronic address: kazem.rahimi@wrh.ox.ac.uk.

PMID: 34774144
PMCID: PMC8585669
DOI: 10.1016/S0140-6736(21)01920-6

Abstract

Background: Blood pressure lowering is an established strategy for preventing microvascular and macrovascular complications of diabetes, but its role in the prevention of diabetes itself is unclear. We aimed to examine this question using individual participant data from major randomised controlled trials.

Methods: We performed a one-stage individual participant data meta-analysis, in which data were pooled to investigate the effect of blood pressure lowering per se on the risk of new-onset type 2 diabetes. An individual participant data network meta-analysis was used to investigate the differential effects of five major classes of antihypertensive drugs on the risk of new-onset type 2 diabetes. Overall, data from 22 studies conducted between 1973 and 2008, were obtained by the Blood Pressure Lowering Treatment Trialists' Collaboration (Oxford University, Oxford, UK). We included all primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of blood pressure lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm. Participants with a known diagnosis of diabetes at baseline and trials conducted in patients with prevalent diabetes were excluded. For the one-stage individual participant data meta-analysis we used stratified Cox proportional hazards model and for the individual participant data network meta-analysis we used logistic regression models to calculate the relative risk (RR) for drug class comparisons.

Findings: 145 939 participants (88 500 [60·6%] men and 57 429 [39·4%] women) from 19 randomised controlled trials were included in the one-stage individual participant data meta-analysis. 22 trials were included in the individual participant data network meta-analysis. After a median follow-up of 4·5 years (IQR 2·0), 9883 participants were diagnosed with new-onset type 2 diabetes. Systolic blood pressure reduction by 5 mm Hg reduced the risk of type 2 diabetes across all trials by 11% (hazard ratio 0·89 [95% CI 0·84-0·95]). Investigation of the effects of five major classes of antihypertensive drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (RR 0·84 [95% 0·76-0·93]) and angiotensin II receptor blockers (RR 0·84 [0·76-0·92]) reduced the risk of new-onset type 2 diabetes; however, the use of β blockers (RR 1·48 [1·27-1·72]) and thiazide diuretics (RR 1·20 [1·07-1·35]) increased this risk, and no material effect was found for calcium channel blockers (RR 1·02 [0·92-1·13]).

Interpretation: Blood pressure lowering is an effective strategy for the prevention of new-onset type 2 diabetes. Established pharmacological interventions, however, have qualitatively and quantitively different effects on diabetes, likely due to their differing off-target effects, with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers having the most favourable outcomes. This evidence supports the indication for selected classes of antihypertensive drugs for the prevention of diabetes, which could further refine the selection of drug choice according to an individual's clinical risk of diabetes.

Funding: British Heart Foundation, National Institute for Health Research, and Oxford Martin School.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests KR reports personal fees from the journals Heart and PLoS Medicine, outside the submitted work. JS reports stock ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Bayer, Pfizer, and AstraZeneca, outside the submitted work. JC reports a grant from the National Health and Medical Research Council of Australia, outside the submitted work. All other authors declare no competing interests.

Figures

**Figure 1**
Kaplan-Meier estimates of survival in the intervention and comparator groups The curve has been truncated at 6 years after randomisation and adjusted for the systolic blood pressure reduction reached at the trial level. All participants with a known diagnosis of diabetes were excluded at baseline. HR=hazard ratio.

**Figure 2**
Blood pressure lowering treatment and risk of new-onset type 2 diabetes, by body-mass index categories at baseline The forest plot shows the hazard ratios and 95% CIs per 5 mm Hg reduction in systolic blood pressure.

**Figure 3**
Estimated effect of major antihypertensive drug classes on the risk of new-onset type 2 diabetes The effect sizes did not standardise for blood pressure reduction between trials to account for off-target effects or non-blood pressure mediated effects of the different drug classes.

See this image and copyright information in PMC

Comment in

Blood pressure lowering in the prevention of type 2 diabetes.
Cavender MA, Wirka RC. Cavender MA, et al. Lancet. 2021 Nov 13;398(10313):1778-1779. doi: 10.1016/S0140-6736(21)02340-0. Lancet. 2021. PMID: 34774133 No abstract available.
Blood pressure lowering drugs differ in their capacity to prevent type 2 diabetes.
Volpe M, Patrono C. Volpe M, et al. Eur Heart J. 2022 Mar 21;43(12):1189-1190. doi: 10.1093/eurheartj/ehab878. Eur Heart J. 2022. PMID: 34977933 No abstract available.
Antihypertensive drugs reduced risk for new-onset type 2 diabetes; effect varies by antihypertensive class.
Tanner M. Tanner M. Ann Intern Med. 2022 Apr;175(4):JC44. doi: 10.7326/J22-0018. Epub 2022 Apr 5. Ann Intern Med. 2022. PMID: 35377716

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Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

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Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis

Authors

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Abstract

Conflict of interest statement

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Medical