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Abstract
Background
Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure.
Methods
We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283.
Findings
We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated.
Interpretation
Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted.
Funding
British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.
Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure.
Methods
We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and thiazide diuretics, was estimated using a network meta-analysis framework. This study is registered with PROSPERO, CRD42018099283.
Findings
We included data from 51 randomised clinical trials published between 1981 and 2014 involving 358 533 participants (58% men), among whom 103 325 (29%) had known type 2 diabetes at baseline. The baseline mean systolic/diastolic blood pressure of those with and without type 2 diabetes was 149/84 mm Hg (SD 19/11) and 153/88 mm Hg (SD 21/12), respectively. Over 4·2 years median follow-up (IQR 3·0–5·0), a 5 mm Hg reduction in systolic blood pressure decreased the risk of major cardiovascular events in both groups, but with a weaker relative treatment effect in participants with type 2 diabetes (HR 0·94 [95% CI 0·91–0·98]) compared with those without type 2 diabetes (0·89 [0·87–0·92]; pinteraction=0·0013). However, absolute risk reductions did not differ substantially between people with and without type 2 diabetes because of the higher absolute cardiovascular risk among participants with type 2 diabetes. We found no reliable evidence for heterogeneity of treatment effects by baseline systolic blood pressure in either group. In keeping with the primary findings, analysis using stratified network meta-analysis showed no evidence that relative treatment effects differed substantially between participants with type 2 diabetes and those without for any of the drug classes investigated.
Interpretation
Although the relative beneficial effects of blood pressure reduction on major cardiovascular events were weaker in participants with type 2 diabetes than in those without, absolute effects were similar. The difference in relative risk reduction was not related to the baseline blood pressure or allocation to different drug classes. Therefore, the adoption of differential blood pressure thresholds, intensities of blood pressure lowering, or drug classes used in people with and without type 2 diabetes is not warranted.
Funding
British Heart Foundation, UK National Institute for Health Research, and Oxford Martin School.
| Original language | English |
|---|---|
| Pages (from-to) | 645-654 |
| Number of pages | 10 |
| Journal | Lancet Diabetes and Endocrinology |
| Volume | 10 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 22 Jul 2022 |
Bibliographical note
Funding Information:MN (grant number FS/19/36/34346), KR (grant number PG/18/65/33872), and DC (grant number PG/18/65/33872) are supported by the British Heart Foundation. KR, DC, and DB are supported by NIHR Oxford Biomedical Research Centre. KR received support from the Oxford Martin School and UKRI Global Challenge Research Fund (grant reference ES/P011055/1). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (project reference MC_UU_00011/1). MW is supported by the Australian National Health and Medical Research Council (investigator grant APP1174120 and program grant APP1149987). NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217). AIA is funded by the Biomedical Research Centre–Oxford Center for Diabetes Endocrinology and Metabolism. WCC received institutional grants from the US National Institutes for Health. RJM is an NIHR Senior Investigator and receives support from the NIHR Oxford and Thames Valley ARC. This manuscript was prepared using Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) research materials obtained from the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Centre and does not necessarily reflect the opinions or views of the ALLHAT, PEACE, or the NHLBI. We acknowledge original depositors of the Australian National Blood Pressure Study data and the Australian Data Archive, and declare that those who did the original analysis and collection of the data bear no responsibility for the further analysis or interpretation of the data.
Funding Information:
MN (grant number FS/19/36/34346), KR (grant number PG/18/65/33872), and DC (grant number PG/18/65/33872) are supported by the British Heart Foundation. KR, DC, and DB are supported by NIHR Oxford Biomedical Research Centre. KR received support from the Oxford Martin School and UKRI Global Challenge Research Fund (grant reference ES/P011055/1). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (project reference MC_UU_00011/1). MW is supported by the Australian National Health and Medical Research Council (investigator grant APP1174120 and program grant APP1149987). NS is supported by the British Heart Foundation Research Excellence Award (RE/18/6/34217). AIA is funded by the Biomedical Research Centre–Oxford Center for Diabetes Endocrinology and Metabolism. WCC received institutional grants from the US National Institutes for Health. RJM is an NIHR Senior Investigator and receives support from the NIHR Oxford and Thames Valley ARC. This manuscript was prepared using Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) research materials obtained from the National Heart, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Centre and does not necessarily reflect the opinions or views of the ALLHAT, PEACE, or the NHLBI. We acknowledge original depositors of the Australian National Blood Pressure Study data and the Australian Data Archive, and declare that those who did the original analysis and collection of the data bear no responsibility for the further analysis or interpretation of the data.
Publisher Copyright:
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
Research Groups and Themes
- Bristol Population Health Science Institute
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This is the final published version of the article (version of record). It first appeared online via Elsevier at https://doi.org/10.1016/S2213-8587(22)00172-3. Please refer to any applicable terms of use of the publisher.
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IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research