Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials
Open accessAbstract
Objective To determine the average reduction in blood pressure, prevalence of adverse effects, and reduction in risk of stroke and ischaemic heart disease events produced by the five main categories of blood pressure lowering drugs according to dose, singly and in combination. Design Meta-analysis of 354 randomised double blind placebo controlled trials of thiazides, β blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers in fixed dose. Subjects 40 000 treated patients and 16 000 patients given placebo. Main outcome measures Placebo adjusted reductions in systolic and diastolic blood pressure and prevalence of adverse effects, according to dose expressed as a multiple of the standard (recommended) doses of the drugs. Results All five categories of drug produced similar reductions in blood pressure. The average reduction was 9.1 mm Hg systolic and 5.5 mm Hg diastolic at standard dose and 7.1 mm Hg systolic and 4.4 mm Hg diastolic (20% lower) at half standard dose. The drugs reduced blood pressure from all pretreatment levels, more so from higher levels; for a 10 mm Hg higher blood pressure the reduction was 1.0 mm Hg systolic and 1.1 mm Hg diastolic greater. The blood pressure lowering effects of different categories of drugs were additive. Symptoms attributable to thiazides, β blockers, and calcium channel blockers were strongly dose related; symptoms caused by ACE inhibitors (mainly cough) were not dose related. Angiotensin II receptor antagonists caused no excess of symptoms. The prevalence of symptoms with two drugs in combination was less than additive. Adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose. Conclusions Combination low dose drug treatment increases efficacy and reduces adverse effects. From the average blood pressure in people who have strokes (150/90 mm Hg) three drugs at half standard dose are estimated to lower blood pressure by 20 mm Hg systolic and 11 mm Hg diastolic and thereby reduce the risk of stroke by 63% and ischaemic heart disease events by 46% at age 60-69.
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The glycosuric effect of SGLT2 inhibition diminishes substantially as kidney function declines, while effects on systolic blood pressure appear preserved across the spectrum of eGFR studied to date, including eGFR below 30.
“While the glycosuric effect of SGLT2 inhibition diminishes substantially as kidney function declines, effects on systolic BP appear preserved across the spectrum of eGFR studied to date, including down to an eGFR <30 mL/min/1.73m 2 .[25][26][27]”
From Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial (2021) · cites this paper as [26]
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“On average, ACEIs or ARBs, thiazide or thiazide-like diuretics, dihydropyridine calcium channel blockers (CCBs), and β-blockers reduce BP to a similar degree 66 and effectively lower cardiovascular risk when used at optimal doses.”
More Versus Less Blood Pressure Lowering: An Update
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- Authors
- Law, M. R., Wald, N. J., Morris, J. K., & Jordan, R. E.
- Affiliations
- University of London (GB)
- Corresponding author
- Law, M R
- ORCID
- Morris, J K
- Venue
- BMJ
- Publisher
- BMJ
- Published
- 2003-06-25
- Volume
- 326
- Issue
- 7404
- Pages
- 1427
- ISSN
- 0007-1447 (ISSN-L)
- 0959-8138
- 1468-5833
- PMC
- PMC162261
- OpenAlex
- W2160547085
- Cited by
- 1,232
- References
- 45
- Citations by year
- 2026: 35 · 2025: 46 · 2024: 41 · 2023: 45 · 2022: 45 · 2021: 52 · 2020: 41 · 2019: 46 · 2018: 34 · 2017: 58 · 2016: 49 · 2015: 37 · 2014: 59 · 2013: 60 · 2012: 80
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.bmj.com/company/legal-information/terms-conditions/legal-information/tdm-licencepolicy (tdm)
- Locations
- BMJ (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Keywords
- antihypertensive drugs, low-dose combination therapy, blood pressure reduction, thiazide diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, adverse drug reactions, dose-response relationship, stroke prevention, ischemic heart disease, hypertension
- MeSH terms
- Antihypertensive Agents, Blood Pressure, Double-Blind Method, Drug Combinations, Humans, Hypertension, Randomized Controlled Trials as Topic, Treatment Outcome, Myocardial Ischemia, Stroke
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