The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review
Open accessAbstract
Abstract.: Background. The UKPDS 34 showed that intensive treatment with metformin significantly reduces macrovascular end‐points and mortality in individuals with newly diagnosed type 2 diabetes compared with intensive treatment with insulin or sulphonylurea derivatives, despite similar glycaemic control. How this should be explained is as yet unclear. We hypothesized that metformin may have a glucose‐lowering independent effect on blood pressure and lipid profile. In order to test this hypothesis we systematically reviewed the literature and pooled the data obtained in a meta‐analysis. Methods. Included were randomized‐controlled trials in patients with type 2 diabetes mellitus and metformin treatment lasting at least 6 weeks. To identify all eligible trials we conducted electronic searches using the bibliographic databases Medline and Embase, contacted the manufacturer and checked obtained publications for cross‐references. Results. Forty‐one studies (3074 patients) provided data on blood pressure and/or lipid profile. When compared with control treatment, metformin associated effects on systolic and diastolic blood pressure and HDL cholesterol were small and statistically not significant [−1.09 mmHg 95% confidence interval (−3.01–0.82), P = 0.30; −0.97 (−2.15–0.21) mmHg, P = 0.11 and +0.01 (−0.02–0.03) mmol L−1, P = 0.50, respectively]. Compared with control treatment, however, metformin decreased plasma triglycerides, total cholesterol and LDL cholesterol significantly [−0.13 (−0.21–−0.04) mmol L−1, P = 0.003; −0.26 (−0.34–−0.18) mmol L−1, P < 0.0001 and −0.22 (−0.31–−0.13) mmol L−1, P < 0.00001, respectively]. We found no indications for publication bias. Of note, glycaemic control as assessed by HbA 1c was better with metformin than with control treatment [−0.74 (−0.84–−0.65) percentage point; P < 0.00001]. When studies were subdivided into tertiles according to increasing difference in glycaemic control between metformin and control treatment, it appeared that in case of near similar glycaemic control metformin had no effect versus control treatment on triglycerides, whereas still there was a significant effect on total and LDL cholesterol. Conclusions. This meta‐analysis of randomized‐controlled clinical trials suggests that metformin has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in patients with type 2 diabetes. This drug, however, independent of its effect on glycaemia, reduces total and LDL cholesterol significantly, but the reductions in these variables are relatively small.
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Many different mechanisms beyond glycemic control have been implicated in vascular protection induced by metformin, including improvements in the inflammatory pathway, coagulation, oxidative stress and glycation, endothelial dysfunction, haemostasis, insulin resistance, lipid profiles, and fat redistribution.
“Many different mechanisms, beyond glycemic control, have been implicated in vascular protection induced by metformin such as improvements in the inflammatory pathway [86], coagulation [87], oxidative stress and glycation [88-92], endothelial dysfunction [88-90], haemostasis [88,91-93], insulin resistance improvement [94], lipid profiles [95,96], and fat redistribution [97,98].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [88]
The endothelial effects of type 2 diabetes are probably direct and not related to decreases in hyperglycemia.
“These effects are probably direct and not related to decreases in hyperglycemia [88].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [88]
Type 2 diabetes is associated with a progressive and generalized impairment of endothelial function that affects the regulation of vasomotor tone, leucocyte adhesion, hemostasis, and fibrinolysis.
“Type 2 diabetes is associated with a progressive and generalized impairment of endothelial function that affects the regulation of vasomotor tone, leucocyte adhesion, hemostasis, and fibrinolysis.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [88]
Therapeutic doses of metformin in type 2 diabetic patients lower circulating levels of several coagulation factors such as plasminogen activator inhibitor, von Willebrand factor, tissue type plasminogen activator, and factor VII.
“Therapeutic doses of metformin in type 2 diabetic patients lower circulating levels of several coagulation factors such as plasminogen activator inhibitor (PAI-1), von Williebrand Factor (vWF), tissue type plasminogen activator [88], factor VII [91].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [88]
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Metformin: An Old But Still the Best Treatment for Type 2 Diabetes
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Self-citation
- Authors
- Wulffelé, M. G., Kooy, A., de Zeeuw, D., Stehouwer, C. D. A., & Gansevoort, R. T.
- Affiliations
- Ziekenhuis Bethesda (NL)
- Amsterdam Cardiovascular Sciences (NL)
- University of Groningen (NL)
- Corresponding author
- Gansevoort, R. T.
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2004-06-03
- Volume
- 256
- Issue
- 1
- Pages
- 1-14
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- OpenAlex
- W2161310510
- Cited by
- 359
- References
- 59
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 9 · 2023: 20 · 2022: 10 · 2021: 19 · 2020: 19 · 2019: 25 · 2018: 15 · 2017: 11 · 2016: 25 · 2015: 21 · 2014: 18 · 2013: 20 · 2012: 12
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- Research Publications (Maastricht University) (acceptedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- metformin, type 2 diabetes, blood pressure, serum cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, glycemic control, HbA1c, sulfonylureas, macrovascular complications, mortality, publication bias, treatment effect heterogeneity
- MeSH terms
- Blood Pressure, Cholesterol, Diabetes Mellitus, Type 2, Humans, Hypoglycemic Agents, Cholesterol, HDL, Cholesterol, LDL, Metformin, Triglycerides, Randomized Controlled Trials as Topic, Cross-Over Studies
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