Metformin was first synthesized almost 100 years ago from Gallega Officinalis. Since 1957, it has been used for the treatment of type 2 diabetes mellitus in Europe, but nowadays is considered a first-line agent for the same disease worldwide. Reduction of intestinal glucose absorption, improvement of peripheral glucose uptake, the heightening of insulin sensitivity, lowering of plasma insulin levels, and reduction of hepatic glucose output represent the physiological basis of metformin antihyperglycemic properties .
The UK Prospective Diabetes trial 34 (UKPDS-34) demonstrated that glucose lowering by metformin compared with no treatment (diet only) reduced all-cause mortality and myocardial infarction (achieved glycated hemoglobin difference of −0.6%) in newly diagnosed type 2 diabetes mellitus overweight patients . In the same trial, indirect comparisons of metformin vs. placebo and other hypoglycemic agents (sulphonylureas or insulin) vs. placebo, suggested that the effects of metformin were significantly different despite similarly achieved glucose reductions.
In patients at risk for type 2 diabetes mellitus – The Diabetes Prevention Program (DPP) trial – metformin reduced the incidence of new onset diabetes mellitus by 31% compared with placebo during a follow-up period of almost 3 years and without substantial achieved glycated hemoglobin difference compared with placebo (less than −0.2%) . A previous meta-analysis in different ethnic settings and cohorts also confirmed that metformin reduces the rate of new onset diabetes mellitus by 40% . However, the use of metformin in patients at risk for diabetes mellitus is not recommended and might only be an ‘off-label’ option.
In both diabetes mellitus patients and at risk for diabetes mellitus patients, metformin was associated with weight loss or less weight gain, and a reduction of insulin resistance compared with placebo was steadily observed. The constant reduction of insulin resistance and body weight [2,3,5] raised the pathophysiologically plausible hypothesis of whether metformin can lower blood pressure (BP) or not.
Earlier in-vivo experimental studies have demonstrated parallel lowering of plasma insulin and BP by metformin in different rat models and experimental design (insulin infusion, fructose-enriched diet), suggesting that hyperinsulinemia-induced hypertension might be a mechanism partly reversed by metformin [6–9] (Table 1). However, in other experimental models, these effects were not observed . Different possible explanations were offered mostly related to either experimental-related or BP measurement-related conditions (restrained vs. less restrained, conscious vs. anesthetized, tail-cuff plethysmography vs. invasive radio-telemetry, young vs. adult animals, hypertensive vs. normotensive animals, diabetic vs. nondiabetic animals, orally vs. intravenously administered metformin).
Another line of evidence from ex-vivo experimental models (Table 1) demonstrated that metformin acts directly on arterial ring segments modulating mechanisms of calcium handling, and attenuating catecholamine and insulin constrictor responses of resistance arteries in rats [11,12]. A withdrawal of sympathetic activity was associated with the acute intravenous administration of metformin in spontaneously hypertensive rats suggesting a neurally mediated mechanism of BP lowering . In-vivo experimental research supported that the hypotensive effects of metformin are enhanced by a high-salt diet, which increases sympathetic nervous system activation in spontaneously hypertensive rats . Metformin was also associated with a reduction in heart rate, a yet consistent finding with metformin-related sympathetic withdrawal [8,10,12]. Lastly, metformin increases urinary sodium excretion through elevations of glomerular filtration rate in essential hypertensive patients but without any effect on office and ambulatory BP after a short observation time of 1 month  (Table 1).
The role of metformin on endothelial function was tested in experimental in-vivo and ex-vivo studies, as well as in clinical research [14,15]. Overall the evidence suggests an improvement in nitric oxide-dependent relaxation, yet a finding that on a long-term might have a favorable effect on BP levels.
In the current issue of Journal of Hypertension, Zhou et al.  present a meta-analysis of randomized trials in patients without diabetes mellitus, with the aim of investigating the effects of metformin on BP levels. Although 26 studies were selected, the total number of participants was quite small (n = 4113). Also, selected studies were scored poorly for selection bias, meaning that the randomization procedure in most of the trials was highly uncertain. In these trials, metformin was tested in various clinical settings (impaired glucose tolerance; polycystic ovary syndrome; hypertension; obesity; schizophrenia) indicating that the main investigational question frequently was different from the assessment of BP response. BP assessment was not the primary purpose of the investigators involved in the different studies selected here, and the methodology of BP measurement in most cases was not described. In all studies, follow-up BP was the final one and not that attained throughout the whole follow-up period. Additionally, more than 1/3 of studies had a follow-up period less than 6 months, which is a very limited period to unmask any BP lowering of metformin. Following metformin treatment, SBP was lowered only by 2 mmHg, whereas DBP was not lowered at all. Hypertension was not largely represented in the selected studies , and previous experimental evidence showed that the lowering effects of metformin on BP are mostly observed in hypertension models. Finally, a previous meta-analysis focused on diabetes mellitus patients showed a neutral effect of metformin on BP levels though in a quite limited number of participants (n = 1600) .
Meta-analyses are hypothesis-raising instruments and cannot replace the results of well designed randomized clinical trials. The present meta-analysis raises the hypothesis of a possible effect of metformin on BP levels in participants without diabetes mellitus. Future clinical trials should focus on the differential effects of metformin on BP by discriminating hypertensive from normotensive patients, as well patients with diabetes mellitus from those at risk for diabetes mellitus. Measurement of dietary salt at baseline and follow-up (e.g. 24-h urinary sodium excretion) might also be important in combination with office BP measurements, at different times during follow-up. Implementation of ambulatory BP monitoring would also be helpful to further refine research in the field.
Conflicts of interest
There are no conflicts of interest.
1. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr
2. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet
3. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med
4. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med
5. Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, Stehouwer CD. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med
6. Verma S, Bhanot S, McNeill JH. Metformin decreases plasma insulin levels and systolic blood pressure in spontaneously hypertensive rats. Am J Physiol
7. Verma S, Yao L, Dumont AS, McNeill JH. Metformin treatment corrects vascular insulin resistance in hypertension. J Hypertens
8. Muntzel MS, Abe A, Petersen JS. Effects of adrenergic, cholinergic, and ganglionic blockade on acute depressor responses to metformin in spontaneously hypertensive rats. J Pharmacol Exp Ther
9. Bhalla RC, Toth KF, Tan E, Bhatty RA, Mathias E, Sharma RV. Vascular effects of metformin: possible mechanisms for its antihypertensive action in the spontaneously hypertensive rat. Am J Hypertens
10. Muntzel MS, Hamidou I, Barrett S. Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats. Hypertension
11. Sharma RV, Bhalla RC. Metformin attenuates agonist-stimulated calcium transients in vascular smooth muscle cells. Clin Exp Hypertens
12. Peuler JD, Miller JA, Bourghli M, Zammam HY, Soltis EE, Sowers JR. Disparate effects of antidiabetic drugs on arterial contraction. Metabolism
13. Semplicini A, Del Prato S, Giusto M, Campagnolo M, Palatini P, Rossi GP, et al. Short-term effects of metformin on insulin sensitivity and sodium homeostasis in essential hypertensives. J Hypertens
14. Katakam PV, Ujhelyi MR, Hoenig M, Miller AW. Metformin improves vascular function in insulin-resistant rats. Hypertension
15. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol
16. Zhou L, Liu H, Wen X, Peng Y, Tian Y, Zhao L. Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trials. J Hypertens
17. Wulffelé MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med