Table 1.
Clinical evidence demonstrating the effect of metformin on endothelial function among diabetic patients
| Articles | Subjects | Intervention in metformin | Assessments | Conclusions |
|---|---|---|---|---|
| Mather, K. J (2001) 152 | Diet-treated T2D | 1000 mg/d, 12 weeks, N = 29 | ACh-stimulated flows:↑; Nitroprusside-stimulated flows: NS; Verapamil-stimulated flows: NS | IR was the sole predictor of endothelium-dependent blood flow following metformin treatment. |
| Abbasi F (2004) 153 | T2D | 1000-2000 mg/d, 12 weeks, N = 16 | sICAM-1↑; sVCAM-1: NS; ET-1: NS | Metformin, either as monotherapy or in combination with a sulfonylurea drug, led to a decrease in several CVD risk factors in patients with T2D. |
| De Jager J (2005) 154 | T2D treated with insulin | 850 mg/d, 16 weeks, N = 196 | vWf↓; sET-1↓; t-PA↓; PAI-1↓; s-ICAM-1: NS; s-VCAM-1↓ | An improvement of endothelial function with metformin in T2D treated with insulin, which was largely unrelated to changes in glycemic control. |
| Skrha J (2007) 155 | T2D | 1700 mg/d, 12 weeks, N = 15 | tPA↓; sVCAM-1↓; sICAM-1↓; Microcirculation by laser Doppler: NS | Metformin treatment promotes endothelium effects associated with a complex of metabolic changes in T2D. |
| Ersoy C (2008) 156 | Obese T2D | 1381 ± 85 mg/d, 12 weeks, N = 24 | PAI-1↑; VEGF↑ | A beneficial effect on VEGF and PAI-1 levels with metformin in obese T2D. |
| Lund SS (2008) 157 | Non-obese T2D without insulin | 2000 mg/d, 16 weeks, N = 83 | PAI-1↓; tPA↓; s ICAM-1↓; sVCAM-1↓; ET-1↓ | Metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycemic levels between treatments. |
| Tousoulis D (2010) 158 | Newly diagnosed DM | 850 mg/d, 6 weeks, N = 15 | Resting FBF: NS; EDD: decrease in combination with atorvastatin | Combined with metformin and atorvastatin for 6 weeks partly prevented the glucose-induced impairment of EDD. |
| Fidan E (2011) 159 | T2D | 850-2550 mg/d, 12 weeks, N = 20 | PAI-1: NS; sICAM-1↓; ET-1: NS; Fibrinogen: NS | Metformin was effective in controlling inflammatory markers in addition to metabolic parameters. |
| Pitocco D (2013) 160 | uncomplicated T1D | 2550 mg/d, 6 months, N = 21 | FMD↑; NMD: NS | Metformin improved FMD and increased PGF2α in uncomplicated T1D. |
| de Jager J (2014) 161 | T2D treated with insulin | 850 mg/d, 4.3 years, N = 131 | vWf↓; sVCAM-1↓; s-ICAM-1↓; t-PA, PAI-1↓; ET-1: NS | Metformin is associated with improvement in some markers of endothelial function in T2D. |
| Kruszelnicka O (2015) 166 | T2D with stable CHD | Previous 1 year, N = 40 | sVCAM-1 ↓, ADMA ↑ | Metformin affects VCAM1 and ADMA levels among T2D patients with stable CHD. |
| Shigiyama F (2017) 162 | T2D treated with metformin | 750-1500 mg/d, 16 weeks, N = 54 | FMD: NS in alone; increase in combination with linagliptin | Among T2D patients with moderate hyperglycemia, metformin plus linagliptin induced both better glycemic control and improvement of endothelial function. |
| Kitao N (2017) 163 | T2D treated with metformin | 1000-1500 mg/d, 12weeks, N = 48 | FMD: NS | Combination of vildagliptin and metformin did not affect endothelial function but exert favorable effects on adipokine with T2D without advanced atherosclerosis. |
| Petrie JR (2017) 167 | T1D at increased risk for CVD | 2000 mg/d, 3 years, N = 219 | Progression of mean cIMT: NS Reactive hyperaemia index: NS |
Metformin did not affect on endothelial function but might have a wider role in cardiovascular risk management. |
| Lunder, M (2018) 164 | T1D | 2000 mg/d, 12 weeks, N = 10 | Beta stiffness: NS in metformin alone; FMD↑ | Empagliflozin on top of metformin treatment significantly improved arterial stiffness compared to metformin in T1D. |
| Schiapaccassa, A (2019) 165 | Obesity T2DM women | 1700 mg/d, 30 days, N = 19 | Nutritive microvascular reactivity↑; Functional capillary density during post-occlusive reactive hyperemia↑ | Metformin was able to improve vascular function in obese newly diagnosed drug-naive T2DM women, through distinct or complementary mechanisms of action on the vascular wall. |
Abbreviations: Ach, acetylcholine; ADMA, asymmetric dimethylarginine; CHD, coronary heart disease; CVD, cardiovascular Disease; DM, diabetes mellitus; EDD, endothelium-dependent vasodilation; ET-1, endothelin-1; FBF, forearm blood flow; FMD, flow mediated dilation; IR, insulin resistance; NMD, nitroglycerin-mediated dilation; NS, non-significant; PAI-1, plasminogen activator inhibitor-1; PGF2α, prostaglandin F2α; s-ICAM-1, soluble intercellular adhesion molecule-1; s-VCAM-1, soluble vascular cell adhesion molecule-1; T1D, type 1 diabetes; T2D, type 2 diabetes; t-PA, tissue plasminogen activator; VEGF, vascular endothelial growth factor; vWf, von willebrand factor.