Table 2.

Quantitative description of the improvement in metabolism and cardiovascular benefits.

Author(s) and Date	Glycemic Benefit	Insulin	Triglycerides, HDL and LDL	Cardiovascular	BMI	BP	Insulin Resistance
Ahmed et al. [19]	HbA1c remained unchanged	Insulin dose reduced in Metformin group (p < 0.001)	An inverse correlation between changes in PACs number and triglycerides (r = −0.6; p = 0.001) in Metformin group	Metformin improved cEPCs, PACs, CFU-Hill’s colonies number, cECs and PACs adhesion (p < 0.05-all variables) to levels seen in healthy volunteers. A 75% rise in cEPCs number in type 1 diabetes patients equates to the reclassification of patients into a lower CVD risk group with approximate Hazard Ratio for CVD death of 0.77 (23% reduction)	Unchanged	Unchanged
Anderson et al. [20]	Metformin had a beneficial effect on HbA1c at 3 months (P = 0.001) and difference in adjusted HbA1c between groups during 12 months was 1.0%; 95% CI 0.4, 1.5 (10.9 mmol/mol; 95% CI 4.4, 16.4), P = 0.001).There was a significant benefit in adjusted (age, sex) HbA1c at 3 months for the metformin group (8.4%; 95% CI 8.0, 8.8) (68 mmol/mol; 95% CI 64, 73) vs placebo group (9.3%; 95% CI 9.0, 9.7) (78 mmol/mol; 95% CI 75, 83) (P = 0.001)	Insulin dose reduced by 0.2 U/kg/d (95% CI 0.1, 0.3, P = 0.001) during 12 months, with effects from 3 months	No significant effect	No significant effect on IMT; Vascular smooth muscle function (GTN) [flow-mediated dilatation/glyceryl trinitrate–mediated dilatation (GTN)] improved, independent of glycosylated hemoglobin (HbA1c), by 3.3% units [95% confidence interval (CI) 0.3, 6.3, P = 0.03]	No significant effect	No significant effect	Enhanced insulin sensitivity.Estimated insulin sensitivity as calculated previously remained 0.2 U higher during 12 months (95% CI 0.06, 0.34, P = 0.005) in the Metformin group compared with placebo
Bjornstad et al. [16]	No significant changes in HbA1c	Greater reductions in total daily insulin dose (−6.4 ± 2.5 U/d versus −0.06 ± 2.6 U/d; P = 0.09) and total daily insulin dose per 1 kg (−0.07 ± 0.04 U·kg−1 d−1 versus −0.02 ± 0.04 U·kg−1 d−1; P = 0.31) were observed in the Metformin group compared with the placebo group	No significant changes	The Metformin group had reduced AA WSS MAX (−0.3 ± 0.4 dyne/cm2 versus 1.5 ± 0.5 dyne/cm2; P = 0.03), AA pulse wave velocity (−1.1 ± 1.20 m/s versus 4.1 ± 1.6 m/s; P = 0.04), and far-wall diastolic carotid intima-media thickness (−0.04 ± 0.01 mm versus −0.00 ± 0.01 mm; P = 0.049) versus placebo. No significant improvements were observed for brachial distensibility Significant reduction of mean IMT in the common carotid artery on Metformin(0.6 ± 0.1 cm vs 0.53 ± 0.1 cm; P = 0.002)	Adolescents with T1DM in the Metformin versus placebo group had reduced weight (−0.5 ± 0.5 kg versus 1.6 ± 0.5 kg; P = 0.004), BMI (−0.2 ± 0.15 kg/m2 versus 0.4 ± 0.15 kg/m2; P = 0.005), and fat mass (−0.7 ± 0.3 kg versus 0.6 ± 0.4 kg; P = 0.01)	No significant change in systolic blood pressure (SBP)	Improved IR as measured by gold-standard hyperinsulinemic euglycemic clamp. Adolescents with T1DM in the Metformin versus placebo group had improved glucose infusion rate/insulin (12.2 ± 3.2 [mg·kg−1 min−1]/μIU/μL versus −2.4 ± 3.6 [mg·kg−1 min−1]/μIU/μL, P = 0.005; 18.6 ± 4.8 [mg·lean kg−1 min−1]/μIU/μL versus −3.4 ± 5.6 [mg·lean kg−1 min−1]/μIU/μL, P = 0.005)
Burchardt et al. [17]	Type 1 diabetes on adjunctive Metformin therapy had improved glycemic control. A significant improvement in fasting glucose levels (177.9 ± 65.7 mg/dl vs 123.8 ± 38.3 mg/dl; P < 0.001), postprandial glycemia (197.7 ± 57.6 mg/dl vs 133.9 ± 44.4 mg/dl; P < 0.001), average glycemia (162.8 ± 36.1 mg/dl vs 134.6 ± 19.8 mg/dl; P < 0.001) and HbA1c (8.6% ± 1.8% vs 7.6% ± 1.2%; 70 ±[–3.8] mmol/mol vs 60 ±[–10.4] mmol/mol; P < 0.001)		After 6 months of adjunctive Metformin therapy a significant increase in the levels of CEL (117.1 ± 33 pg/ml vs 118.2 ± 33 pg/ml; P < 0.001), Lp-PLA2 (82.4 ± 45.6 pg/ml vs 83.4 ± 45.6 pg/ml; P < 0.001), and a reduction in the levels of glycated LDL (1.5 ± 1.6 mg/dl vs 1.0 ± 0.5 mg/dl; P = 0.006) and triglycerides (130.1 ± 72 mg/dl vs 105.5 ± 65.2 mg/dl; P < 0.001) were observed. A trend towards increased HDL cholesterol levels (56 ± 12.6 mg/dl vs 60.9 ± 12.9 mg/dl; P = 0.07) was observed		Weight reduction (90 ± 16 kg vs 87 ± 15 kg, P = 0.054)		Enhanced tissue sensitivity to insulin
Cree-Green et al. [14]	Change in HbA1c (%) in placebo group (N = 16) 0.37 + 0.59; in Metformin group (N = 19) 0.15 + 1.24; adjusted p value 0.562			No significant differences between groups were observed	Change in BMI z score in placebo group (N = 16) 0.02 + 0.08, in Metformin group (N = 19) −0.04 + 0.10; adjusted p value 0.041 (p < 0.05–0.01)		Improvements in whole-body IR and peripheral muscle IR: whole-body IR measured by hyperinsulinemic-euglycemic clamp [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (20.002, 1.867) dL/kg/min, P = 0.05]
Libman et al. [15]	At 13-week follow-up, reduction in HbA1c was greater with Metformin (−0.2%) than placebo (0.1%; mean difference, −0.3% [95% CI, −0.6% to 0.0%]; P = .02). However, this differential effect was not sustained at 26-week follow up when mean change in HbA1c from baseline was 0.2% in each group (mean difference, 0% [95% CI, −0.3% to 0.3%]; P = .92)	At 26-week follow-up, total daily insulin per kg of body weight was reduced by at least 25% from baseline among 23% (16) of participants in the metformin group vs 1% (1) of participants in the placebo group (mean difference, 21% [95% CI, 11% to 32%]; P = .003)	No significant differences between groups were observed	A potential decrease in the risk of CVD and other complications as a result of improved insulin sensitivity, a significant decrease in BMI, and body composition	24% (17) of participants in the Metformin group and 7% (5) of participants in the placebo group had a reduction in BMI z score of 10% or greater from baseline to 26 weeks (mean difference, 17% [95% CI, 5% to 29%]; P = .01)	No significant differences between groups were observed	Changes in body weight composition and insulin requirements may have improved insulin sensitivity
Nadeau et al. [22]	Girls in the Metformin group had lower HbA1c at 3 months (9.79 ± 1.67–9.39 ± 1.93%, p = 0.06), but boys did not (9.36 ± 0.88–9.32 ± 1.29%, p = 0.9). The overweight/obese participants in the metformin group had a significantly lower HbA1c at 3 months (9.42 ± 1.06–8.78 ± 1.17%, p = 0.03), and a lower HbA1c at 6 months (9.42 ± 1.06–8.84 ± 1.09%, p = 0.08), whereas normal weight participants had no significant HbA1c changes from baseline	In the metformin group a significant decrease in daily insulin dose in U and U/kg between 0 and 3 months (U, p < 0.03; U/kg, p = 0.035) as well as between 0 and 6 months (U, p < 0.05; U/kg p = 0.014)	No changes in lipids at 6 months, lipids were not measured at the 3-month visit		A significant decrease in BMI z-score within the Metformin group between baseline and 3 months (p = 0.02) and between baseline and 6 months (p = 0.01). A significant decrease in waist circumference within the Metformin group between baseline and 3 months (p = 0.003) and between baseline and 6 months (p < 0.02). Among overweight/obese participants, waist circumferences tended to decrease from at 3 months (84.9 ± 6.5–82.9 ± 5.0 cm, p = 0.12) to at 6 months (84.9 ± 6.5–83.2 ± 5.3 cm, p = 0.06), as did BMI z-score at 6 months (1.45 ± 0.14–1.25 ± 0.33, p = 0.07). Similarly, waist circumference among normal weight participants decreased significantly at 3 months (73.6 ± 7.5–71.8 ± 7.4 cm, p = 0.01), and tended to do so at 6 months (73.6 ± 7.5–72.7 ± 6.8, p = 0.12), as did BMI z-score (0.49 ± 0.53 at 0 months–0.33 ± 0.61 at 3 months, p < 0.05; 0.41 ± 0.47 at 6 months, p = 0.10)	A significant increase in systolic blood pressure was noted in the placebo group at 3 months compared to baseline (p = 0.03)	Improved insulin sensitivity as evidenced by a significant decrease in insulin dose
Setoodeh et al. [12]	HbA1c level was significantly reduced during the study (p < 0.001) and following a 12 months period	Dosage of insulin significantly decreased (p < 0.001)	Serum lipid was decreased (p = 0.7) before (95.7 ± 22.8) after (94.8 ± 30.1)		Weight and BMI were increased (p < 0.001)		The insulin sensitivity was not measured directly.The evidence indicating the decrease of HbA1c as well as insulin level could be considered as an indicator for the improvement of insulin sensitivity in cases who received Metformin
Ziaee et al. [13]	Decrease in FBS levels on Metformin before (168.80 ± 19.90) after (113.56 ± 14.90) (p < 0.001). Decrease in HbA1C on Metformin before (8.36 ± 0.80) after (8.02 ± 0.63) (p value 0.143).		A significant decrease in TG levels (p < 0.045)			A significant reduction of systolic (p = 0.02) and diastolic (p = 0.03) blood pressure
Zawada et al. [11]	The mean decrease in FBS and HbA1C after treatment with Metformin was significantly higher than treatment with acarbose (p < 0.001). A significant reduction of fasting glucose (p = 0.01), postprandial glucose (p = 0.00002), and mean daily glucose (p = 0.02). There was a reduction in HbA1c (9.3 till 8.9%), but it was not statistically significant	A significant reduction in total daily insulin requirements (p = 0.02)	A significant improvement of triglycerides (p = 0.002) and non-HDL cholesterol (p = 0.01)		A statistically significant reduction in total adipose tissue (4.8 ± 4.0 vs. 2.9 ± 4.4 kg, p = 0.03), waist circumference (96.4 ± 9.5 vs. 89.1 ± 11.1 cm, p = 0.003), and Visceral adiposity index (VAI) (4.1 ± 2.4 vs. 2.5 ± 1.8, p = 0.006)