Table 1.

The summary of articles.

Author(s) and date	Questions, variables, objectives, hypothesis	Design, sample, setting	Findings	Notes
Ahmed et al. (2016)	Does adjunctive Metformin use have cardiovascular benefit, without causing hypoglycemic effect in adolescents with TIDM? Independent variables: Sex and age T1DM, Metfomin Dependent variables: Insulin dose HbA1C Lipid profile Lab results Blood glucose BMI Objectives: To assess the impact of Metformin on endothelial cells and endothelial progenitor cells in Type 1 diabetes. Hypothesis: Metformin can help improve endothelial dysfunction and reduce CVD risk.	Randomized Control Quantitative Improvement Study. 23 participants in the Treatment Group 9 in the Standard Group 23 healthy volunteers Study visit Telephone visit Queen Elizabeth Hospital, Gateshead or the Royal Victoria Infirmary, Newcastle, UK	After treating the participants with Metformin there was an improvement in CVD, while the levels of HbA1c remained the same. Metformin functions independently of hypoglycemic effect.	For the first time the research showed that in treatment group, in which participants received Metformin, there were changes in the markers of vascular/endothelial damage. CFU-Hill’s colonies and cECs are the markers of CVD risk. Metformin had a favorable effect on these makers. Also, the levels of HbA1c have improved.
Anderson et al. (2017)	Will metformin improve the vascular function in children with type 1 diabetes? Will early intervention reduce cardiovascular disease in children with type1 diabetes? Variables: Independent: Ethnicity Sex Age T1DM Variables: Dependent: HbA1c GTN Insulin dose BMI Objectives: To evaluate the effect of Metformin on vascular function in children with type 1 diabetes. Hypothesis: Metformin will improve vascular function in children with type 1 diabetes.	Quantitative study. Twelve-month double-blind, randomized, placebo-controlled trial. 90 children with type 1 diabetes ages 8 to 18 years old with greater than 50 percentile body mass index. Tertiary pediatric diabetes clinic.	Metformin improved vascular smooth muscle function and HbA1c, and lowered insulin dose in type 1 diabetes children. No participant experienced severe hypoglycemia which was attributed to the consistency in care. The number of moderate hypoglycemia cases did not increase significantly. The retention rate was high.	Participants with type 1 diabetes at the onset of adolescence adhered to the therapy and benefitted the most at three months. Their HbA1c improved due to increased insulin sensitivity during 12 months.
Bjornstad et al. (2018)	Will Metformin as an adjunctive therapy to insulin improve insulin resistance and vascular dysfunction? What are the clinical implications, since glycemic control is most difficult during adolescence? Independent variables: Age, sex, Tanner stage, Metformin Dependent variables: Insulin dose, blood glucose, urine ketones, BMI, insulin sensitivity surrogate markers, MRI changes of ascending and descending aorta. Objectives: The purpose of the study is to demonstrate the use of Metformin as a safe oral medication, which can improve insulin resistance, BMI and offer potential cardio protective effects long term. Hypothesis: Adolescents with type 1 diabetes have impaired vascular function. Will the addition of Metformin as adjunctive therapy improve insulin resistance and vascular dysfunction?	Randomized double-blind placebo-control 48 adolescents with type 1 diabetes who went through a baseline comprehensive evaluation of insulin sensitivity, body composition, and vascular health for three months. Children’s Hospital in Colorado	The current study confirmed that insulin resistance, which was measured by hyperinsulinemic euglycemic clamp, improves in adolescents with type 1 diabetes with the addition of Metformin as adjunctive therapy versus a placebo study.	The current study confirmed that insulin resistance which is measured by hyperinsulinemic euglycemic clamp improves in adolescents with type 1 diabetes with the addition of Metformin as adjunctive therapy when compared to placebo.
Burchardt et al. (2016)	Does the addition of Metformin have a positive effect on atherogenic lipid fractions in relation to lipoprotein-associated phospholipase and cholesteryl ester lipase, and improve the intima-media thickness of the common carotid artery in young type 1 diabetics with excess body fat? Independent variables: Age, sex, diagnosis of T1DM Dependent variables: Metformin dose, Insulin dose, FBS, atherogenic lipid fractions in relation to lipoprotein-associated phospholipase, cholesteryl ester lipase, intima-media thickness, BMI Objective: To determine if the addition of Metformin has a positive effect on the cardiovascular risk factors. Hypothesis: The addition of Metformin is able to reduce lipoprotein-associated phospholipase, and cholesteryl ester lipase as well as reduce the intima-media thickness of the common carotid artery in T1DM who are overweight.	Open-label randomized clinical trial The study included 84 patients (47 men, 37 women) at a mean age of 33.2 years. A total of 42 participants. A total of 42 patients were randomized to the arm receiving adjunctive Metformin at a dose of 1000 ± 500 mg/d (insulin-plus-metformin group). The control group comprised another 42 people randomly assigned to the insulin-only arm (control group, insulin group).	Young type 1 diabetics who were treated with metformin had a reduction in mean carotid intima-media thickness, which could be due to weight reduction, and there was a decrease in atherogenic glycated LDL levels. This was not seen in patients who were treated with insulin alone.	This is a credible study, which can be reproduced and repeated. The variables should remain the same, and it shows there is a benefit of having Metformin as an adjunctive therapy. One of the limitations of the study is that it does not include the potential for error.
Cree-Green et al. (2019)	Insulin resistance increases the risk for cardiovascular disease and mortality in adults. Will metformin decrease the risk of cardiovascular disease caused by insulin resistance? Independent Variables: Sex, Age, Diagnosis of T1DM, Metformin Dependent Variables: Insulin dose, BMI, tissue specific insulin resistance, HbA1c, FBS. Objective: To demonstrate if Metformin as an adjunctive therapy to insulin treatment improves insulin resistance and BMI of youth with type 1 diabetes. Insulin resistance increases the risk for cardiovascular disease and mortality in adults. Will Metformin decrease the risk of cardiovascular disease caused by insulin resistance? Hypothesis: Metformin will decrease the risk of cardiovascular disease caused by insulin resistance.	Multi-center Double-blind, placebo-controlled, randomized trial. participants ages 12–20 with an HbA1c of 7.5–9.9, a BMI being in the 85th percentile, total daily insulin dosage of 0.8 units/kg/day, and self-monitor blood glucose three or more times a day. Participants per site: University of Colorado Anschutz Medical Campus had a total of 11 participants; Yale University had 6 participate, Nemours Children’s Specialty Care included 3 participants; Indiana University included 5; University of Minnesota had 3; University of Iowa, 6; Children’s Hospital of Pittsburgh, 3. This yielded a total of 37 participants.	The change in insulin sensitivity favored metformin in regards to whole body insulin resistance and peripheral insulin resistance. Metformin did not impact insulin suppression of endogenous glucose release. Adipose insulin resistance was not assessable with traditional methods in this insulin resistant population. Metformin appears to improve whole body peripheral insulin resistance in youth who are overweight or considered obese.	A major limitation of this study is the small sample size, this does now allow for evaluation of effect on sex, ethnicity, or differing insulin regimens. Secondary study measures, such as change in GDR is close to being significant but suggests a possibility of type 2 error because the sample size is too small. The inclusion criteria was strict in terms of HbA1c, and weight which limits the population of type 1 diabetics to certain parameters.
Libman et al. (2015)	Will Metformin as an adjunct to insulin improve the glycemic control among overweight and obese adolescents with type 1 diabetes? Variables Independent: Sex, Age, Diagnosis of T1DM, Metformin Variables Dependent: BMI Daily insulin dose Body fat Weight gain HbA1c levels Objectives: To assess the efficacy and safety of metformin as an adjunct to insulin in treating overweight adolescents with type 1 diabetes. Hypothesis: Metformin improves glycemic control in overweight or obese adolescents with type 1 diabetes.	Quantitative study, 6 months, multi-center, placebo-controlled, randomized clinical trial. 140 adolescents aged 12 to 19 years with type 1 diabetes and BMI of 94th percentile along with HbA1c of 8.8%. Referred from 26 different pediatric endocrinology clinics.	Metformin did not help overweight adolescents with type 1 diabetes during the six months of treatment. It only increased a risk for gastrointestinal adverse events.	Participants experienced hypoglycemia after 6 weeks of starting metformin. They had their insulin dose adjusted during that time. There were no episodes of lactic acidosis, which is consistent with other reports of Metformin use in youth.
Nadeau et al. (2015)	Will a low dose of Metformin improve BMI and insulin sensitivity in adolescents with type 1 diabetes mellitus? Independent Variables Metformin Age Height Dependent: Variables BMI HbA1c Insulin dose Blood pressure Fasting lipids Waist circumference Objectives: To determine the effects of low dose Metformin in adolescents with type 1 diabetes mellitus. Hypothesis: Metformin will improve metabolic parameters in adolescent with type 1 diabetes mellitus.	Randomized, double -blinded, placebo-controlled trial. 74 pubertal adolescents, ages 13 to 20 years old with type 1 diabetes mellitus. Participants were recruited from the Barbara Davis Center for Childhood Diabetes and the Denver metro area	Low dose Metformin improves BMI and insulin sensitivity in adolescents with type 1 diabetes mellitus.	The results show a positive impact of Metformin in T1DM youth on insulin sensitivity, BMI and body composition. That promises more options in treatments of CVD and other complications. Metformin helped both, the overweight and normal weight groups, so future studies will need to assess the impact of Metformin on T1DM-associated complications.
Setoodeh et al. (2017)	Will Metformin reduce HbA1c and insulin as an adjunct therapy in adolescents with type 1 diabetes? Independent Variable: Metformin T1DM diagnosis Dependent Variables: BMI Weight HbA1c Triglyceride and cholesterol levels Insulin dose Objectives: To investigate the effect of Metformin as an adjunct therapy in adolescents with poorly controlled type 1 diabetes. Hypothesis Metformin as an adjunct therapy decreases insulin resistance in adolescent population by increasing sensitivity to the insulin.	Quasi-experimental (an uncontrolled before and after) study. 29 patients were analyzed from ages 10–17 with type 1 diabetes mellitus. Endocrinology clinic of children’s medical center of Tehran University of Medical Science in Iran.	Adjunct therapy reduced HbA1c level and insulin dose in adolescents with type 1 diabetes mellitus after 12 months of treatment.	Prior to this study, Metformin as adjunct therapy was tested on type 2 diabetes patients with successful outcomes. This study results show that type 1 diabetes patients can benefit from it as well. In a 12-month period, Metformin used in combination with insulin lowered insulin resistance in type 1 diabetes participants.
Zawada et al. (2015)	Does Metformin as a concomitant therapy have an effect on anthropometric parameters such as visceral adiposity, and body fat accumulation in patients with type 1 diabetes who are treated with insulin therapy? Independent Variable: Age, sex, Diagnosis of T1DM, Metformin Dependent Variable: Insulin dose, weight, body fat percentage, waist circumference, urine ketones. Objective The purpose of this study was to evaluate the effect of Metformin as a concomitant therapy on anthropometric parameters such as visceral adiposity, and body fat accumulation in patients with type 1 diabetes who were treated with insulin therapy. Hypothesis Metformin treatment might reduce fat accumulation and improve metabolic control as well as decrease the incidence of insulin resistance and insulin dosage. Weight gain and obesity are possible complications of insulin therapy. Failure to reduce insulin dose during remission may cause undesirable clinical and biochemical consequences. This can cause increased appetite, decreased insulin sensitivity and cause weight gain.	Pilot prospective study had a group of 45 patients enrolled (28 women, and 11 men) but only 39 people participated. The study group consisted of type 1 diabetics with increased body fat measured according to the WHO criteria, with age and gender considered. The body fat was assessed using electrical impedance. These patients were hospitalized in the Department of Internal Medicine and Diabetology, Poznań University of Medical Science, in 2010–2011. They were enrolled in a pilot group of Metformin Therapy in a Type 1 Diabetes Mellitus program which was registered as a clinical trial.	In the group of patients treated with Metformin, a significant improvement in lipid profile was observed. The Diabetes Treatment Satisfaction Questionnaire results after 6 months showed a significant increase in satisfaction with treatment. There was no significant change in incidence of acetonuria. There was a reduction in body fat and waist circumference. They were able to observe a reduction in daily insulin requirement, fasting, postprandial and mean daily glucose. The VAI reduced as well, showing an improvement in triglycerides and non-HDL.	The limitations in this study is that there were no control group. They didn’t-test the patients against those using insulin alone, and the patients using insulin and metformin adjunctively. While the results seem to be clinically significant, the size of the group was small and primarily female. This study can be duplicated using a broader demographic of patients. The article shows that adjunctive therapy with Metformin did have a positive impact on fat accumulation and metabolic control.
Ziaee et al. (2017)	Does the use of adjunctive Metformin to insulin, or a combination of Metformin and acarbose therapy provide metabolic control and decrease insulin requirements? Independent Variable: Age, sex, diagnosis of T1DM, Tanner stage, Metfomin, Acarbose. Dependent Variables: FBS, Post-Prandial Blood glucose, insulin dose, HbA1c, Cholesterol levels, triglycerides, LDL, HDL Objective: The aim of this study was to compare adjunctive therapy of Metformin and acarbose in patients with type 1 diabetes. Hypothesis The use of adjunctive Metformin to insulin therapy, or dual Metformin and acarbose therapy will provide metabolic control and decrease insulin requirements.	A single-center, placebo-controlled study, participants were referred from their endocrinologist’s office. The participants met the age criteria of: 15–25 years, puberty stage of 2–5 Tanner, at least three-year history of diabetes, HbA1C 7–11 (within the recent six months). 40 participants, all of them remained in the program.	The results of this experiment, show that the addition of acarbose to Metformin type 1 diabetics who are primarily controlled with insulin is well tolerated and improves metabolic control. The use of the dual therapy had shown a decrease in fasting blood glucose and HbA1C, which had a remarkable effect on 2-h post prandial levels, triglycerides, cholesterol level, LDL and regular insulin use.	The results of the study favored the use of Metformin and acarbose as adjunctive therapy. The results also showed a clinical difference in the metabolic parameters. To enhance his study the sample size should be larger, and the age group of participants should be broadened. The study has placebo-control groups, but it did not publish before and after results for comparison.