A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes

Abstract

ContextInsulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.ObjectiveTo compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.HypothesisAdjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.Design, Setting, and ParticipantsA 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.ResultsOver the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.ConclusionsThis 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.Trial RegistrationClinicalTrial.gov NCT01334125

The Effect of Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes

“…The proposed mechanism is elevated levels of growth hormone (anti-insulin hormones) and sex steroids, during the period of active pubertal maturation [15].…”

“…Various studies of adjunctive metformin therapy in children and adult have reported different results for HbA1c values [7,10,[15][16][17][18][19][20][21][22][23][24]. -1]: Comparing the level of outcome variables before and after the addition of metformin tablet to patient's insulin therapy.…”

“…We used before and after study design because there are many confounding factors such as socioeconomic status, lifestyle, diet, education, patient compliance in the control of diabetes and in our cases parental education and parental involvement in diabetes management [15]. Although, the necessary training about lifestyle was given to patients and parents, but intake of calories and physical activity level was not monitored and analysed.…”

“…Some studies have investigated the effect of the addition of metformin to insulin on glycaemic control in patients with T1DM but their reports were different [15][16][17][18][19][20][21][22][23][24]. More studies are recommended to be conducted in order to confirm the metformin effect [6].…”

Metformin: od mehanizmov delovanja do napredne klinične uporabe

“…Dodatek metfomina insulinu je povezan z zmanjšanjem porabe insulina tudi pri bolnikih s sladkorno boleznijo tipa 1, rezultati o pogostosti pojavnosti hipoglikemij ob kombiniranem zdravljenju pa so različni (44,45). Glede na podatke metaanalize Vella in sodelavcev se dnevna poraba insulina ob kombiniranem zdravljenju z metforminom zmanjša za 5,7-10,1 enote/dan, ob tem se HbA1c zniža za 0,6-0,9 %, telesna teža za 1,7-6,0 kg ter raven celokupnega holesterola za 0,3-0,41 mmol/l.…”