Ergocalciferol in New-onset Type 1 diabetes: A Randomized Controlled Trial

Background: The impact of the anti-inflammatory and immunomodulatory actions of Vitamin D on the duration of partial clinical remission (PR) in youth with type 1 diabetes (T1D) is unclear. Objective: To determine the effect of adjunctive ergocalciferol on residual β-cell function (RBCF) and PR in youth with newly-diagnosed T1D who were maintained on a standardized insulin treatment protocol. Hypothesis: Ergocalciferol supplementation increases RBCF and prolongs PR. Methods: A 12-month randomized, double-blind, placebo-controlled trial of 50,000 IU of ergocalciferol per week for 2 months, and then once every 2 weeks for 10 months, versus placebo in 36 subjects of ages 10-21years(y), with T1D ofmonths, and a stimulated C-peptide (SCP) level of ≥0.2nmol/L (≥0.6ng/mL). The ergocalciferol group had 18 randomized subjects (10m/ 8f), mean age 13.3±2.8y; while the control group had 18 subjects (14m/4f), age 14.3±2.9y. Results: The ergocalciferol treatment group had significantly higher serum 25-hydroxyvitamin D at 6 months (p=0.01) and 9 months (p=0.02) than the placebo group. At 12 months, the ergocalciferol group had a significantly lower serum TNF-α concentration (p=0.03). There were no significant differences between the groups at each timepoint from baseline to 12 months for SCP concentration (p=0.08), HbA1c (p=0.09), insulin-dose-adjusted A1c (IDAA1c), or total daily dose of insulin. Temporal trends for rising HbA1c (p=0.044) and IDAA1c (p=0.015) were significantly blunted in the ergocalciferol group. Conclusions: Ergocalciferol significantly reduced serum TNF-α concentration and the rates of increase in both A1c and IDAA1c suggesting a protection of RBCF and PR in youth with newly-diagnosed T1D

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

Insulin 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.To 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.Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.A 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.Over 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.This 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.ClinicalTrial.gov NCT01334125

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

Manuscript abstract: CONTEXT: Insulin 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. OBJECTIVE: To 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. HYPOTHESIS: Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D. DESIGN, SETTING, AND PARTICIPANTS: A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c \u3e8% (64 mmol/mol), BMI \u3e85%, and T1D \u3e 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. RESULTS: Over 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. CONCLUSIONS: This 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

Data from: The Cardiovascular Effects of Adjunctive Metformin Therapy in Overweight/obese Youth with Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial

This dataset is the primary data source for a manuscript submitted for publication. Manuscript abstract: Context: The cardiovascular effect of adjunctive metformin therapy in overweight/obese youth with type 1 diabetes (T1D) is unknown. Objective: To compare the effect of prolonged, adjunctive metformin vs. placebo therapy on markers of cardiovascular risk in overweight/obese youth with T1D based on differences in total cholesterol (TC)/ high-density lipoprotein (HDL) ratio, triglycerides (TG)/HDL ratio, Atherogenic Index of Plasma (AIP) log [TG/HDL] ratio, adiponectin/leptin ratio, and 25-hydroxyvitamin D [25(OH)D] concentration. Hypothesis: Adjunctive metformin therapy will improve markers of cardiovascular health in overweight/obese youth with T1D. Setting: University outpatient facility. Design and Participants: A 9-mo randomized, double-blind, placebo-controlled trial of metformin (1000 mg daily) and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c \u3e8%, BMI \u3e85%, and T1D \u3e 12 months. The metformin group consisted of 15 subjects (8 m/7f), of age 15.0±2.5 y; while the control group consisted of 13 subjects (5m/8f), of age 14.5±3.1y. Participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose between 90-120 mg/dL. Results: After adjusting for age, gender, BMI, and baseline values, the metformin group had a clinically significant reduction in TC/HDL of 0.5 unit: 3.5[3.0-4.1] vs. 4.0 [3.3-4.4] (p=0.578); and TG/HDL of 1.0 unit, 2.6 [1.1-4.3] vs. 3.6 [2.0-5.2] (p=0.476); and AIP of 0.44 unit: -0.23 ± 0.9 vs. 0.21 ± 0.8 (p=0.251). Conversely, the metformin group had a clinically significant elevation in adiponectin/leptin ratio of 0.8 unit: 2.0[0.84-3.2] vs. 1.2[0.11-2.3], (p=0.057); and a mean serum 25(OH)D in the vitamin D sufficiency range, 31.3 ng/mL [22.3-40.4] compared to the placebo group\u27s lower mean 25(OH)D of 25.8 ng/mL [14.1-35.9], (p=0.337). Conclusions: Prolonged adjunctive metformin therapy may be cardio-protective in overweight/obese youth with T1D

Summary of Daily Plasma Glucose Goals.

<p>Summary of Daily Plasma Glucose Goals.</p

CONSORT Flow Diagram.

<p>CONSORT Flow Diagram.</p

Anthropometric and Biochemical Characteristics of the Subjects and Controls at Baseline/Randomization.

<p>Table 3 shows the group-specific comparisons of anthropometric and biochemical parameters at baseline using paired <i>t</i> tests or its non-parametric equivalent where indicated. Subject characteristics were summarized using means ± standard deviations (SD). Independent proportions (e.g., race, gender) were compared using Fisher’s exact test*. SDS standard deviation score; WC waist circumference; TDD total daily dose; HbA1c hemoglobin A1c. All participants received long-acting insulin detemir and short-acting insulin aspart. Significant <i>p</i> values are bolded.</p

Comparison of changes in hemoglobin A1c values between the placebo and metformin groups during the trial.

<p>Comparison of changes in hemoglobin A1c values between the placebo and metformin groups during the trial.</p

Estimated marginal means for changes in outcome parameters A, B, C, D.

<p>A. Hemoglobin A1c: Over the course of our 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). B. Fasting plasma glucose (FPG): For the duration of the interventional phase of the study, the 18.9 mg/dL difference in FPG between the groups was not significant (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). C. Total daily dose (TDD) of long-acting insulin: the 0.25 unit/ kg TDD decrease of long-acting insulin per kg body weight per day (1.15 units/kg [0.89 to 1.41] for placebo versus 0.90 units/kg [0.64 to 1.16] for metformin) was not significant (p = 0.221). D. Total daily dose of short-acting insulin: the 0.01 unit/kg/day for the TDD of short-acting insulin per kg body weight/day did not vary between the groups (p = 0.936). The difference between the time points was marginally significant (p = 0.090), as well as the interaction between time and groups (p = 0.079).</p

Titration Algorithm for Long-acting Insulin Analog–Detemir.

<p>Titration Algorithm for Long-acting Insulin Analog–Detemir.</p