Diabetes and Obesity Journal Club Carina Signori, D.O., M.P.H. “Treatment Options for Type 2 Diabetes in Adolescents and Youth” study Diabetes and Obesity Journal Club Carina Signori, D.O., M.P.H.

Introduction Childhood obesity and type 2 diabetes are increasing in children. TODAY study Multicenter, randomized clinical trial Funded by National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) Compared metformin monotherapy (M-alone) vs Metformin + rosiglitazone (M+R) and Metformin with intensive lifestyle intervention program (M+L). In children ages 10-17yo with type 2 DM. Hypothesis Combination therapy started early in the course of youth-onset type 2 DM would maintain acceptable glycemic control better than metformin alone.

Methods Randomized in 1:1:1 ratio Metformin Alone: 1000mg BID Metformin + Rosiglitazone 4mg BID Metformin + lifestyle intervention Goal was sustained moderate weight loss (7-10% initial body weight). Diet (1200-1500 cal/d) Physical activity (200-300 minutes/week moderate vigorous intensity activity) Family intervention to help support participant. Met with participant initially weekly, then twice weekly then monthly. Primary Objective: Compare treatment groups with regard to the time to treatment failure = Persistently elevated A1c (≥ 8%) over 6 months or Persistent metabolic decompensation (inability to wean off insulin within 3 months after its initiation or a 2nd episode of decompensation within 3 months after stopping insulin).

Run in phase: - Lasted 2-6 months - Period of weaning off nonstudy DM meds and starting and titrating up metformin 76.5% of participants 75.4% of participants Randomization Final participants 57.7% of participants

Primary Outcome 319/699 (45.6%) reached primary outcome with median time to treatment failure =11.5 months. Overall rates of failure: M-Alone: 51.7% (95% CI 45.3-58.2) M+R: 38.6% (95% CI, 32.4-44.9) M+L: 46.6% (95% CI, 40.2-53.0) M+R led to 25.3% decrease in occurence of primary outcome compared to M-Alone (P=0.006). M+L was intermediate (but significantly different from M-Alone or M + R).

Weight Loss and BMI BMI over time (up to 60 months) differed in overall comparison and between groups (P<0.001). M + R: largest increase in BMI. M + L: least increase in BMI However, BMI not determinant of tx failure (at BL or over time). Change in percent overweight at 6 months: M-Alone -1.42% M+R: +0.81% M+L: -3.64% Change in percent overweight at 24 months: M-Alone -4.42% M+R: +0.89% M+L: -5.02% A reduction by 7% is considered meaningful: There were a greater proprotion of patients at 6 months that had this in M+ L (31.2%) vs M+R (16.7%, P<0.001) but did not differ in the M-Alone group (24.3%).

Subgroup Analyses In Girls: In Boys: M-Alone = M+R = M+L M+R was more effective than boys (P=0.03). M+R > M-Alone (P=0.002) M+R > M+L (P=0.006) In Boys: M-Alone = M+R = M+L

Subgroup Analyses Race or ethnic group alone had a significant effect on outcome (P=0.006). M-Alone was less effective in non-Hispanic Blacks then non-Hispanic whites (P=0.01) or Hispanics (P<0.001). Adherence did not differ based on sex, race/ethnic group, age, baseline BMI or baseline A1c. Decreased with time (from 84% at time study (month 8) completed to 57% at month 60).

Serious adverse events were reported by 19.2% of participants 18.1% 14.6% 24.8%

Conclusions In this study, metformin alone resulted in durable glycemic control in only half the participants. M+R improved durability of glycemic control. Despite an increase in BMI and fat mass The addition of lifestyle intervention was not better than M+R. Sex and race may affect success of treatment. There was no increase in adverse events in M+R compared to the other 2 groups.