1. 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.

2. 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.

3. 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 ( cal/d)
Physical activity ( 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).

4. 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

7. 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 )
M+R: 38.6% (95% CI, )
M+L: 46.6% (95% CI, )
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).

8. 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%).

9. 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

10. 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).

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

12. 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.