Abstract

METHODS

Adolescents ages 12–19 years were recruited through posted advertisements or through contact with primary care providers. Interested participants were invited to a screening visit at which time a family history, physical exam, and fasting laboratory evaluation were obtained. Participants who had fasting insulin level >25 microunits/ml or HOMA (Homeostasis model assessment: fasting insulin in microunits/ml × fasting glucose in millimoles/liter/22.5) > 3.5 and 2 out of 3 risk factors (presence of acanthosis nigricans, obesity (BMI >95% for age), or family history of T2DM) were invited to participate in the study. Exclusion criteria included pre-existing diabetes, pregnancy, heart disease, serum gamma-glutamyl transferase (GGT) over 1.5 times the upper limit of normal, or creatinine > 1.5 mg/dl.

We utilized a randomized, placebo controlled double blind design. The protocol was approved by the Colorado Multiple Institutional Review Board (COMIRB). Eligible subjects were invited to the Pediatric (Clinical Translational Research Center CTRC) at the Children’s Hospital in Denver, CO after an overnight fast of at least 10 hours. At this first visit, samples were drawn for insulin, glucose, lipid panel [cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and triglycerides], creatinine, and GGT or (in the last 50 subjects) aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Female subjects not practicing adequate contraception had a urine pregnancy test. Age, race, BMI, blood pressure (BP), sexual history, alcohol consumption, exercise history, and family history of diabetes were recorded. Subjects then underwent a 2-hour oral glucose tolerance test with a 75 gram glucose load.

Subjects completed a food frequency questionnaire and received written information about symptoms of diabetes from a study physician. They watched a video that emphasized modest calorie reduction, decreased fat and simple sugar consumption, increased fiber, fruit and vegetable intake, and regular aerobic exercise. Subjects then worked with a dietician or study investigator to choose 3 goals for themselves, related to dietary or exercise changes. They were assisted in choosing very specific goals that were attainable in a 1-month period, for example decreasing soda intake from 3 daily to 1 daily. All subjects were encouraged to choose at least one goal related to exercise. They were given a calendar and instructed to record progress on their goals and record if they took the medication.

Upon completion of the baseline visit, subjects were randomized 2:1 by the CTRC pharmacist to receive metformin or placebo. Randomization was stratified by race (AA or other) and fasting insulin level (greater than or less than 40 IU/ml). Subjects were started on metformin or placebo 500 mg once daily. At one month, the dose increased to 500 mg twice daily, followed by an increase to 850 mg twice daily at 2 months. If gastrointestinal side effects persisted for more than 2 weeks, the dose was lowered to the previously tolerated dose.

Subjects were seen monthly for measurement of weight and BP, urine pregnancy test if indicated, assessment of adherence to goals, contraception, alcohol consumption, and adherence with and tolerability of treatment. The research assistant met subjects at a convenient location chosen by the subject; the only requirement being the presence of a scale. The majority of follow-up visits were conducted at schools. A pill count was to be completed at each visit; however, most pill counts were estimated by subjects, as they were unable to carry medications at school. In this population of largely indigent patients followed at school-based health centers subjects were considered adherent if 4 or more medication bottles were dispensed over the 6^th month study. With this cut-off, subjects should have taken the maximum dose of metformin for at least 2 months. Subjects were allowed to modify their personal goals at each visit. The research assistant was trained by the study dietician to assess whether subjects had been adherent with their goals and to encourage change to more or less difficult goals if necessary.

At 6 months, the subjects returned to the Pediatric CTRC after a 10 hour fast. Outcome measures obtained included fasting insulin, fasting and 2-hour glucose, lipid panel, BMI, and BP. Subjects again completed a food frequency questionnaire. Subjects were also interviewed regarding lifestyle changes they had made during the 6-month study period. The interview was conducted in a motivational style to promote continued healthy lifestyle changes by an interviewer unaware of group assignment. Responses per subject could be multiple. Subject responses were grouped into categories based on similar themes.

All laboratory assays, except serum insulin, were performed by standard clinical laboratory procedure at the Children’s Hospital in Denver. Insulin assay was performed by microparticle enzyme immunoassay (Diagnostic Systems Lab) at the Core Laboratory of the General Clinical Research Center at the University of Colorado at Denver and Health Sciences Center. The sensitivity of the assay is 3 microunits/ml . Within day precision is 5.2 microunits/ml; between-day precision is 9.8 microunits/ml.

T-tests and stepwise logistic regression analysis were performed to analyze the relationship between selected variables (sex, medication group, and specific goal type including increase in exercise, decrease in portion size, increase in positive dietary choices, and decrease in negative dietary choices) to a decrease in BMI of >5% or more. All statistical analyses were performed using SPSS/PC (version 14; 2006_[H1]).

RESULTS

85 subjects were enrolled (Table I). The mean age was 15.7 years (range 12–19 years) and mean BMI 39.7 kg/m2 (range 28–55). 71% of the subjects were female. 58% Hispanic, 34% AA. 80% of metformin subjects and 64% of placebo subjects completed the 6-month visit (NS). 50% of metformin and 48% of placebo subjects completed at least 5 of 7 possible visits. There were no differences in sex, BMI, or change in weight at last visit between participants in the metformin and placebo groups dropping out of the study before the 6-month visit.

DISCUSSION

As a group, subjects taking metformin did not lose more weight than those taking placebo, indicating that metformin is not, by itself, a robust promoter of weight loss. Indeed, some subjects with good adherence to metformin, particularly among the boys, gained weight, indicating that metformin alone does not necessarily lead to weight loss. However, in these obese, predominately minority adolescents with insulin-resistance, all subjects who lost a clinically significant amount of weight were taking metformin. 36% of subjects with excellent metformin adherence and 23% of those with good metformin adherence were able to attain a BMI loss of 5% or more, compared with no subjects on placebo. Among subjects reporting decreased portion size, those taking metformin were more likely to lose weight: 70% of metformin adherent subjects compared with only 20% of placebo adherent subjects. Weight loss also correlated linearly with metformin adherence; subjects with excellent adherence with metformin were most likely to decrease BMI by 5%, followed by those with moderate adherence, those with less than desirable adherence, followed by subjects on placebo with good adherence, with non-adherent placebo subjects gaining the most weight.

There were sex differences in response to metformin. Girls taking metformin had a significant decrease in BMI compared with placebo, although this was not seen among the male participants. Furthermore, girls were twice as likely as boys to decrease their BMI by 5%, and were less likely to gain weight than boys. The reasons for the sex difference in response to metformin are not clear. This may represent true sex differences in the action of metformin or underlying differences in mechanism or degree of insulin resistance. Alternatively, girls were more likely to report a decrease in portion size than boys, whether they were taking metformin or placebo. Given the apparent interaction between portion size change and weight loss with metformin on the one hand and the interaction between sex and decreased portion size on the other, the difference in reported lifestyle changes may account for the higher frequency of successful weight loss in girls. However, the relatively small number of boys in the study may obscure the results because boys did show a trend towards improved weight with medication, although less impressive than in girls.

Previous attempts at lifestyle modification in the research setting have been very intensive (usually 2–4 times a month) and costly [11], and would be difficult to replicate in a practice setting. The type of lifestyle modification program used here- personal goal setting- can be replicated in primary care. In this study, subjects almost universally felt that goal setting was helpful to them, regardless of outcome. Subjects who were able to decrease their BMI by 5% (all on metformin) reported having decreased portion size and showed a trend towards decreased negative dietary choices such as soda, junk food, or fast food. A larger sample size might have demonstrated a decrease in negative food choices to be statistically significant.

There are a number of limitations to this study. Subjects that dropped out of the study after the first off-site visit had almost universally gained weight, whether they were on metformin or placebo. If placebo subjects were more likely to drop out because of failure to lose weight in the program, the difference in weight loss between the two groups may have been greater. However, the distribution of drop-outs between the metformin and placebo groups does not indicate that the weight loss seen in the two groups would have been substantially altered. In subjects that did not complete the 6-month visit but had at least one off-site visit, most subjects had gained weight, implying that lack of success with weight loss may have led to early discontinuation of the study in a significant subset of subjects. This effect was seen both in subjects on placebo and on metformin. The rate of dropouts does suggest that many adolescents will not continue with a program that does not show rapid results. The drop-out rate was higher (although not statistically significant) in placebo subjects, which led to lower numbers of placebo subjects in the final analysis. However, there were more placebo than metformin subjects that completed multiple off-site visits but did not complete the 6-month visit, indicating that the overall participation in the study between the groups was similar.

The weights at intermediate visits were not analyzed because off-site weights were not on calibrated scales and heights were not obtained at these intermediate visits. There were subjects that had not taken metformin for several months prior to the 6-month visit. Some subjects may have lost more weight at an intermediate point in the study. Using only the 6-month measurements may have underestimated maximum weight loss in some subjects.

The dose of metformin was escalated slowly, with the maximum dose of medication not reached until the 3^rd visit (2 months after initiation of the study). If subjects receiving metformin who dropped out early had received higher doses of metformin sooner, they may have been less likely to drop out. Furthermore, because initial weight loss is likely to reinforce positive lifestyle change, more rapid escalation of dose and/or higher maximum dose might have resulted in larger difference in weight loss between the metformin and placebo groups.

The relatively small number of subjects may have influenced the lack of observed benefit in laboratory values. Furthermore, the study group was composed of mostly Hispanic and African- American adolescents with elevated fasting insulin levels and severe obesity. The outcomes may be different in patients of other racial and ethnic background with varying degrees of insulin resistance or obesity. For example, a previous study has shown that metformin is more effective in Caucasian than African- American subjects, [12] and our population had few Caucasian subjects. Therefore, the effects of metformin efficacy should be studied in larger groups of ethnically diverse adolescents.

Finally, this study examined the use of metformin for only 6 months. Given that the efficacy of many weight loss interventions wanes with time, future research should address whether beneficial effects of metformin persist over a longer period of time, as well as whether any of these effects persist after medication is discontinued.

These results indicate that metformin was beneficial as a weight loss medication in a subset of obese adolescents with insulin resistance. Conversely, personal goal setting alone did not show evidence of substantial benefit, as even subjects with excellent adherence to placebo and personal goal setting sessions were unable to attain significant weight loss. Girls taking metformin had a significant decrease in BMI compared with those taking placebo and were much less likely to gain weight than boys; they were also much more likely to report decrease in portion size. Increasing metformin adherence was associated with a higher likelihood of significant BMI decrease.

ACKNOWLEDGMENTS

Footnotes

Contributor Information

Kathy Love-Osborne, Division of Adolescent Medicine, Department of Pediatrics, University of Colorado at Denver and Health Sciences Center, Denver CO. Eastside Teen Clinic, Denver Health and Hospitals, 501 28^th St. Denver, CO 80205, Office: (303) 436-4688. Fax: (303) 436-4665., Email: [email protected].

Jeanelle Sheeder, University of Colorado at Denver and Health Sciences Center, Denver CO.

Phil Zeitler, Division of Endocrinology, Department of Pediatrics and Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Denver CO.

REFERENCES