News Author: Laurie Barclay, MD
March 1, 2010 — Metformin hydrochloride extended release (XR) with lifestyle intervention may be helpful for the treatment of adolescent obesity, according to the results of a multicenter, randomized controlled trial reported in the February issue of the Archives of Pediatrics & Adolescent Medicine.
"Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported," write Darrell M. Wilson, MD, from Lucile Salter Packard Children's Hospital, Stanford University School of Medicine in Stanford, California, and colleagues from the Glaser Pediatric Research Network Obesity Study Group. "Therefore, we conducted a 48-week randomized, double-blind, placebo-controlled trial of...XR metformin therapy in nondiabetic obese adolescents, followed by a 48-week monitoring period after completion of treatment."
Metformin’s Small, but Significant, Effect on BMI
The goal of the study was to test the hypothesis that 48 weeks of daily metformin XR treatment would reduce body mass index (BMI) in obese adolescents vs placebo.
From October 2003 to August 2007 at the 6 centers of the Glaser Pediatric Research Network, 78 obese adolescents following a lifestyle intervention program underwent a 1-month run-in period and were then randomly assigned 1:1 to receive 48 weeks of treatment with metformin hydrochloride XR, 2000 mg once daily or an identical placebo. At baseline, BMI was at least in the 95th percentile, and age range was 13 to 18 years. The main study endpoint was change in BMI, after adjustment for site, sex, race, ethnicity, and age, and group assignment.
Mean adjusted BMI increased by 0.2 ± 0.5 in the placebo group and decreased by 0.9 ± 0.5 in the metformin XR group (P = .03) after 48 weeks of treatment, and this difference persisted for 12 to 24 weeks after cessation of treatment. There were no significant effects of metformin on body composition, abdominal fat, or insulin indices.
On the basis of these findings, the investigators concluded that metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program and was safe and well tolerated.
Independent Commentator Responds to Findings
"The relevance of a small amount of weight reduction without clear evidence of metabolic benefit is uncertain," Kathleen M. Hoeger, MD, MPH, associate professor of obstetrics and gynecology and director of the Reproductive Endocrine Division, University of Rochester Medical Center in New York, told Medscape Pediatrics when asked for independent comment.
"There did not appear to be an interactive effect of the lifestyle program, which did not appear effective," said Dr. Hoeger, who has recently published the effect of metformin on polycystic ovary syndrome in obese adolescent women (J Clin Endocrinol Metab. 2008;93:4299-4306. Epub 2008 Aug 26). "On the positive side, there did not appear to be significant side effects to use of relatively high doses of metformin (2000 mg daily) in this population."
Study Strengths and Limitations
When asked about strengths and limitations of this study, Dr. Hoeger noted that it had "a robust protocol with appropriate randomization and placebo control that is lacking from many studies involving metformin in adolescents.
The study is limited by the relatively high dropout rate of 50%, which is common in lifestyle modification long-term studies; however, the authors attempted to assess this impact with projection of last weight forward, which did not change the study conclusions. Nonetheless, the number of subjects completing the trial was smaller than anticipated in the power calculations, which assumed only a 20% attrition rate, reducing the power of the study."
The study authors acknowledge that the study was not specifically powered to evaluate the effect of metformin on insulin and lipid indices. Dr. Hoeger also pointed out that this study had a mixed population that did not account for the possible effect of pubertal stage, or possible polycystic ovary syndrome in the female subjects, both of which may affect insulin resistance, and could potentially affect response to metformin. However, controlling for age and insulin measures did not affect the findings.
"Finally, the study did find significant reduction in BMI in the metformin group during treatment, but this was overall <3% of BMI and disappeared after discontinuation of the metformin," Dr. Hoeger said. "The program for lifestyle intervention did not appear to be very effective in the initial assessment. However, the placebo group did continue to have modest weight reduction in the long-term assessment at 100 weeks, whereas the metformin group regained a significant amount of weight lost."
The investigators note that although metformin may have an important role in the treatment of adolescent obesity, longer-term studies will be needed to clarify the effects of metformin treatment on obesity-related disease risk in these patients.
"It would be helpful to have a larger trial with a more effective lifestyle intervention program that may allow for more careful study of subgroups, which may be more likely to have an impact from metformin intervention," Dr. Hoeger concluded.
"Clearly, that is challenging in this age group, as few studies have been able to demonstrate long-term management of weight with lifestyle interventions alone. Additional weight loss medications may be more appropriate management if lifestyle modifications fail; however, careful study must be done in these age groups to assess not just weight loss but significant overall health improvement."
Bristol-Myers Squibb provided active drug (GlucophageXR) and placebos. The Glaser Pediatric Research Network is funded by the Elizabeth Glaser Pediatric Research Foundation, a program of the Elizabeth Glaser Pediatric AIDS Foundation. The study was supported by the Elizabeth Glaser Pediatric Research Foundation and the National Institutes of Health–supported Clinical Research Centers.
Dr. Hoeger has disclosed no financial relationships.
Arch Pediatr Adolesc Med. 2010;164:116-123.
source : http://cme.medscape.com/viewarticle/717702?src=cmemp&uac=97984HK
regards, taniafdi ^_^
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