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Metformin ineffective for long-term metabolic improvements in teen obesity
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Adolescents with obesity assigned to long-term metformin therapy experienced initial improvements in BMI and insulin resistance that were not sustained after 3 years, according to findings published in Nutrition & Diabetes.
Metformin, approved for the treatment of type 2 diabetes in children aged at least 10 years, has been the focus of multiple trials as an additional therapy in the treatment of pediatric obesity, Yvette E. Lentferink, MSc, of the department of pediatrics at St. Antonius Hospital in Nieuwegein, the Netherlands, and colleagues wrote in the study background. The drug has been associated with small but significant reductions in weight and is generally well-tolerated, they noted.
“Studies on the efficacy of metformin in adolescents are ... predominantly limited to a follow-up period of 6 months,” the researchers wrote. “Only a few studies have been performed with a longer follow-up period with a maximum up to 24 months. Consequently, it is unclear whether prolonged metformin treatment in adolescents will result in long-lasting positive effects on weight.”
Lentferink and colleagues analyzed data from 31 adolescents participating in an open-label extension study that followed an 18-month, double-blind, randomized controlled trial evaluating the effects of long-term metformin therapy conducted at St. Antonius Hospital and Jeroen Bosch Hospital in the Netherlands (84% with obesity; 45% with insulin resistance). After completing the randomized controlled trial, all participants with a BMI standard deviation score (SDS) greater than 2.3 and homeostatic model assessment of insulin resistance of at least 3.4 (n = 22) were offered continued metformin therapy, of which 11 agreed to proceed with treatment and completed the open-label phase (five assigned to metformin during the original trial; six assigned to placebo). Researchers also analyzed data from 20 adolescents who were not eligible for metformin treatment during the open-label phase, including 18 who were assigned metformin during the randomized controlled trial and 11 who were assigned to placebo. Mean age of all participants was 15 years; mean BMI was 31.2 kg/m² and mean HOMA-IR was 3.4.
Study endpoints were change in BMI and change in HOMA-IR. Researchers also evaluated safety and tolerability, as well as change in HbA1c, body fat percentage, quality of life and physical fitness.
Researchers found that adolescents who were assigned metformin during the randomized controlled trial and continued therapy during the extension phase experienced an increase in BMI (mean increase, 2.2%) and in HOMA-IR (mean increase, 13.7%). In participants assigned to placebo during the randomized controlled trial who opted for metformin therapy during the extension, researchers observed a stabilization in BMI after an initial decrease (mean increase, 0.5%), as well as a decrease in HOMA-IR (mean decrease, 1.1%).
“Our results suggest that the BMI continues to increase despite prolonged metformin treatment,” the researchers wrote. “This finding is in contrast with the long-term effects of metformin in non-diabetic adults, in which metformin treatment resulted in significantly more weight loss in comparison with placebo after 2.8 years and even after 10 years.”
Metformin was generally well-tolerated, with two participants reporting nausea and four reporting diarrhea. Two participants discontinued the study due to gastrointestinal adverse effects.
At the end of the study, one participant developed type 2 diabetes, three developed impaired fasting glucose and four developed impaired glucose tolerance. Within the cohort, 23% had high triglyceride levels, 36% had low HDL levels, two participants developed high blood pressure and one participant developed microalbuminuria by the conclusion of the study, according to researchers.
The researchers also noted that some participants reported not taking their metformin tablets daily, implying undertreatment, and that the recommended dosage for adolescents is 2,000 mg per day, whereas the maximum recommended dose for adults is 3,000 mg per day.
“While metformin treatment in metformin-naive participants seems to result in an initial decrease in BMI and HOMA-IR, there is no evidence for sustained effect after prolonged use in adolescents,” the researchers wrote. “Limited compliance and/or insufficient dose may explain the differences in long-term effects between adolescents and adults.” – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.
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