Supervised by: Amanda Liu, BEng, MSc. Amanda spent her undergraduate years studying Biochemical Engineering at UCL (University College London), where she was awarded First Class Honours. She then completed her Master’s degree in Clinical and Therapeutic Neuroscience at the University of Oxford. She is currently studying Medicine (Graduate Entry) at the University of Cambridge.
Diabetes impairs the body’s ability to process glucose and utilize insulin. This occurs when either the pancreas does not produce enough insulin or when cells resist insulin when the pancreas makes it. There are three types of diabetes: Type 1, Type 2, and Gestational. Type 2 diabetes is experienced by 95% of people with diabetes. Pediatric cases of this chronic disease have spiked in recent years, raising the question of which treatment is the ideal option for these patients. One of the most well-known studies to explore this phenomenon was done by the TODAY study group in 2021. A portion of type two diabetics in the United States were chosen and prescribed metformin-based medications. These patients were followed up with fifteen years later and participated in assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease. Other studies include those conducted by the New England Journal of Medicine on the long-term complication of childhood diabetes; and an article published by Pfizer hypothesizing the future of diabetes. These studies focus on the pediatric prescription of metformin—often coupled with lifestyle changes or other medication—as metformin is one of the only medications permitted for use in pediatric cases. These studies demonstrate the efficacy of metformin and highlight the current obstacles in prescription treatment for pediatric diabetes—such as the lack of approved medicines and existing studies looking into long-term efficacy.
Diabetes is a chronic disease that affects the processing of glucose for fuel. This lack of effective processing is caused by either the pancreas not making enough insulin or cells becoming resistant to the insulin being produced and not allowing the sugar into them. Type two diabetes used to be called “Adult-Onset Diabetes”; however, there has been a severe increase in pediatric cases due to the rise of childhood obesity. Pediatric cases of type two diabetes are still lower than the number of type one cases, but that may not hold true in the future (Tamborlane). Between 2002-2015, the number of people aged under 20 diagnosed with type two diabetes in the United States increased by 4.8% yearly (Centers for Disease Control and Prevention, 2020).
Adult type two diabetes and pediatric type two diabetes are similar in how the condition occurs and progresses (Tamborlane). The main differences are that in pediatric cases, there are fewer medication options approved by the Food and Drug Administration (FDA) and that glucose tolerance also decreases faster in children and adolescents. These factors result in prediabetic children developing type two diabetes more rapidly than adults in the same condition (Tamborlane). Type two diabetes can be diagnosed due to symptoms such as increased thirst, frequent urination, increased hunger, fatigue, blurry vision, darkened areas of skin—specifically around the neck, armpits, and groin—and frequent infections. Most often, type two diabetes is diagnosed by measuring a patient’s glycated hemoglobin A1C (blood sugar). A normal amount would be less than 5.7%; between 5.7% and 6.4% is considered prediabetic, and over 6.5% is considered diabetic (Mayo Clinic Staff, 2021). There are other ways to diagnose the disease, such as random blood sugar tests, fasting blood sugar tests, or an oral glucose test, but testing for levels of glycated hemoglobin A1C is the most common. It is recommended that people over the age of 45, who are overweight or obese, women who have previously had gestational diabetes, and people with a family history of the disease get routinely screened for diabetes to avoid more than any necessary complications (Mayo Clinic Staff, 2021).
The most common treatment for children with type two diabetes is Metformin. Metformin is a drug used to reduce the amount of sugar a child’s liver releases into the bloodstream, helps cells use insulin more effectively, and lowers glucose in the liver (Mayo Clinic Staff, 2022). Metformin is one of the only medications approved for pediatric use—the other option being insulin. Metformin has been approved by the Food and Drug Administration (FDA) for use in children above ten (Tamborlane). That being said, the drug is still used with caution in patients under twelve. Unfortunately, the use of metformin can come with side effects, including nausea, abdominal pain, bloating, and diarrhea. These symptoms can also be very prominent in the case of a Vitamin B12 deficiency in the patient. All side-effects caused by medication prescribed for diabetes arrive alongside any pre-existing complications the patient may experience, including immunocompromisation, increased risk of respiratory infection, chronic kidney disease and nerve damage.
The results found have been derived from multiple studies conducted by other groups. One major study conducted by the TODAY study group, observed the efficacy of different treatments on newly diagnosed pediatric patients (Narasimhan & Weinstock, 2014). This same study included a follow-up with the patients 15 years later to observe any long-term complications that may have arisen (TODAY study group, 2021). Other studies pertaining to the use of metformin—specifically concerning pediatric type two diabetes—by other groups, such as the New England Journal of Medicine, and independent groups are also covered.
Relevant studies generally observe three different metformin-based treatment options: metformin monotherapy or combination therapy with metformin, and either lifestyle changes or rosiglitazone: a thiazolidinedione which increases insulin sensitivity. Metformin monotherapy has been observed to be moderately effective in reducing BMI in a short-term period—around six months (Van der Aa et al., 2014). This property of metformin, alongside several clinical trials that display metformin’s capability to delay the onset of type 2 diabetes in prediabetes patients, makes metformin monotherapy a strong candidate for certain pediatric prediabetes patients (Soliman et al., 2020). Metformin monotherapy in patients already presenting with type 2 diabetes is effective in the short term, showing significant improvement in patients’ glycemic control after just eight weeks of treatment (Soliman et al., 2020). However, metformin monotherapy is not always enough. The TODAY Study Group found that only 48.3% of patients using metformin monotherapy were able to maintain glycemic control, defined as having an A1C blood sugar level below 8% (Narasimhan & Weinstock, 2014).
Metformin, in combination with lifestyle changes, was marginally more effective than metformin monotherapy, with 53.4% of patients maintaining glycemic control (Narasimhan & Weinstock, 2014). Those prescribed this course of treatment also displayed the most minor increase in BMI but did not have a significant impact on the efficacy of treatment (Narasimhan & Weinstock, 2014). While lifestyle changes are not very effective in some cases, recent studies have encountered cases where lifestyle changes have contributed to significant drops in obesity rates (Van der Aa et al., 2014). This treatment is an option with variable short-term and long-term results, but it is still more effective than metformin monotherapy alone.
The third treatment was a combination of metformin with rosiglitazone and had the best results regarding glycemic control, with a 61.4% maintenance rate. Despite its higher efficacy in glycemic control, this treatment option remains not recommended for long-term use due to side effects; such as an increased probability of bone fractures, coupled with an increased likelihood of contracting pneumonia and other lower respiratory tract infections (Narasimhan & Weinstock, 2014, Singh et al., 2011). Even in the relatively short duration of the TODAY study, minor decreases in patients’ bone mineral density were already being observed. Whether rosiglitazone’s impact on bones could be reversible or harm the future development of pediatric patients’ bones is still unknown (Narasimhan & Weinstock, 2014).
The follow-up study of the TODAY study group gives a rare insight into the long-term effects of pediatric-onset type two diabetes. The patients in this study were initially diagnosed with type two diabetes between the ages of 12-15 and were initially prescribed one of the aforementioned treatments. They were followed up with the second half of this study roughly 15 years later. By the time of the second study, 50% of patients were taking more intensive treatments of metformin and insulin, yet around a quarter were not taking any medication at all. Only 19% of patients had blood sugar in the nondiabetes range: a steep decline from 75% of patients in this blood sugar range when initially started on medication. BMI for all patients remained in the range of 35-37.5: obese. As for complications regarding diabetes, by 15 years after diagnosis, 60% of patients had at least one complication, whilst one in five patients had at least two. The cumulative frequencies can give a rough indication of the percentage of patients affected by different complications after 15 years. These percentages were calculated within the study. The cumulative frequency for hypertension was 67.5%, kidney disease was 58.4%, and nerve disease was 32.4%. Anyone diagnosed with diabetes as a child has a high probability of developing any of these complications up to 15 years after being diagnosed, and there would likely be worse to come in the following years (TODAY Study Group, 2021). Overall, the treatment of pediatric patients with metformin is effective to an extent, but not as much as when used in adult cases of type two diabetes (Narasimhan & Weinstock, 2014). Combination treatments are shown to be more effective but have caveats that need to be considered.
These studies show that although metformin is effective at maintaining glycemic control, its efficacy still has some drawbacks. Metformin proved to be effective for a portion of patients and showed better results when combined with other treatments—though this improvement was only marginal. This slight improvement, however, remains highly patient-dependent, especially with the practices of lifestyle changes and education as treatment. Lifestyle changes, though a popular supplementary treatment, are less effective with children than in adults, as children have less control and discipline over their own lives (Narasimhan & Weinstock, 2014). Even when implemented properly, lifestyle changes can only be effective if the patient follows through with the changes for the rest of their life. The results from the studies above show that even though it is somewhat effective, metformin is not always the “best fit” for pediatric cases due to the sheer percentage of patients who are not able to maintain their blood sugar with it and combined therapies, which in themselves also have issues as detailed above. Metformin is still a viable option due to the lack of medications approved for pediatric use and its lack of highly apparent and debilitating side effects. Metformin with different therapies can still make the drug more effective than current studies conclude. This future is becoming increasingly possible with more medications being approved for use in pediatrics.
The lack of research into medications for pediatric patients remains a significant obstacle in effectively treating the condition. The long-term effects of these treatments on pediatric patients are still unknown, meaning their value as a treatment is not fully understood. Obtaining a better understanding of these medications’ long-term effects is necessary for the decision to give these medications to young children for, possibly, the rest of their lives. Rosiglitazone is a clear example of why this information is needed, as even though it showed the best results in the studies, the known long-term effects ruled it out as a “default” option for doctors to use with newly diagnosed patients. Fortunately, more long-term studies are being implemented to better understand pediatric type 2 diabetes, which will pave the way for better adjustment of treatment options and the exact mechanisms of the condition, which are different in pediatric diabetes.
Abbasi, A., Juszczyk, D., van Jaarsveld, C. H. M., & Gulliford, M. C. (2017). Body Mass Index and Incident Type 1 and Type 2 Diabetes in Children and Young Adults: A Retrospective Cohort Study. Journal of the Endocrine Society, 1(5), 524-537. https://academic.oup.com/jes/article/1/5/524/3754347?login=false
Not very much is known about the association between obesity and trends in pediatric diabetes, so this study by the Endocrine Society looked at the Body Mass Index (BMI) of children and young adults with type one and type two diabetes and the significant increase in obesity.
Centers for Disease Control and Prevention (Ed.). (2020, February 11). Rates of New Diagnosed Cases of Type 1 and Type 2 Diabetes Continue to Rise Among Children, Teens. Centers for Disease Control and Prevention. Retrieved August 19, 2022, from https://www.cdc.gov/diabetes/research/reports/children-diabetes-rates-rise.html
This article by the Centers for Disease Control and Prevention (CDC) discussed the recent spike in pediatric cases of diabetes. They also found a varied rate of increase in children with type one diabetes but a constant rate in those with type two.
Loke, Y. K., Singh, S., & Furberg, C. D. (2009). Long-term use of thiazolidinediones and fractures in type 2 diabetes: A meta-analysis. Canadian Medical Association Journal, 180(1), 32-39. https://doi.org/10.1503/cmaj.080486
This study looked at the possibility and reasoning for increased bone fractures in people with long-term use of rosiglitazone and pioglitazone. They found that long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, yet it does not significantly affect men with type two diabetes.
TODAY Study Group. (2021). Long-Term complications in youth-onset type 2 diabetes. New England Journal of Medicine, 385(5), 416-426. https://doi.org/10.1056/NEJMoa2100165
The Today Study Group took a portion of type two diabetics in the United States and treated them with metformin-based medications. These patients were followed up with sixteen years later and participated in assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease.
Mayo Clinic Staff. (2021, January 20). Type 2 diabetes. Mayo Clinic. Retrieved July 30, 2022, from https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/symptoms-causes/syc-20351193
MayoClinic writers write an informative article about the symptoms, causes, and treatments of diabetes.
Mayo Clinic Staff. (2022, March 31). Type 2 diabetes in children. Mayo Clinic. Retrieved August 6, 2022, from https://www.mayoclinic.org/diseases-conditions/type-2-diabetes-in-children/symptoms-causes/syc-20355318
MayoClinic writers discuss the differences and similarities of type two diabetes in children and adults. Tested and approved medications are also explored.
Narasimhan, S., & Weinstock, R. S. (2014). Youth-Onset type 2 diabetes mellitus: Lessons learned from the TODAY study. Mayo Clinic Proceedings, 89(6), 806-816. https://doi.org/10.1016/j.mayocp.2014.01.009
MayoClinic writers analyzed a study by the Today Study Group that took a portion of type two diabetics in the United States and treated them with metformin-based medications. These patients were followed up with sixteen years later and participated in assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease.
Pfizer Inc. (2022). The future of diabetes. Pfizer. Retrieved August 20, 2022, from https://www.pfizer.com/news/articles/the_future_of_diabetes
Pfizer is one of the world’s leading pharmaceutical companies and helped to develop many vaccines and medications. In this article, Pfizer’s writers describe the possible future of diabetes; these improvements include overriding glucose absorption in the kidneys and possibly ridding the finger prick from glucose measurements.
Rosenbloom, A. L., Silverstein, J. H., Amemiya, S., Zeitler, P., & Klingensmith, G. J. (2009, August 28). Type 2 diabetes in children and adolescents. Wiley Online Library. Retrieved August 6, 2022, from https://onlinelibrary.wiley.com/doi/full/10.1111/j.1399-5448.2009.00584.x
As type two diabetes becomes an increased risk in pediatrics, a study was published in 2009 detailing the definition and classification of non-T1DM diabetes.
Singh, S., Loke, Y. K., & Furberg, C. D. (2011). Long-term use of thiazolidinediones and the associated risk of pneumonia or lower respiratory tract infection: Systematic review and meta-analysis. Thorax, 66(5), 383-388. https://doi.org/10.1136/thx.2010.152777
Writers Singh, Loke, and Furberg explore the immunocompromisation caused by diabetes. They focus on the increased risk of pneumonia and other lower respiratory infections caused by—or associated with—thiazolidinediones.
Soliman, A., De sanctis, V., Alaaraj, N., & Hamed, N. (2020). The clinical application of metformin in children and adolescents: A short update. Acta Bio Medica Atenei Parmensis, 91(3), e2020086. https://doi.org/10.23750/abm.v91i3.10127
This is a long-term study focusing on the medical prescription of metformin—as a medication for patients with type two diabetes—in children and adolescents.
Tamborlane, W. (n.d.). T2D in children and adolescents [Infographic]. https://ema.europa.eu/en/documents/presentation/presentation-type-2-diabetes-children-adolescents-william-tamborlane_en.pdf
William Tamborlane is a professor at Yale School of Medicine and constructed this PDF slideshow to detail the effects of type two diabetes in children and adolescents.
Van der aa, M. P., Elst, M. A., Van mil, E. G., Knibbe, C. A., & Van der vorst, M. M. (2014). METFORMIN: An efficacy, safety and pharmacokinetic study on the short-term and long-term use in obese children and adolescents – study protocol of a randomized controlled study. Trials, 15(1). https://doi.org/10.1186/1745-6215-15-207
This metformin experiment was conducted over two 18-month intervals. One interval involved the prescription of metformin, and the other used a placebo medication.