Treatment Options for Type 2 Diabetes in Youth Remain Limited

Treatment Options for Type 2 Diabetes in Youth Remain Limited Colette Meehan, MD, and Janet Silverstein, MD

T

he incidence and prevalence of type 2 diabetes (T2D) in youth are steadily increasing. The Centers for Disease Control and Prevention recently published the projected prevalence of T2D in youth using the SEARCH for Diabetes in Youth Study database from 2001 for prevalence and 2002 for incidence. Based on these data and assuming a 2.3% increase annually, it is predicted that the prevalence of T2D in youth could quadruple in 40 years.1 As in adults with T2D, adolescents develop macrovascular and microvascular complications, including albuminuria, hypertension, and dyslipidemia. These complications occur earlier and appear to be more rapidly progressive in youths than in adults.2 Thus, prevention and treatment of T2D is paramount. Prevention begins with addressing known risk factors for developing T2D, the most important of which is obesity. Most youths with T2D have a body mass index (BMI) greater than the 85th percentile and are diagnosed between the ages of 10 and 16 years, around the time of puberty and the associated physiologic insulin resistance.3 Occurrence is familial; 74%100% of adolescents with T2D have an affected first or second degree relative.4 Other risk factors for developing T2D are large for gestational age or small for gestational age birthweights and high risk ethnicities. American Indians are the most affected, followed in decreasing order by African Americans, Hispanics, Asian/Pacific Islanders, and non-Hispanic Whites.3 Understanding the pathophysiology of diabetes has led to the development of novel treatments. T2D is due to insulin resistance and a relative insulin deficiency due to beta cell dysfunction with eventual beta cell failure. The time to beta cell failure in youth is more rapid than in adulthood, with the rate of beta cell function declining by
20% per year in 6 youths who underwent clamp studies.5 Explanations for the beta cell failure include beta cell exhaustion because of increased insulin secretion to compensate for insulin resistance, desensitization of the beta cell because of hyperglycemia (glucotoxicity), lipotoxicity, and a reduction of beta cell mass from amyloid deposition.6 At diagnosis, many youths have insulin resistance and glucose toxicity and require initial treatment with insulin. Once glucose control is established, most patients transition to

BMI DPP-4 FDA GLP-1 Hb INGAP RYGB T2D

Body mass index Dipeptidyl peptidase IV Food and Drug Administration Glucagon-like peptide 1 Hemoglobin Islet cell neogenesis-associated protein Roux-en-Y gastric bypass Type 2 diabetes

oral medication alone or in conjunction with insulin. Lifestyle modification in an effort to achieve weight loss is the cornerstone of treatment, though infrequently sustainable. Overall weight loss and lifestyle changes have been shown to delay or slow the progression of T2D. Achieving a 5% weight loss in adults reduced or delayed the development of T2D and decreased the cardiovascular comorbidities associated with obesity in those with “prediabetes.”7 Multiple studies have shown that lifestyle modifications are more effective than treatment with metformin alone in slowing the progression of T2D in adults. A 43% reduction of progression to T2D at 20 years was found in the Da Qing study8 and at 7 years in the Finnish Diabetes Prevention Study.9 In the US Diabetes Prevention Program Outcomes Study, a 34% reduction of progression to T2D was seen at 10 years.10 Unfortunately, lasting lifestyle changes are difficult for youth and adults with T2D. The barriers to achieving optimal control include lack of understanding of the disease, poor adherence to medications, and lack of financial resources. A systematic review of 28 articles from 20002012 synthesized self-reported barriers to medication adherence by adolescents with chronic illness and reported the top 5 barriers to be forgetting, physical well-being (avoidance of side effects, undesirable changes in appearance, feeling well and believing they did not need their medication), conflicts with their parents, striving for normality, desire for peers’ acceptance, and not wanting to feel different than their peers.11 Many of these youth are from families of low socioeconomic status, which can impact adherence to their diabetes regimen. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth Study cohort, 41.5% of the participants’ families had an annual household income of less than $25 000, 26.3% of their parents received an education level less than a high school degree, and only 38.8% lived with both biological parents.12 Youths and their families with limited financial resources face an undue economic burden. According to the 2014 National Diabetes Statistics Report, the estimated costs associated with the medical care of people with diabetes were 2.3 times higher than in those without diabetes.13 In addition to lack of family resources, youths may also have difficulty interacting with their peers. Twenty-four

From the Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL J.S. is conducting clinical trials for Daichi Sankyo and Boehringer Ingelheim; and serves as an Editorial Board member for The Journal of Pediatrics. C.M. declares no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.11.015

20

Volume 170  March 2016 adolescents with T2D participating in a focus group stated that they experienced barriers related to social situations, including embarrassment, feeling different from their peers, and having difficulty seeking acceptance from their peers. They also had difficulty balancing diabetes care with their other social and school demands, resulting in decreased attention to their disease.14 Adults with T2D face similar barriers. A systematic review of 80 articles evaluating barriers to diabetes management in adults included poor adherence (failure to take medication, attend physician appointments, and reluctance to start insulin), lack of knowledge about T2D and poor understanding of health outcomes, culture (food and dietary preference, lifestyles, traditional and religious beliefs, and beliefs about health in general), financial strain, competing comorbidities, and lack of social support.15 Thus, even when youths leave the care of their pediatricians and become adults, many barriers persist. Overall, the treatment of youths with T2D is not only limited by few treatment options, but also many developmental impediments as they navigate the journey from adolescence to adulthood. This article will focus on the current approved treatments available to adolescents with T2D, discuss newer classes of medications (Table), review clinical trials being conducted in youth with T2D, and the role of bariatric surgery.

Methods A literature search was conducted using PubMed with librarian assistance. We included systematic reviews4,16-21 as well as retrospective and randomized prospective trials of medications and bariatric surgery that were limited to persons under the age of 18 years with T2D. Only research from the past 10 years was considered. We also reviewed ClinicalTrials.gov looking at active trials using the search terms “type 2 diabetes children” and “type 2 diabetes pediatrics.” Approved Therapies in Children The only Food and Drug Administration (FDA)-approved medications for the treatment of T2D in youth are metformin and insulin, with lifestyle change considered to be a key component of management. Nonetheless, the ability to maintain lifestyle changes is usually transient in youth and, therefore, is rarely successful for treatment of T2D when used alone. Thus, the current recommendation is to initiate treatment with metformin or insulin in addition to lifestyle changes.17

Metformin. The FDA in December 2000 approved metformin for youths less than 18 years of age with T2D. No other oral medications have been approved for this age group. Traditionally, metformin was thought to mainly act to increase hepatic insulin sensitivity, with resultant decrease in the production of glucose in the liver, increased glucose utilization, and decreased lipogenesis.22 Multiple mechanisms of action have been proposed with the most common

explanation being the activation of 50 adenosine monophosphate-protein kinase by metformin. Meng et al23 have shown that low concentrations of metformin promote the formation of the heterotrimeric 50 adenosine monophosphateprotein kinase (abg) complex in primary hepatocytes, thus suppressing glucose production. Experiments in rats have shown that metformin results in increased conversion of lactate to pyruvate by inhibiting the mitochondrial isoform of glycerophosphate dehydrogenase, thus, limiting the availability of the gluconeogenic precursors glycerol and lactate.24 Recently, a phase 2, 12-week, placebo-controlled trial of 240 subjects found that delayed-release metformin (formulated for lower bowel release) had a
40% increase in potency compared with extended-release metformin, leading the authors to conclude that metformin may have a lower-bowel mechanism of action as well.25 Benefits of treatment with metformin are lack of weight gain with reports of weight loss when used in conjunction with diet and exercise26 and low risk of hypoglycemia. Some initial weight loss can be due to associated gastrointestinal symptoms, including diarrhea, abdominal cramping, and flatulence. Besides gastrointestinal side effects, metformin also increases the risk of vitamin B-12 deficiency. Lactic acidosis is a potential adverse event listed on the package insert, but no instances of lactic acidosis have been reported in children. This complication had contraindicated the use of metformin in patients with chronic kidney disease, though, recent studies have shown that metformin may be used in those with mild to moderate chronic kidney disease, with appropriate dosage reduction based on the estimated glomerular filtration rate.27 Because of the success of metformin, many studies have focused on comparing potential new T2D drugs with metformin either alone or in combination with metformin. In general, the addition of another medication to metformin lowers hemoglobin (Hb)A1c no more than 1%.28 The Treatment Options for Type 2 Diabetes in Adolescents and Youth Study, a multicenter randomized trial in the US, compared 3 treatment regimens for new onset T2D in 10to 17-year-old youths: (1) monotherapy with metformin; (2) metformin with the thiazolidinedione, rosiglitazone; or (3) metformin with an intensive lifestyle intervention. Thiazolidinediones bind to the peroxisome proliferatoractivated receptor, thus, increasing insulin sensitivity. There was an 8- to 24-week run in period and at least 2 years of follow-up in this study. One-half of the participants could not maintain glycemic control with metformin alone over 4 years. The most effective therapy was metformin and rosiglitazone. Metformin alone was inferior to metformin plus lifestyle changes. There was an associated increase in central adiposity in the metformin plus rosiglitazone group, a side effect, which must be considered when choosing a treatment plan.29 Rosiglitazone is not approved for use in pediatric patients because of concerns about increased risk of heart attacks and strokes,2 although recent data indicate rosiglitazone is not associated with increased cardiovascular risk.30 At this point, no long-term studies evaluating the efficacy and safety of thiazolidenediones in youth have been completed. 21

THE JOURNAL OF PEDIATRICS



www.jpeds.com

Insulin. In addition to lifestyle changes, insulin, with or without metformin, should be given at T2D diagnosis if the HbA1c is $9.5%, if serum glucose concentration is >250 mg/dL, if ketones are present, or if the type of diabetes is unknown.17 Once glucose control is established, glucose toxicity and diabetes symptoms have resolved, and metabolic state has been stabilized, the insulin dose may be able to be tapered. There has been recent interest in inhaled insulin as an alternative to injectable insulin. A study in 2007 comparing injectable insulin with inhaled insulin in adults and adolescents 12-17 years old (mean age
3 years) over a 24-week period showed more favorable patient satisfaction with inhaled insulin with higher quality of life and fewer adherence barriers noted.31 A rapid acting premeal inhaled insulin (Afrezza, Mannkind Corporation, Danbury, Connecticut), is available in the US and approved for adults, but clinical trials in pediatric subjects have not been done. The insulin comes in packets of 4 units and 8 units and combinations of these 2 dosage forms are used in the inhaler to deliver the required insulin dose. Barriers for treating youth with T2D with inhaled insulin include increased cost and difficulty with dosing, which would make titrating smaller doses in younger children difficult. In addition, some children and adults have cough, especially during the first 4 weeks of using the inhaler, with improvement thereafter. Afrezza is contraindicated in adults with chronic lung disease, so children with asthma would be unable to use it. Inhaled insulin also increases the risk of acute bronchospasm and is not recommended for use in smokers. Preliminary data indicates that inhaled insulin is associated with an increased risk of decreased forced expiratory volume in one second compared with subcutaneously administered insulin aspart with improvement to baseline by 4 weeks after discontinuation of the inhaled drug. Afrezza is not the first inhaled insulin to come to market. In 2006, Exubera (Pfizer Inc, New York, New York) was approved, but withdrawn in 2007 because of decreased lung function on pulmonary function testing as Exubera remained in the lungs for up to 12 hours. However, Afrezza uses a technosphere insulin inhalation powder, which has been tested in adults and did not show changes in forced expiratory volume in one second after 24 weeks, as only 0.3% of the insulin remained in the lungs after 12 hours (ClinicalTrials.gov: NCT01451398). A safety and tolerability study to evaluate Afrezza in 4- to 17-year-olds is recruiting subjects (ClinicalTrials.gov: NCT02527265). New formulations of subcutaneous insulin include u300 (300 u/mL) glargine, a more concentrated basal insulin, which is appropriate for youths using large doses of insulin to decrease injected volume. Insulin u300 glargine has not yet been approved by the FDA for pediatric use. Another long-acting basal insulin currently undergoing further cardiovascular safety trials is insulin degludec, a conjugated hexadecanoic acid, which shows promise for children who want to sleep in, as the half-life is 25 hours and the duration of action is at least 42 hours. Insulin degludec has been studied in adults with T2D and in children with T1D in a 26-week ran22

Volume 170 domized control trial followed by a 26-week extension. The 350 children from 1-17 years of age with type 1 diabetes who participated in a trial comparing insulin detemir with insulin degludec experienced a 30% reduction in basal insulin doses without an increased rate of hypoglycemia, and a significantly lower rate of hyperglycemia with ketosis.32 Another long-acting insulin undergoing clinical trials is pegylated insulin lispro (addition of polyethylene glycol to lispro) that has seemed promising to reduce hepatic gluconeogenesis and promote weight loss, but further studies are needed to evaluate reported elevated triglycerides and transaminases in early phase trials.33 There were no clinical trials in children listed on ClinicalTrials.gov for these newer insulins. T2D Drugs Being Studied in Pediatric Clinical Trials Bile Acid Sequestrant. Colesevelam (Welchol, Daiichi Sankyo Inc, Tokyo, Japan) is a bile acid sequestrant initially used to treat hyperlipidemia that was found to improve glycemic control during a randomized, placebo-controlled trial evaluating the effect of colesevelam on low-density lipoprotein-cholesterol lowering when added to treatment in adults with T2D being treated with a sulfonylurea or metformin. Similar findings were found in a pooled analysis of 696 patients participating in 3 clinical studies of 26 weeks duration.34,35 A meta-analysis of 6 trials of 8-26 weeks duration comparing colesevelam to placebo showed a decrease of HbA1c of 0.5%.36 Colesevelam seems to increase glucagonlike peptide 1 (GLP-1) secretion and may increase peripheral insulin sensitivity.37 A phase 4 clinical trial evaluating colesevelam as either monotherapy or as an add-on to metformin therapy to improve glycemic control in 10- to 17-year-old adolescents is on-going (ClinicalTrials.gov: NCT01258075). Recruitment and retention have been difficult in this patient population.

GLP-1 Agonists. GLP-1 is a member of the incretin family of hormones. GLP-1 is released from intestinal L-cells in response to a food bolus and improves glycemic control via glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, inhibition of hepatic glucose production, and slowing of gastric emptying.38 GLP-1 receptors are located in the satiety center of the hypothalamus, thus reducing appetite, and GLP-1 agonists have been associated with a weight loss of roughly 2 kg in adults38 that is thought to be due to a reduction of fat mass.39 The incretin mimetics, GLP-1 receptor agonists, first came to market in 2005. They are injected subcutaneously and bind to the GLP-1 receptors expressed on parietal cells in the stomach, pancreatic islets, brain, heart, and kidney. In a metaanalysis of 17 randomized trials with a minimum of 8 weeks duration in adults, GLP-1 agonists decreased mean HbA1c by about 1% (1.22% once daily liraglutide vs 0.79% twice daily exenatide).40 FDA-approved GLP-1 agonists include exenatide given twice daily, exenatide extended release agent given weekly, and 3 preparations given daily: liraglutide, albiglutide, and dulaglutide. Exenatide has also Meehan and Silverstein

March 2016 been evaluated as a weight loss therapy in youth. Over a 6month period, 26 youths, 12-19 years of age, had an average weight loss of 3.26 kg.41 The most common side effect was nausea that appeared to be dose-dependent. There is a theoretical increased risk of hypoglycemia. Episodes of mild hypoglycemia for liraglutide were dose dependent, with 0.178 episodes per participant year for the 1.2 mg dose and 0.370 episodes/y with 1.8 mg.42 A phase 3 clinical trial is evaluating the safety and efficacy of exenatide as monotherapy over a 28-week period for T2D in youths age 10-17 years (ClinicalTrials.gov: NCT00658021). Another clinical trial comparing liraglutide and metformin with metformin monotherapy over a 26-week period is ongoing in children 10-16 years of age (ClinicalTrials.gov: NCT01541215).

Dipeptidyl Peptidase IV Inhibitors. Incretins are degraded by the enzyme, dipeptidyl peptidase IV (DPP-4). DPP-4 inhibitors result in increased concentrations of incretins by blocking the degradation of GLP-1, and glucosedependent insulinotropic peptide,43 resulting in the stimulation of postprandial insulin release. DPP-4 inhibitors are given orally and were first approved by the FDA in 2006 in adults but have not been approved for use in children. In adults, DPP-4 inhibitors improve glycemic control when given as monotherapy or in combination with metformin. A systematic review and meta-analysis of 31 randomized controlled trials over 12-54 weeks in adults showed a 0.77% decrease in HbA1c from baseline.44 This class of oral medications has a low risk of hypoglycemia and is weight neutral. FDA-approved formulations include sitagliptin, saxagliptin, linagliptin, and alogliptin. Phase 3 clinical trials evaluating the safety and efficacy of sitagliptin alone (ClinicalTrials.gov: NCT01485614) or in combination with metformin (ClinicalTrials.gov: NCT01472367 and NCT01760447) in 10- to 17-year-old youths with T2D over a 20-week period are on-going. In addition, 2 phase 3 clinical trials evaluating saxagliptin in 10to 17-year-old youth with T2D over a 16-week period as monotherapy (ClinicalTrials.gov: NCT01204775) or in combination with metformin (ClinicalTrials.gov: NCT01434186) are on-going. A phase 2 clinical trial to find safe and effective dosing of linagliptin compared with placebo, in 10- to 17-year-olds with T2D (ClinicalTrials.gov: NCT01342484) is recruiting youths, and a phase 1 study evaluating the pharmacokinetics, pharmacodynamics, and safety of alogliptin have been completed in the pediatric age group (ClinicalTrials. gov: NCT00957268). In August 2015, the FDA released a drug safety communication that 33 cases of severe arthralgia in adults were reported to the FDA Adverse Event Reporting System database and that most resolved a month after discontinuing the DPP-4 inhibitor. Ten patients required hospitalization because of severe joint pain and 8 patients had their arthralgia return after restarting the DPP-4 inhibitor. This report underscores the importance of periodically reviewing the FDA adverse event reporting system database to evaluate the safety of medications outside of clinical trials, especially medications with which we have little experience. Treatment Options for Type 2 Diabetes in Youth Remain Limited

MEDICAL PROGRESS Other Medications. Pramlintide was approved by the FDA in 2005 as an adjunct to insulin to decrease postprandial glucose excursions. It is a synthetic analogue of amylin and is injected subcutaneously before meals. Amylin is produced by the pancreatic beta cells and cosecreted with insulin. It increases satiety at the level of the hypothalamus, slows gastric emptying, and suppresses postprandial glucagon secretion, resulting in decreased postmeal glucose excursions.45 In adults with T2D on insulin therapy, pramlintide improved glycemic control with a 0.7% reduction in HbA1c and weight loss of 1-2 kg over 16 weeks of the trial.46 Pramlintide has not been FDA-approved for use in children. A review of ClinicalTrials.gov showed a 2009 study evaluating the effect of pramlintide on postmeal glucose concentrations in children but was listed as unverified, and we were unable to find any record of the results of this trial (ClinicalTrials. gov: NCT00950677). The megalitinides were approved in 1997 by the FDA for adults. They are available in the US as repaglinide and nateglinide. This class of medication causes a rapid release of insulin by acting on the adenosine triphosphate sensitive potassium channel of the pancreatic beta cell to secrete insulin. These agents are potentially beneficial for the prevention and treatment of post meal glucose excursions. Yet, the megalintinides are not approved for use in children and there were no clinical trials listed for youth on ClinicalTrials.gov. A new class of oral glucose-lowering medications approved by the FDA in 2013 for use in adults is the sodium-glucose cotransporter 2 inhibitors. FDA-approved formulations in this class include dapagliflozin, canagliflozin, and empagliflozin. The FDA released a drug safety communication in May 2015 concerning an increased risk of atypical ketoacidosis with mildly elevated glucose, <200 mg/dL in some reports, with this class of medications. There were 20 cases reported in the FDA Adverse Event Reporting System database with the average time of onset at 2 weeks following initiation of drug therapy. Sodium-glucose cotransporter 2 inhibitors promote renal excretion of glucose at the level of the proximal tubule causing an osmotic diuresis, thus lowering serum glucose levels.47 The FDA released another drug safety communication in September 2015, specifically for canagliflozin in elderly individuals regarding decreased bone mineral density at the hip and lower spine compared with placebo with a risk of fracture as early as within 12 weeks of therapy. A systematic review of 7 trials (12-52 weeks duration) showed a 0.52%-0.95% reduction of HbA1c. Several trials compared dapagliflozin (n = 6), canagliflozin (n = 1) to dual or triple therapy with metformin/sulphonylureas/ insulin/DPP-4 inhibitors.48 A clinical trial to evaluate the pharmacokinetics of a single dose of empagliflozin in children and adolescents age 10-18 years with T2D is recruiting participants (ClinicalTrials.gov: NCT02121483). Islet cell neogenesis-associated protein (INGAP) peptide is a 16 kDa regulatory protein with an active 15 amino acid segment peptide that enhances islet cell neogenesis. An early 90-day study evaluating the effects of INGAP in adults 23

THE JOURNAL OF PEDIATRICS



www.jpeds.com

showed an increase in C-peptide secretion in type 1 diabetes and improved glycemic control in T2D by increasing beta cell mass with an improvement of HbA1c by 0.47%-0.94%.49

Surgical Therapy. Bariatric surgery is recommended for youths with a bone age greater than 14 years in girls and greater than 15 years in boys who meet criteria.50 In 2013, the American Heart Association released a statement to address extreme obesity (BMI $120% of the 95th percentile) in youths with a BMI $35 kg/m2 who had severe comorbidities including T2D, obstructive sleep apnea, steatohepatitis with fibrosis, and disabling orthopedic problems.51 Youths with a BMI $40 kg/m2 with less severe comorbidities (insulin resistance, hypertension, dyslipidemia, mild obstructive sleep apnea, and impaired weight-related quality of life).50 The Adolescent Morbid Obesity Surgery Study in Sweden looked at the 2-year outcome for youths 13-18 years old with extreme obesity (BMI 36-69 kg/m2) who received laparoscopic Roux-en-Y gastric bypass (RYGB, n = 81) compared with those who received conventional care (n = 81). The mean BMI before surgery was 45.5 kg/m2 and 30.2 kg/m2 after surgery. Hyperinsulinemia was reduced from 70% at baseline to 3% at 2 years.52 Similar metabolic changes were also seen in the follow-up of 8 extremely obese adolescents (mean age 17 years) who received bariatric surgery with an 8-year follow-up that showed remission of diabetes in 7 with the sole patient taking insulin before the surgery having a reduction in insulin dose and improved glycemic control.53 However, the costs and risks must be considered before recommending bariatric surgery. Access to care for bariatric surgery has been limited by hesitancy of primary care practitioners to refer obese youths with T2D to a multidisciplinary bariatric center. It is difficult to obtain approval from their insurance companies, with more than 50% of initial insurance prior authorization requests being denied. However, eventually 80% received insurance approval after multiple appeals (up to 5).54 The Teen-Longitudinal Assessment of Bariatric Surgery study looked at perioperative complications after gastric bypass surgery and found that out of 242 patients, 19 youths had 20 major complications and 36 had minor complications with most occurring before discharge and included 1 intraoperative splenic injury necessitating splenectomy; 7 had early reoperation for intestinal obstruction, bleeding, and confirmed or suspected gastrointestinal leak; 4 minor injuries to solid organs; and 6 urinary tract infections or complications from catheterization. Between discharge and 30 days after surgery, 7 youths had major complications that included 2 patients with pulmonary embolus and 4 with gastrointestinal leaks and 27 had minor complications that included abdominal/gastrointestinal complaints and dehydration requiring readmission for inpatient management.55 The 5% major complication rate seen in this study was comparable with extremely obese adults who had gastric bypass surgery. Long-term vitamin and mineral deficiencies are a common consequence of RYGB surgery and often require lifelong 24

Volume 170 supplementation. Monitoring and supplementation for fat soluble vitamin deficiencies should be considered in malabsorptive procedures (RYGB, laparoscopic biliopancreatic diversion, and laparoscopic biliopancreatic diversion with duodenal switch). According to the 2013 Clinical Practice Guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric patient for adults, supplementation with oral calcium citrate and vitamin D to prevent secondary hyperparathyroidism is recommended. Phosphate replacement also may be needed due to vitamin D deficiency. Folic acid should be provided to all women of child bearing age. For all types of bariatric surgery, deficiencies of iron, vitamin B12, thiamine, folate, protein, copper, selenium, and zinc are possible. Hence, electrolytes, vitamin, and mineral levels need to be monitored closely and supplementation, such as a multivitamins with minerals, provided.56 Patients should also undergo a psychological evaluation as depressive disorders, anxiety disorders, eating disorders, and higher suicide rates have been well documented in adults who undergo bariatric surgery.57-59 In youth, a study evaluating the effect of weight on suicidal risk behavior over a 12-month period showed that suicidal ideation was increased in obese or extremely obese adolescents but was unrelated to suicide attempts.60 Another short-term study looking at health-related quality of life and depressive symptoms in adolescents with extreme obesity who underwent RYGB had improvement in quality of life over the first postoperative year.61 Longer term studies are needed in youth to fully understand the long-term psychologic consequences of bariatric surgery as adolescents mature into adults.

Discussion Only 2 medications are FDA-approved for the treatment of youth with T2D: metformin and insulin. Recruitment of children and adolescents with T2D for clinical trials is limited as many clinical trials are looking for subjects who are between 10 and 17 years of age and have not been started on insulin therapy, an exclusion criterion for almost all of the T2D clinical trials. A recent commentary in Diabetes Care recommended that the age range of availability be increased from 10-17 years to 10-21 years to increase the pool of potential subjects.62 Another method is to perform a single study with 1 control group and multiple arms of different experimental drugs and using T2D registries for postapproval safety studies.62 Large pediatric T2D consortia might also provide a large pool of patients for safety and efficacy trials. T2D in youth is rarely successfully treated with dietary modifications and increased activity alone. A 2010 metaanalysis of the effects of behavioral modification to effect lifestyle change on glycemic control in children and adolescents with T2D found no high quality evidence to suggest lifestyle modification improves either short- or long-term glycemic control.18 Therefore, medication is almost always needed to reach glycemic goals. The only 2 FDA-approved medications for the treatment of youth with T2D are metformin and Meehan and Silverstein

MEDICAL PROGRESS

March 2016

Table. Summary of medications Medications

Class

Mechanism of action

Route

FDA-approved age

Increases satiety, slows gastric emptying, and suppresses postprandial glucagon secretion, resulting in decreased postmeal glucose excursions Improves hepatic insulin sensitivity. Increases GLP-1 and PYY Increases GLP-1 secretion and may increase peripheral insulin sensitivity Inhibits DPP-4 from degrading GLP-1 and GIP

Subcutaneous injection

>18 y

Oral

10-18 y

Oral

>10 y†

Oral

>18 y

Pramlintide

Amylin analogue

Metformin

Biguanide

Colesevelam*

Bile acid sequestrant

Alogliptin* Linagliptin* Saxagliptin* Sitagliptin* Albiglutide Dulaglutide Exenatide* Liraglutide* Afrezza

DPP-4 inhibitors Glucagon-like peptide agonists

Increase release of GLP-1, which stimulates release of insulin

Subcutaneous injection

>18 y

Rapid-acting insulin

Inhaled

>18 y

Degludec*

Long-acting insulin

Subcutaneous injection

Awaiting new drug application to FDA

Detemir

Long-acting insulin

Subcutaneous injection

$6 y

Glargine u300

Long-acting insulin

Subcutaneous injection

>18 y for the u300 (300 u/mL) form >5 y for the u100 (100 u/mL) form

Peglispro*

Long-acting insulin

Subcutaneous injection

Nateglinide Repaglinide

Megalitinides

Oral

Awaiting new drug application to FDA $3 y for the nonpegylated lispro >18 y

Canagliflozin Dapagliflozin Empagliflozin*

Sodium-glucose cotransporter 2 inhibitors

Pulmonary absorption of regular human insulin into systemic circulation Addition of hexadecanoic acid to lysine allows for multihexamer depot for slow insulin release Addition of a fatty acid to lysine facilitates insulin binding to albumin resulting in slow insulin release Substitution of glycine and addition of 2 arginines at the carboxy terminal causes crystallization at physiologic pH resulting in slow insulin release Reversal of lysine and proline at the carboxy terminal with the addition of PEG results in slow insulin release Causes rapid secretion of insulin by acting on the ATP sensitive potassium channel of pancreatic beta cells Promotes renal excretion of glucose at the level of the proximal tubule causing an osmotic diuresis

Oral

>18 y

GIP, glucose-dependent insulinotropic peptide; PEG, polyethylene glycol; PYY, peptide YY; ATP, adenosine triphosphate. *On-going clinical trials in pediatrics. †Lipid lowering only, www.accessdata.fda.gov.

insulin. Even with approval of the newer classes of medications, lifestyle modification will remain an important part of treatment. At diagnosis of T2D, insulin with or without metformin will remain the initial therapy if ketosis and/or glucose toxicity are present. Metformin alone can be initiated if HbA1c is <9.5% and glucose <250 mg/dL without ketosis. Adjunctive therapy with the newer agents would be indicated if glycemic targets are not met. As most patients with T2D are obese, treatment with GLP-1 agonists and DPP-4 inhibitors could be considered, as they have a beneficial or nonadverse effect on weight and their mechanism of action complements that of metformin. Although the injectable GLP-1 agonists result in satiety, whereas the DPP-4 inhibitors do not, adolescents may prefer the DPP-4 inhibitors because they are taken Treatment Options for Type 2 Diabetes in Youth Remain Limited

orally. Many youths with T2D do not like injections. Inhaled insulin is an alternative to injectable insulin, but because obstructive sleep apnea is not uncommon in youth with T2D, safety studies would need to be performed in this population before its use can be recommended. When approved in youth, the longer acting insulins will allow for greater flexibility in lifestyle, while allowing patients to have more consistent blood glucose levels given that some adolescents go to bed late and arise late. Adolescents who have hyperlipidemia and T2D may be good candidates for coleselevam treatment as this drug targets both lipids and glucose concentrations. The role of INGAP peptides is promising, but larger trials are needed before its use in pediatric patients can be recommended. 25

THE JOURNAL OF PEDIATRICS



www.jpeds.com

The treatment options for pediatric T2D remain limited pending adequate safety and efficacy studies of the newer classes of drugs and surgery. Innovative ways of conducting such studies may be needed in order to successfully recruit adequate numbers of subjects into clinical trials. n Submitted for publication Jun 22, 2015; last revision received Oct 7, 2015; accepted Nov 5, 2015. Reprint requests: Janet Silverstein, MD, Division of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, FL 32610. E-mail: [email protected]

References 1. Imperatore G, Boyle JP, Thompson TJ, Case D, Dabelea D, Hamman RF, et al. Projections of type 1 and type 2 diabetes burden in the U.S. population aged <20 years through 2050: dynamic modeling of incidence, mortality, and population growth. Diabetes Care 2012;35:2515-20. 2. Narasimhan S, Weinstock RS. Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study. Mayo Clin Proc 2014;89:806-16. 3. Dabelea D, Bell RA, D’Agostino RB Jr, Imperatore G, Johansen JM, Linder B, et al. Incidence of diabetes in youth in the United States. JAMA 2007;297:2716-24. 4. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care 2000;23:381-9. 5. Bacha F, Gungor N, Lee S, Arslanian SA. Progressive deterioration of bcell function in obese youth with type 2 diabetes. Pediatr Diabetes 2013; 14:106-11. 6. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047-58. 7. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403. 8. Li G, Zhang P, Wang J, Gregg EW, Yang W, Gong Q, et al. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008;371: 1783-9. 9. Lindstr€ om J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemi€ o K, et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 2006;368:1673-9. 10. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al. Diabetes Prevention Program Research Group: 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009;374:1677-86. 11. Hanghøj S, Boisen KA. Self-reported barriers to medication adherence among chronically ill adolescents: a systematic review. J Adolesc Health 2014;54:121-38. 12. Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, et al., TODAY Study Group. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247-56. 13. Prevention CDC. National Diabetes Statistics Report: Estimates of diabetes and its burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014. 14. Mulvaney SA, Mudasiru E, Schlundt DG, Baughman CL, Fleming M, VanderWoude A, et al. Self-management in type 2 diabetes: the adolescent perspective. Diabetes Educ 2008;34:674-82. 15. Nam S, Chesla C, Stotts NA, Kroon L, Janson SL. Barriers to diabetes management: patient and provider factors. Diabetes Res Clin Pract 2011;93:1-9. 16. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet 2014;383:1068-83.

26

Volume 170 17. Springer SC, Silverstein J, Copeland K, Moore KR, Prazar GE, Raymer T, et al. Management of type 2 diabetes mellitus in children and adolescents. Pediatrics 2013;131:e648-64. 18. Johnson ST, Newton AS, Chopra M, Buckingham J, Huang TTK, Franks PW, et al. In search of quality evidence for lifestyle management and glycemic control in children and adolescents with type 2 diabetes: a systematic review. BMC Pediatr 2010;10:97. 19. George MM, Copeland KC. Current treatment options for type 2 diabetes mellitus in youth: today’s realities and lessons from the TODAY study. Curr Diab Rep 2013;13:72-80. 20. Zeitler P, Fu J, Tandon N, Nadeau K, Urakami T, Barrett T, et al., International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. Type 2 diabetes in the child and adolescent. Pediatr Diabetes 2014;20:26-46. 21. American Diabetes Association. Standards of medical care in diabetes— 2014. Diabetes Care 2014;37(Suppl 1):S14-80. 22. Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49:2063-9. 23. Meng S, Cao J, He Q, Xiong L, Chang E, Radovick S, et al. Metformin activates AMP-activated protein kinase by promoting formation of the alphabetagamma heterotrimeric complex. J Biol Chem 2015;290: 3793-802. 24. Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med 2014;371:1547-8. 25. Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation. Results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 2015. Epub ahead of print. 26. Freemark M, Bursey D. The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes. Pediatrics 2001;107:E55. 27. Inzucchi SE, Lipska KJ, Mayo H, Bailey CJ, McGuire DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014;312:2668-75. 28. Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med 2011;154:602-13. 29. Zeitler P, Epstein L, Grey M, Hirst K, Kaufman F, Tamborlane W, et al. Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes 2007;8:74-87. 30. Bach RG, Brooks MM, Lombardero M, Genuth S, Donner TW, Garber A, et al. Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Circulation 2013; 128:785-94. 31. Testa MA, Simonson DC. Satisfaction and quality of life with premeal inhaled versus injected insulin in adolescents and adults with type 1 diabetes. Diabetes Care 2007;30:1399-405. 32. Thalange N, Deeb L, Iotova V, Kawamura T, Klingensmith G, Philotheou A, et al. Insulin degludec in combination with bolus insulin aspart is safe and effective in children and adolescents with type 1 diabetes. Pediatr Diabetes 2015;16:164-76. 33. Caparrotta TM, Evans M. PEGylated insulin Lispro, (LY2605541)—a new basal insulin analogue. Diabetes Obes Metab 2014;16:388-95. 34. Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008;31:1479-84. 35. Bays HE. Colesevelam hydrochloride added to background metformin therapy in patients with type 2 diabetes mellitus: a pooled analysis from 3 clinical studies. Endocr Pract 2011;17:933-8. 36. Ooi CP, Loke SC. Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review. Diabet Med 2014;31:2-14.

Meehan and Silverstein

March 2016 37. Zema MJ. Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action. Core Evid 2012;7:61-75. 38. Tasyurek HM, Altunbas HA, Balci MK, Sanlioglu S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab Res Rev 2014;30:354-71. 39. Gallwitz B, Haupt A, Kraus P, Peters N, Petto H, Dotta F, et al. Changes in body composition after 9 months of treatment with exenatide twice daily versus glimepiride: comment letter on Jendle, et al. Diabetes Obes Metab 2010;12:1127-8. 40. Shyangdan DS, Royle P, Clar C, Sharma P, Waugh N, Snaith A. Glucagon-like peptide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev 2011;CD006423. 41. Kelly AS, Rudser KD, Nathan BM, Fox CK, Metzig AM, Coombes BJ, et al. The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial. JAMA Pediatr 2013;167: 355-60. 42. Brown DX, Evans M. Choosing between GLP-1 receptor agonists and DPP-4 inhibitors: a pharmacological perspective. J Nutr Metab 2012; 2012:381713. 43. Thornberry NA, Gallwitz B. Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract Res Clin Endocrinol Metab 2009;23:479-86. 44. Esposito K, Chiodini P, Maiorino MI, Capuano A, Cozzolino D, Petrizzo M, et al. A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ Open 2015;5: e005892. 45. Schmitz O, Brock B, Rungby J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 2004;53(Suppl 3):S233-8. 46. Riddle M, Frias J, Zhang B, Maier H, Brown C, Lutz K, et al. Pramlintide improved glycemic control and reduced weight in patients with type 2 diabetes using basal insulin. Diabetes Care 2007;30:2794-9. 47. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013;159: 262-74. 48. Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open 2012;2: e001007. 49. Dungan KM, Buse JB, Ratner RE. Effects of therapy in type 1 and type 2 diabetes mellitus with a peptide derived from islet neogenesis associated protein (INGAP). Diabetes Metab Res Rev 2009;25:558-65.

Treatment Options for Type 2 Diabetes in Youth Remain Limited

MEDICAL PROGRESS 50. Wasserman H, Inge TH. Bariatric surgery in obese adolescents: opportunities and challenges. Pediatr Ann 2014;43:e230-6. 51. Kelly AS, Barlow SE, Rao G, Inge TH, Hayman LL, Steinberger J, et al. Severe obesity in children and adolescents: identification, associated health risks, and treatment approaches: a scientific statement from the American Heart Association. Circulation 2013;128:1689-712. 52. Olbers T, Gronowitz E, Werling M, Marlid S, Flodmark CE, Peltonen M, et al. Two-year outcome of laparoscopic Roux-en-Y gastric bypass in adolescents with severe obesity: results from a Swedish Nationwide Study (AMOS). Int J Obes 2012;36:1388-95. 53. Sinha M, Stanley TL, Webb J, Scirica C, Corey K, Pratt J, et al. Metabolic effects of Roux-en-Y gastric bypass in obese adolescents and young adults. J Pediatr Gastroenterol Nutr 2013;56:528-31. 54. Thakkar RK, Michalsky MP. Update on bariatric surgery in adolescence. Curr Opin Pediatr 2015;27:370-6. 55. Inge TH, Zeller MH, Jenkins TM, Helmrath M, Brandt ML, Michalsky MP, et al. Perioperative outcomes of adolescents undergoing bariatric surgery: the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. JAMA Pediatr 2014;168:47-53. 56. Mechanick JI, Youdim A, Jones DB, Garvey WT, Hurley DL, McMahon MM, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient—2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic and Bariatric Surgery. Obesity 2013;21(Suppl 1):S1-27. 57. Mitchell JE, Selzer F, Kalarchian MA, Devlin MJ, Strain GW, Elder KA, et al. Psychopathology before surgery in the Longitudinal Assessment of Bariatric Surgery-3 (LABS-3) Psychosocial Study. Surg Obes Relat Dis 2012;8:533-41. 58. Peterhansel C, Petroff D, Klinitzke G, Kersting A, Wagner B. Risk of completed suicide after bariatric surgery: a systematic review. Obes Rev 2013;14:369-82. 59. Tindle HA, Omalu B, Courcoulas A, Marcus M, Hammers J, Kuller LH. Risk of suicide after long-term follow-up from bariatric surgery. Am J Med 2010;123:1036-42. 60. Zeller MH, Reiter-Purtill J, Jenkins TM, Ratcliff MB. Adolescent suicidal behavior across the excess weight status spectrum. Obesity 2013; 21:1039-45. 61. Zeller MH, Modi AC, Noll JG, Long JD, Inge TH. Psychosocial functioning improves following adolescent bariatric surgery. Obesity 2009; 17:985-90. 62. Tamborlane WV, Klingensmith G. Crisis in care: limited treatment options for type 2 diabetes in adolescents and youth. Diabetes Care 2013;36: 1777-8.

27