Version May 2024
INTRODUCTION — Data on the long-term outcome of adolescent-onset type 2 diabetes mellitus (T2DM) are only now becoming available, including emerging data from more than a decade of follow-up from the TODAY study cohort [1-6]. Studies in adults show that T2DM and its comorbidities are important risk factors for vascular disease. It is likely, therefore, that identifying and treating children and adolescents with T2DM will improve long-term outcomes; however, it is important to appreciate that pediatric-onset T2DM differs from adult-onset disease, especially regarding durability of glycemic control [7,8] and earlier emergence of complications [5].
Only a few studies have examined the management of T2DM in the pediatric age group. The largest clinical trial, Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY study), has shown that oral agent monotherapy does not maintain durable glycemic control in a majority of patients with adolescent-onset T2DM (see 'Approach to treatment' below). Thus, it is important to optimize treatment using a combination of pharmacologic and nonpharmacologic interventions, with close monitoring and follow-up.
Ideally, the care of an adolescent with T2DM should be managed by a multidisciplinary team, including an endocrinologist, nurse educator, dietitian, mental health professional, and sometimes an exercise physiologist. However, in locations where these resources are not available, patients can be managed by primary care clinicians, following the guidelines outlined in this topic review [9-12]. Patients who do not achieve good glycemic control on metformin monotherapy should be managed by or in consultation with an endocrinologist and diabetes educator, if at all possible. Family involvement is essential to initiate and support the lifestyle changes required in the management of a pediatric patient with this disorder.
The management of T2DM in children and adolescents is presented here. The epidemiology, presentation, diagnosis, comorbidities, and complications of pediatric T2DM are discussed separately. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents" and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus".)
DEFINITIONS
●Diabetes – Diabetes mellitus can be diagnosed based on abnormal plasma glucose (fasting or random) and oral glucose tolerance test, or hemoglobin A1c (A1C). Thresholds for diagnosing diabetes with each of these tests are shown in the table (table 1). (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Diagnosis'.)
●Obesity – T2DM is closely linked to excess weight. Body mass index (BMI) provides an index for weight in relation to height. In children and adolescents, obesity is defined as a BMI ≥95th percentile for age and sex. Overweight is defined as a BMI ≥85th and <95th percentile. Almost all youth with T2DM are overweight or obese. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Definitions'.)
GOALS — The goals of managing a child or adolescent with T2DM are:
●To achieve and maintain near-normal glycemic control (see 'Goals for glycemic control' below)
●To improve insulin sensitivity and potentially improve insulin secretion, which results in improved glycemic control
●To identify and treat, if necessary, comorbidities such as hypertension, dyslipidemia, and nonalcoholic fatty liver disease (see "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus")
●To prevent the vascular complications of T2DM (see "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Other microvascular complications')
●To avoid unplanned pregnancies in young women with T2DM, due to high risk of adverse outcomes [13] (see 'Pregnancy prevention and risk' below)
NONPHARMACOLOGIC THERAPY — Weight reduction improves glycemic control and is a crucial component of successful management of T2DM in youth. Lifestyle modifications to reduce body weight should be initiated in all patients with this disorder (algorithm 1) [14,15].
Nutrition therapy — Individualized nutrition therapy can be effective in improving glycemic control. Nutritional goals include [14-16]:
●Improve glycemic control by balancing food intake with physical activity. This may include providing small meals to avoid wide glycemic excursions.
●Provide a diet that reduces caloric intake but also improves dietary quality to meet the nutritional requirements for normal health and growth.
The patient and family should consult with a registered dietitian with experience in pediatric nutrition and diabetes if possible [12]. The dietitian can provide instruction on how to adjust dietary habits and behaviors to ensure adequate nutrition while reducing caloric intake. Consultation with a dietitian is particularly important for patients who do not achieve good glycemic control in the initial phases of treatment and require intensification of treatment. (See 'Dietary prescription' below.)
Weight goals — In children and adolescents with T2DM, the optimal goal is a 7 to 10 percent decrease in body weight in those who have completed linear growth, or a body mass index (BMI) <85th percentile for age and sex in those still growing [17]. Excessive weight causes peripheral insulin resistance and decreases insulin-mediated glucose uptake, which, in turn, places greater demands upon the already stressed insulin-producing beta cells. In adults with T2DM, weight loss reduces insulin resistance and improves insulin secretion. Similar benefits of weight reduction are seen in the pediatric age group. In obese children without T2DM, decreases in BMI of 0.5 kg/m2 or more lead to improvements in insulin sensitivity [18]. Furthermore, in 20 adolescent patients with T2DM treated with very low-calorie diets for one to four months, BMI dropped from 43.5 to 39.3 kg/m2, hemoglobin A1c (A1C) decreased from 8.8 to 7.4 percent, and pharmacologic agents were discontinued in all but 1 of the 20 participants [19]. However, very low-calorie diets may not be appropriate for longer duration treatment in children and adolescents.
Most youth with T2DM are at least 12 years old and have severe obesity; therefore, an intensive approach to weight management is warranted (ie, weight reduction rather than weight maintenance is indicated). Moreover, most youth with T2DM are in the later stages of pubertal growth and are already at or nearly at adult stature [20].
Although the goal is weight reduction, it is prudent to approach this goal stepwise. For many patients and families, it may be appropriate to set an initial goal of weight maintenance. After successful weight maintenance, further dietary intervention can focus on gradual weight loss to reach a BMI <85th percentile. A weight loss rate of 0.5 to 1 kg per month is a reasonable goal for growing youth. Adolescents who have completed puberty should have a weight loss goal of approximately 0.5 to 1 kg per week, which is the same weight loss goal recommended for adults with T2DM. This goal is challenging and may be difficult to achieve for some adolescents.
The effects of weight loss surgery on glycemic control is discussed below. (See 'Surgical therapy' below.)
Dietary prescription — Although dietary prescriptions for patients with diabetes have traditionally used meal planning (ie, patient receives recommendations for the number of servings to consume from the different food groups), this approach is often difficult to follow long-term. In addition, meal planning can place too much focus on the child, while detracting from the importance of family changes in eating.
Dietary treatment for children with obesity, with or without T2DM, focuses on a gradual change of family and individual dietary habits to better achieve long-term goals [12,16]. The dietary counseling begins by determining the patient's and family's dietary preferences; patterns of physical activity, as well as sedentary behaviors ("screen time"); family time and financial constraints; cultural background; and educational level. Once sufficient data are obtained, the counselor can begin to give advice to move the patient toward a more healthful diet. (See "Prevention and management of childhood obesity in the primary care setting".)
Patients are most likely to adhere to a diet that is adapted to their preferences and habits. Thus, dietary goals should include input from the child and family and be measurable and achievable. Important targets for counseling include (table 2):
●Decrease portion sizes.
●Substitute a fruit or vegetable for a carbohydrate-rich food. Use of glycemic index to guide food choices is an acceptable approach but has not been established to improve weight management or glycemic control [21].
●Decrease or eliminate high-caloric beverages (eg, sugar-containing soft drinks, juices) and replace them with water or calorie-free beverages.
●Reduce the frequency of eating out and increase family meals at home. In particular, youth who frequently consume fast food are more likely to have a higher caloric intake, leading to excess weight gain. Nutrition therapy should include guidance on the frequency and selection of food consumed away from home. (See "Adolescent eating habits", section on 'Fast foods'.)
Because treatment often focuses on changing behaviors, frequent visits to the dietitian and/or practitioner may be needed for ongoing assessment and support. Counseling visits at least every four weeks allows the family to implement changes and maintain motivation and provides reinforcement. The addition of a mental health clinician to the care team is important to support healthy behavioral change strategies. Ideally, the mental health clinician should have knowledge of diabetes management and the particular psychosocial challenges associated with youth-onset T2DM [22].
Physical activity — Increased physical activity, independent of its effect on body weight, improves insulin sensitivity [23]. (See "Exercise guidance in adults with diabetes mellitus".)
Youth with T2DM should be encouraged to engage in moderate to vigorous physical activity for at least one hour daily, with strength training at least three times weekly, and to decrease sedentary behaviors, eg, limiting nonacademic "screen time" (eg, television, video game, mobile device, and computer) to less than two hours daily [14,15]. In some cases, it is appropriate to start with more modest goals and then gradually reduce the allowed screen time.
Other guidance — Screening for and counseling regarding high-risk behaviors, including smoking, vaping, and alcohol use, should be performed at diagnosis and regularly thereafter [14,15]. While these behaviors can be harmful to any individual, those with T2DM are particularly vulnerable. (See "Prevention of smoking and vaping initiation in children and adolescents" and "Management of smoking and vaping cessation in adolescents" and "Contraception: Issues specific to adolescents".)
PHARMACOLOGIC AGENTS — Metformin and insulin are the first-line therapies for treatment of T2DM in children and adolescents, as adjuncts to diet and exercise. The glucagon-like peptide 1 (GLP-1) agonists liraglutide, extended-release exenatide, and dulaglutide are now approved by the US Food and Drug Administration (FDA) and are useful second-line agents. It is likely that there will be increasing use of these GLP-1 agonists before insulin initiation, given their potential benefits on weight as well as glycemic control. Further, a new study suggests benefits of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which led to FDA regulatory approval of one agent (see 'Trials of SGLT2 inhibitors' below). Consensus guidelines inform the initial and ongoing pharmacologic management of youth-onset T2DM [14,15].
Primary options
●Metformin – Metformin is the first-line therapy for most patients, in conjunction with nonpharmacologic therapy (see 'Metformin' below). It is the only biguanide available in the United States. It improves insulin responsiveness by increasing insulin-mediated glucose uptake in the peripheral tissues and also by decreasing hepatic glucose production. Metformin has the additional benefit of producing modest weight loss; this is in contrast to the weight gain often associated with insulin, thiazolidinedione, or sulfonylurea therapy. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)
●Insulin – Insulin therapy is used initially for patients who present with ketosis or severe hyperglycemia, or for patients who have mixed features of type 1 and type 2 diabetes, as described below (see 'Insulin' below). Insulin therapy is helpful for these patients because they have inadequate insulin production (due to impaired beta cell function), in addition to insulin resistance. Guidelines recommend that insulin be used when random plasma glucose concentrations are ≥250 mg/dL or hemoglobin A1c (A1C) is >9 percent (75 mmol/mol) [11]. A high proportion of individuals with T2DM ultimately require insulin therapy. (See "Insulin therapy in type 2 diabetes mellitus".)
●GLP-1 agonists – Liraglutide, extended-release exenatide, and dulaglutide are approved in the United States for use in pediatric patients ≥10 years with T2DM, as an adjunct to diet and exercise management to achieve glycemic control [24]. These drugs are incretin mimetics that act to increase glucose-dependent insulin secretion from beta cells and help to ensure an appropriate insulin response following ingestion of a meal. They may have the additional benefit of promoting modest weight loss, probably due to delayed gastric emptying and possibly through central effects on appetite. Studies in adults also show benefits on cardiovascular outcomes. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
Liraglutide is administered by subcutaneous injection once daily. Extended-release exenatide and dulaglutide are long-acting agents that are administered once weekly; this infrequent dosing reduces treatment burden compared with short-acting analogs, which may improve adherence. (See 'Trials of GLP-1 agonists' below and 'Indications for dual or triple therapy' below.)
Semaglutide is another long-acting GLP-1 agonist that is approved in the United States for T2DM in adults (in oral or subcutaneous formulation) or for weight management in adults and adolescents (subcutaneous formulation). (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus" and "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy'.)
Other drugs — Other agents used in adults with T2DM, but only rarely in youth, include:
●SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, empagliflozin, sotagliflozin [a dual SGLT1/2 inhibitor]) are second-line agents for management of T2DM in selected adults. SGLT2 is located in the proximal collecting tubule of the nephron. By inhibiting SGLT2, these agents increase urinary glucose excretion, reduce blood glucose levels, and improve A1C. In addition, there is an associated decrease in body weight. Many of these agents have benefits on cardiorenal outcomes in adults, but they also increase the risk of diabetic ketoacidosis. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
Several SGLT2 inhibitors have been investigated in the pediatric population with T2DM, including completed trials of dapagliflozin (NCT02725593, NCT03199053) and empagliflozin (NCT03429543) (see 'Trials of SGLT2 inhibitors' below). The latter trial led to FDA approval in youth ≥10 years with T2DM.
●Dipeptidyl peptidase 4 (DPP-4) inhibitors (eg, sitagliptin, linagliptin) increase insulin production and decrease the liver's production of glucose. They do not have significant effects on body weight and do not cause hypoglycemia. There are ongoing phase 3 studies of dapagliflozin with saxagliptin (NCT03199053) or canagliflozin (NCT03170518) in pediatric patients with T2DM. (See 'Trials of DPP-4 inhibitors' below and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
●Sulfonylureas (eg, glyburide and glimepiride) and meglitinides act by increasing insulin secretion. In adults, these agents have been shown to improve glycemic control but also increase body weight and convey a moderate risk of hypoglycemia. In a randomized trial in 285 youth with T2DM, glimepiride and metformin improved A1C levels to a similar degree (A1C reduced to <7 percent in 42 and 48 percent of participants, respectively). However, glimepiride caused weight gain, whereas metformin did not (0.26 kg/m2 for glimepiride versus -0.33 kg/m2 for metformin, p = 0.003) [25]. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus".)
●Thiazolidinediones, such as pioglitazone, increase insulin sensitivity and may also improve insulin secretion by preserving pancreatic beta cell function. The use of thiazolidinediones in pediatric patients was studied in the TODAY study (with rosiglitazone) [26] (see 'TODAY study' below). However, these agents are not first-line choices for any age group, due to adverse effects (including weight gain, fluid retention, heart failure, and decreased bone density), and are not approved by the FDA for use in pediatric patients with T2DM. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)
●Amylin analogs (eg, pramlintide acetate) are used to slow gastric emptying and suppress glucagon secretion, which leads to suppression of endogenous glucose output from the liver. They are administered by subcutaneous injection and are only approved for use in adult patients taking concomitant insulin. Pramlintide causes modest reductions in glycemia and body weight. (See "Amylin analogs for the treatment of diabetes mellitus".)
●Alpha-glucosidase inhibitors (eg, acarbose) delay the absorption of carbohydrates; lipase inhibitors reduce the absorption of fat. They are less effective for hyperglycemia than metformin or sulfonylureas and their use is limited by frequent gastrointestinal side effects. These drugs are only approved in adults ages 18 years and older. (See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus".)
KEY CLINICAL TRIALS — Management of T2DM in adolescents is informed by a large randomized trial of pharmacologic and nonpharmacologic therapies (TODAY study) [20,26,27]. The use of liraglutide, extended-release exenatide, and dulaglutide in the pediatric age group is based on indirect evidence from trials in adults and relatively small trials in children and adolescents.
TODAY study — The TODAY study evaluated medical treatment options in youth with T2DM and found that metformin monotherapy did not achieve durable glycemic control for a majority of participants, suggesting a need for combination pharmacotherapy early in the disease course.
The study enrolled nearly 700 youth with T2DM and randomized treatment to metformin alone, metformin plus an intensive lifestyle intervention, or metformin plus rosiglitazone [26]. Metformin was titrated to 1000 mg twice daily. During the treatment period (mean duration 3.8 years), nearly one-half of participants treated with metformin (with or without lifestyle intervention) experienced loss of glycemic control after a median time of approximately 11 months. The group treated with adjunctive rosiglitazone had slightly better glycemic outcomes, but this therapy is no longer a consideration, because of the adverse effects of rosiglitazone. Metformin appeared to have a minor benefit on weight outcomes. In an open-label extension in which participants were treated with metformin (with insulin if clinically indicated), an additional 15 percent of participants experienced loss of glycemic control after a median 5.5 years since beginning metformin [6].
Metformin was generally well tolerated. Episodes of severe hypoglycemia occurred in <1 percent of each treatment group [26]. Approximately 20 percent of participants encountered serious adverse events during the study, most of which were not considered related to study treatment.
Trials of GLP-1 agonists — Liraglutide, extended-release exenatide, and dulaglutide are approved by the US Food and Drug Administration (FDA) for children ≥10 years with T2DM.
●Liraglutide – The safety and efficacy of liraglutide as an adjunct to metformin therapy was shown in a randomized trial of 134 participants aged 10 to 17 years with T2DM (ELLIPSE trial, NCT01541215) [24]. After 26 weeks of therapy, patients treated with liraglutide along with metformin had significantly better glycemic control compared with those treated with metformin alone (change in hemoglobin A1c [A1C] relative to baseline of -0.64 percentage points versus +0.42 percentage points), as well as improvements in blood lipid profiles. At 26 weeks, 86 percent of participants assigned to liraglutide completed treatment without insulin rescue therapy, compared with 67 percent of participants assigned to placebo. Rescue therapy included basal insulin, and if hyperglycemia persisted, rapid-acting insulin was added. In an open-label extension, treatment with liraglutide with metformin for one year was associated with modest weight loss compared with metformin alone (-1.9 kg versus +0.87 kg).
The main adverse effects were gastrointestinal symptoms (nausea or vomiting), reported by 25 to 30 percent of participants treated with liraglutide and metformin, compared with 9 to 13 percent in those treated with metformin alone, and typically occurring during the first two months of therapy.
This trial was the basis for the FDA's 2019 approval of liraglutide for this age group.
●Extended-release exenatide – The safety and efficacy of extended-release exenatide in pediatric patients was evaluated in a randomized trial in 83 participants aged 10 to 17 years with T2DM as an adjunct to management with lifestyle measures (diet and exercise) with or without standard pharmacologic intervention (primarily metformin and/or insulin) (NCT01554618) [28,29]. Patients were randomized 5:2 to exenatide 2 mg or placebo. After 24 weeks of therapy, patients treated with exenatide had significantly improved glycemic control (change in A1C from baseline -0.36 versus +0.49 percentage points for placebo, with 0.85 percentage points between-group difference, p = 0.012). Changes in fasting glucose, body weight, and systolic blood pressure at 24 weeks favored exenatide, although none were statistically significant. Body weight was -0.17 kg with exenatide versus +0.88 kg for placebo. Gastrointestinal symptoms were similar between treatment and control groups (22 and 26 percent, respectively), and there were low rates of hypoglycemia during the trial.
This trial was the basis for the FDA's 2021 approval of exenatide once weekly (brand name: Bydureon BCise) for this age group. Exenatide is also available as a shorter-acting formulation (brand name: Byetta) for twice-daily administration, but this formulation was not effective in a clinical trial in adolescents (NCT00658021) and is not approved for this age group in the United States.
●Dulaglutide – Dulaglutide was evaluated in a 26-week randomized trial in 154 participants 10 to 17 years old with T2DM as an adjunct to lifestyle measures (diet and exercise), with or without standard pharmacologic intervention (metformin with or without basal insulin) [30]. Participants were randomized to receive dulaglutide at a dose of 0.75 or 1.5 mg weekly, or placebo. After 26 weeks of therapy, those treated with dulaglutide had significantly better glycemic control (change in A1C from baseline -0.6 and -0.75 percentage points for dulaglutide 0.75 mg and 1.5 mg, respectively) compared with placebo (+0.6 percentage points). There were no between-group differences in BMI. Adverse effects were similar to those described in adults. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
This trial was the basis for the FDA's 2022 approval of dulaglutide once weekly (brand name: Trulicity) in pediatric patients 10 years of age and older with T2DM.
Similar to other GLP-1 agonists, dulaglutide has a boxed warning for risk of thyroid C cell tumors. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Contraindications and precautions'.)
Other GLP-1 agonists, including oral or subcutaneous semaglutide, are approved by the FDA for T2DM in adults but not adolescents (see "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus"). One specific formulation of subcutaneous semaglutide (brand name: Wegovy) is approved for weight management in adolescents aged 12 years and older but not specifically for T2DM. (See "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy'.)
Trials of SGLT2 inhibitors
●Dapagliflozin – Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was evaluated in a 24-week randomized trial in 72 adolescents and young adults with T2DM (10 to 24 years [74 percent <18 years]) in North America, the United Kingdom, and the European Union (NCT02725593) [31]. This efficacy trial was followed by a 28-week open-label safety extension phase, during which all participants received dapagliflozin 10 mg. In the intent-to-treat analysis, the primary outcome of change in A1C from baseline to 24 weeks favored the dapagliflozin group, but the difference was not statistically significant (between-group difference -0.75 percent, 95% CI -1.65 to 0.15). In a prespecified per protocol analysis, there was a significant difference in mean A1C change, favoring the dapagliflozin group compared with placebo (change in A1C -0.51 for dapagliflozin versus +0.62 for placebo; between-group difference -1.13 percent, 95% CI -1.99 to -0.26). Adverse events were similar between groups and included nonsevere hypoglycemia (28 percent for dapagliflozin versus 18 percent for placebo).
Based on this trial, dapagliflozin was approved by the European Medicines Agency for use in children 10 years and older for treatment of insufficiently controlled T2DM, in addition to diet and exercise [32]. It may be used when metformin is not tolerated or in addition to other approved therapies for youth with T2DM. Of note, SGLT2 inhibitors are associated with an increased risk for ketoacidosis and other potential adverse events such as necrotizing fasciitis. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
In another randomized trial in adolescents 10 to 17 years old, dapagliflozin reduced A1C by 1.03 percentage points compared with placebo, with an increase in nonserious headaches (15 versus 5 percent) (NCT03199053) [33]. This trial also included a comparison group randomized to receive the dipeptidyl peptidase 4 (DPP-4) inhibitor saxagliptin versus the same placebo group. (See 'Trials of DPP-4 inhibitors' below.)
●Empagliflozin – Empagliflozin, an SGLT2 inhibitor, was evaluated in a randomized trial in 158 adolescents 10 to 17 years old with T2DM, followed by a 26-week blinded safety extension phase, during which all participants received active treatment (DINAMO study; NCT03429543) [34]. After 26 weeks of therapy, empagliflozin significantly improved glycemic control (adjusted mean change from baseline in A1C -0.84 percentage points; change in fasting glucose -35.2 mg/dL). Changes in body weight and blood pressure at 26 weeks favored empagliflozin, although none were statistically significant. The risk for hypoglycemia was higher among patients treated with empagliflozin (19.2 percent) compared with placebo (7.5 percent), similar to findings in adults. There were no cases of severe hypoglycemia or diabetic ketoacidosis. Safety outcomes at 26 and 52 weeks were similar to those seen in studies of empagliflozin in adults with T2DM. This trial was the basis for the FDA's 2023 approval of empagliflozin and empagliflozin-metformin for pediatric patients 10 years and older with T2DM [35,36].
The trial also included a comparison group randomized to receive the DPP-4 inhibitor linagliptin versus the same placebo group. (See 'Trials of DPP-4 inhibitors' below.)
Trials of DPP-4 inhibitors
●Sitagliptin – Clinical trials of sitagliptin suggests that it has little or no benefit on glycemic control for adolescents with T2DM, either as initial oral therapy or as an adjunct to treatment with metformin. In one trial, sitagliptin was evaluated as the initial oral therapy, with or without insulin, in a 20-week randomized trial in 190 adolescents with T2DM, followed by a 34-week blinded safety extension phase of sitagliptin versus metformin (NCT01485614) [37]. At weeks 20 and 54, there were no significant between-group differences in the change in A1C or in adverse events. A second trial evaluated sitagliptin versus placebo in 220 adolescents with inadequately controlled T2DM treated with metformin with or without insulin (NCT01472367, NCT01760447) [38]. Addition of sitagliptin to the regimen was associated with a modest improvement in A1C (change from baseline -0.49 percentage points) at 20 weeks, which was not sustained at 54 weeks. Thus, adjunctive treatment with sitagliptin did not provide durable glycemic benefit.
●Linagliptin – Similarly, a clinical trial of linagliptin did not show improved glycemic control in adolescents with T2DM. The study began with a 26-week randomized trial, followed by a 26-week blinded safety extension phase (DINAMO study; NCT03429543) [34]. At week 26, the adjusted mean change in A1C from baseline was not significantly different between the linagliptin and placebo groups. At 52 weeks, the linagliptin group had a further increase in A1C.
●Saxagliptin – Similarly, a trial of saxagliptin in adolescents found no significant improvement in A1C compared with placebo (NCT03199053) [33].
APPROACH TO TREATMENT — For initial treatment of adolescents with T2DM, we recommend both pharmacologic and nonpharmacologic therapy (lifestyle modification) for all patients. Laboratory measures of glycemia should be routinely monitored, and medication type and dose adjusted as needed.
The approach described below is consistent with the updated consensus guidelines from the International Society for Pediatric and Adolescent Diabetes (ISPAD) and the American Diabetes Association (ADA) [14,15]. These recommendations are based on a combination of expert opinion, observational studies, and the clinical trials of the drugs described above [20,26,27]. For some agents, the clinical trials and regulatory approvals occurred after publication of the most recent guidelines. (See 'Key clinical trials' above.)
Goals for glycemic control — We recommend the goal of strict glycemic control, defined as hemoglobin A1c (A1C) <7 percent (<53 mmol/mol), for children and adolescents with T2DM [14,15]. While clinical guidelines utilize failure to meet A1C targets as an indication to titrate therapy, in clinical practice, we also use a pattern of elevated fasting plasma glucose (FPG) levels as an indication to intensify therapy, generally using a target of FPG <130 mg/dL (7.2 mmol/L). More stringent targets (A1C <6.5 percent [47.5 mmol/mol] and FPG <110 mg/dL [6.1 mmol/L]) may be appropriate in some patients, such as those with shorter duration of diabetes or those who achieve weight loss [14,15].
If these goals seem unrealistic in the short term for an individual patient, it is reasonable initially to set a higher target (eg, A1C <7.5 or 8 percent [<58 or 64 mmol/mol]), then lower the target as tolerated by the patient. Use of realistic and attainable goals may help to engage the patient and promote adherence to medical and lifestyle therapies [11]. It should be understood that these goals define an ideal target for glycemic control; higher thresholds are used to define treatment failure and for adding a second agent to the pharmacotherapeutic regimen. (See 'Indications for dual or triple therapy' below.)
A1C reflects long-term glycemic control and is typically measured every three months. Although traditionally reported as a percent, worldwide, A1C is increasingly reported as mmol/mol (calculator 1). Blood glucose can be monitored by the patient and family using capillary samples (fingersticks) and a glucose meter. Serial measurements of fasting, premeal, and interprandial blood glucose concentrations provide direct feedback on daily glycemic control that guides ongoing care. (See "Measurements of chronic glycemia in diabetes mellitus".)
The role of continuous glucose monitoring (CGM) for the study and care of T2DM in youth is evolving. Studies of CGM as a tool for glycemic control in youth-onset T2DM are limited [39]. However, the ADA guidelines suggest CGM for adolescents who use insulin, based primarily on its utility in adults with insulin-treated T2DM [14,40,41]. We agree with this rationale and offer the technology when possible. Given that T2DM in adolescents is a more rapidly progressive disease than in adults, further studies utilizing CGM to improve outcomes in this population are needed. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Insulin treated'.)
Maintaining near-normal glycemic control has been shown to decrease the risk of long-term vascular complications in adults with T2DM and in children and adults with type 1 diabetes mellitus (T1DM). In adults with T2DM, a major randomized trial (United Kingdom Prospective Diabetes Study [UKPDS]) demonstrated that strict glycemic control (A1C ≤7 percent) reduced the risk of microvascular complications. Similar data are not available for youth with T2DM, but benefits of strict glycemic control can be inferred from these similar patient groups. (See "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Complications and screening in children and adolescents with type 1 diabetes mellitus".)
The goal of strict glycemic control is challenging to achieve. In the TODAY study cited above, 6 percent of individuals entering the run-in period were unable to maintain a modest goal of A1C <8 percent despite adequate adherence to metformin and were therefore excluded prior to randomization [20]. Among the patients who were initially able to maintain A1C <8 percent, approximately one-half failed to maintain this level of glycemic control on metformin (with or without rosiglitazone) during the study [26]. By contrast, in the ELLIPSE trial, good glycemic control (A1C <7 percent) was achieved by 64 percent of participants treated with the combination of liraglutide and metformin for 26 weeks [24].
Initial treatment — We suggest the following approach to initial management, consistent with consensus guidelines published by the ADA and ISPAD [14,15]. All patients should receive nonpharmacologic therapy consisting of counseling to support lifestyle changes that are likely to optimize insulin sensitivity, including weight reduction and physical activity (see 'Nonpharmacologic therapy' above). In addition, all patients should be treated with metformin and/or insulin, as outlined below (algorithm 1):
Metformin — In metabolically stable adolescents with T2DM and no contraindications, we suggest metformin as initial therapy, in conjunction with nonpharmacologic therapy (diet and physical activity). The results of the TODAY trial indicate that most patients will have an initial response to metformin; however, only approximately 50 percent of patients will have a sustained response. Consensus guidelines suggest that the initial regimen should depend on the degree of dysglycemia [14,15]:
●Metformin monotherapy – For patients with A1C <8.5 percent and no symptoms.
●Combination therapy with basal insulin and metformin – For patients with A1C ≥8.5 percent and hyperglycemic symptoms (polyuria, polydipsia, nocturia, or weight loss) and without ketoacidosis.
●Insulin alone – Patients who present with ketosis or ketoacidosis should initially be treated with insulin and not metformin. Metformin should be added to the regimen only after the ketosis has cleared and blood glucose values have returned to normal or near-normal concentrations with insulin therapy. (See 'Insulin' below.)
In pediatric patients, metformin is started at an oral dose of 500 mg administered once a day. The dose can be gradually increased by 500 mg increments at one-week intervals until the maximal daily dose of 2000 mg is achieved after four weeks. This is generally given as 1000 mg twice daily. Some clinicians start at the higher dose of 1000 mg daily, but clinical practice suggests that slower titration can reduce gastrointestinal side effects. The medication should be taken with meals to reduce gastrointestinal distress. Extended-release preparations of metformin administered once daily should be considered in patients who have difficulty adhering to twice-daily dosing.
Metformin is contraindicated in patients with hepatitis, impaired renal function, cirrhosis, alcoholism, cardiopulmonary insufficiency, or mitochondrial disease (including maternally inherited diabetes and deafness [MIDD] and other forms of mitochondrial diabetes) because it can cause lactic acidosis in these settings [42,43]. Therefore, we recommend that baseline liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and creatinine be measured before starting metformin therapy. If the liver enzyme levels are greater than 2.5 times the upper limit of normal, or if the serum creatinine is markedly abnormal, we recommend not starting metformin. In this situation, insulin therapy should be continued or initiated and liver enzyme levels should be measured after three to six months.
Patients taking metformin are advised to take a daily multivitamin because the absorption of vitamin B12 and folic acid can be compromised. T2DM and polycystic ovary syndrome frequently cooccur. With metformin therapy, females who previously had irregular menses and anovulatory cycles may regain normal menstrual cycles, thereby increasing their risk of unplanned pregnancy. Therefore, all females treated with metformin should be counseled regarding the need for birth control. Patients receiving metformin who are planning to undergo elective surgery should be advised to stop the metformin 24 hours before the surgery and to resume the metformin 48 hours after the procedure, provided that there are no complications. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)
Insulin — We recommend insulin therapy (starting with basal insulin with rapid-acting insulin added for ketosis or persistent hyperglycemia) for selected adolescents with T2DM and any of the following characteristics:
●Patients with ketosis or ketoacidosis. Patients with ketosis but no ketoacidosis usually can be managed as outpatients. Those with ketoacidosis should be managed as inpatients, with intravenous therapy. (See "Diabetic ketoacidosis in children: Treatment and complications".)
●Patients with mixed features of T2DM and T1DM (table 3) in whom the diagnosis is not clear. Distinguishing between the two causes of diabetes is based on clinical presentation, history, and laboratory studies. As an example, if evidence of islet cell autoimmunity is absent (negative islet cell autoantibodies) and the fasting C-peptide level is >0.6 ng/mL after stabilization (indicating substantial insulin production), then the diabetes is likely to be type 2. However, some patients may have mixed features and are difficult to classify. Such patients usually should be treated with insulin therapy. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Type 2 versus type 1 diabetes'.)
●Patients with marked hyperglycemia (plasma glucose ≥250 mg/dL [13.9 mmol/L] or A1C ≥8.5 percent) [14,15]. The rationale for insulin treatment in these patients is that severe hyperglycemia is toxic to pancreatic beta cells and treatment with insulin can help to restore endogenous insulin production.
The presence of very severe hyperglycemia (plasma glucose ≥600 mg/dL [33 mmol/L]) suggests the possibility of hyperosmolar hyperglycemic state, which is a medical emergency and requires special management. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents", section on 'Hyperosmolar hyperglycemic state'.)
Because patients with T2DM are insulin resistant, relatively high doses of insulin are needed to restore glycemic control. A typical starting dose for insulin is in the range of 0.75 to 1.25 units/kg/day (total daily dose) but may be as high as 2 units/kg per day. Glycemic control should be evaluated by self-monitoring blood glucose (fingersticks) and adjusting the insulin dose accordingly. Self-monitoring should be performed three or more times daily for patients using multiple daily insulin injections [11]. (See 'Monitoring therapy' below.)
Once ketosis has resolved and the plasma glucose has returned to normal or near-normal concentrations, metformin can be added. Some patients can then be gradually weaned off of insulin therapy and onto metformin monotherapy. To wean patients who are on basal insulin only, the insulin dose typically is tapered gradually over two to six weeks, provided that the fasting blood glucose can be maintained in the target range (<130 mg/dL and, ideally, <100 mg/dL). Patients who are not able to achieve this target range with metformin alone will require continued combination therapy with basal insulin. Patients who initially require a multiple daily injection regimen consisting of both long- and rapid-acting insulin analogs may first be transitioned to a single daily dose of long-acting basal insulin. If glycemic targets are persistently maintained, the insulin dose may be reduced and eventually discontinued.
Ongoing care — Ongoing therapeutic choices depend on the response of patients to initial therapy.
Monitoring therapy — Patients on either metformin or insulin therapy should be monitored with the following steps (algorithm 1):
●Periodic review of weight and body mass index (BMI), diet, and physical activity (table 2). The frequency of this monitoring and counseling may vary from every one to four months, depending on the patient's degree of obesity, lifestyle habits, and need for support for weight management. (See 'Weight goals' above.)
●Blood glucose self-monitoring – This should be performed at least three times daily for patients who are treated with multiple daily insulin injections or have an intercurrent illness, when changing dose or treatment regimens, or when patients are failing to meet goals for glycemic control [11]. Less frequent blood glucose self-monitoring (twice daily: fasting and two hours postprandial) is acceptable for patients on a stable regimen of long-acting insulin or metformin with good glycemic control in the absence of hypoglycemia. For those on a multiple daily injection regimen that includes prandial insulin, one should consider use of a continuous glucose monitor, especially given the positive impact of this device in adults with T2DM [44]. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Type 2 diabetes'.)
●Monitoring of A1C – This should be performed approximately every three months for most patients, especially for those failing to attain glycemic targets. A1C can be checked at six-month intervals for those with stable glycemic control at target levels. (See 'Goals for glycemic control' above.)
●Other laboratory tests are performed as part of routine testing for and management of comorbidities. (See "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus".)
Intensification of therapy
Stepwise approach — Patients who do not achieve or make progress toward attaining goals for glycemic control (ideally A1C <7 percent and FPG of <130 mg/dL [7.2 mmol/L]) require intensification of therapy [11] (see 'Goals for glycemic control' above). Intensification of therapy consists of one or more of the following steps (algorithm 1):
●Increased nonpharmacologic intervention (eg, more frequent nutritional counseling and increased physical activity)
●Review of medication adherence, followed by problem-solving to overcome management barriers
●More frequent blood glucose monitoring (three or more times daily)
●Change in medication (increase in dose or change in regimen)
Indications for dual or triple therapy — If an additional medication is needed, our choice depends on the patient's current regimen:
●Failure of monotherapy – For youth who fail monotherapy with metformin (at maximal tolerated dose), we suggest adding one of the following:
•A glucagon-like peptide (GLP-1) agonist – Liraglutide, extended-release exenatide, or dulaglutide
•Basal insulin
•A sodium-glucose cotransporter 2 (SGLT2) inhibitor – Empagliflozin, dapagliflozin (where available)
In our practice, we take this step for patients who have persistent A1C values of ≥8 percent for three to six months, despite intensified lifestyle interventions and monitoring, as described above. We usually add basal insulin in this situation, based on the greater clinical experience with this agent, but a GLP-1 agonist is an appropriate alternative, especially given its potential benefit on weight loss.
The choice between these three options depends on patient and clinician preference. Key considerations are:
•GLP-1 agonists (eg, liraglutide, extended-release exenatide, or dulaglutide) are at least as effective as basal insulin, may promote weight loss, and offer ease of dose titration, based on adult studies [45]; the glycemic benefits were confirmed in small pediatric trials (see 'Key clinical trials' above). Liraglutide requires daily subcutaneous injections. Extended-release exenatide and dulaglutide are dosed once weekly, which reduces the treatment burden compared with liraglutide or insulin. In addition, dulaglutide offers the option of dose titration if glycemic control is not achieved after four weeks. However, these GLP-1 agonists may be more costly than insulin, and there are no long-term data on their use in adolescents and no head-to-head studies comparing their efficacy with that of insulin in this age group (and only a few studies in adults).
Indirect evidence from several sources suggests possible advantages of GLP-1 agonists over insulin:
-Cardiovascular benefits of GLP-1 agonists in adults with T2DM and obesity (see "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Clinical outcomes')
-Substantial weight loss achieved by weekly subcutaneous semaglutide in adolescents with obesity (see "Prevention and management of childhood obesity in the primary care setting", section on 'Pharmacotherapy')
-The potential for serious adverse complications of youth-onset T2DM observed in the TODAY long-term follow-up study [5] (see 'TODAY study' above)
-Failure of metformin or insulin to preserve beta cell function in the RISE Peds Study [46] (data are also lacking as to whether GLP-1 agonists may have a protective effect on beta cells in humans) (see "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Gastrointestinal peptides')
Cost and insurance coverage of GLP-1 agonists may be considerations for some patients. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)
•Insulin has the advantage of greater clinical experience in adolescents and adults including long-term outcomes but the disadvantages of weight gain, need for frequent dose adjustment, risk of hypoglycemia, and need for frequent blood glucose monitoring.
•SGLT2 inhibitors (empagliflozin or dapagliflozin where available) may be a preferred option for patients reluctant or unwilling to start injection therapy. Furthermore, addition of an oral agent may help with treatment adherence. For others, these agents may be less preferred alternatives due to more modest glycemic and weight loss effects compared with GLP-1 agonists, based on studies in adults [47,48]. The SGLT2 inhibitors may offer advantages regarding cardiovascular and kidney benefits, as demonstrated in studies in adults (similar to GLP-1 agonists). (See 'Trials of SGLT2 inhibitors' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus".)
●Failure of dual therapy – For youth who are already on combination therapy with metformin (at maximal tolerated dose) and basal insulin and still fail to achieve glycemic control, we suggest adding a GLP-1 agonist (liraglutide, extended-release exenatide, or dulaglutide) or an SGLT2 inhibitor as a third agent rather than adding prandial rapid-acting insulin. Our rationale is that the GLP-1 agonists require fewer injections (once daily or once weekly, in addition to the injection for basal insulin), than a prandial insulin regimen (three daily injections). The efficacy and safety of exenatide and liraglutide are supported by data from small clinical trials in pediatric patients. An SGLT2 inhibitor is another potential add-on option to avoid adding prandial insulin. Similarly, the efficacy and safety of SGLT2 inhibitors are supported by data from small clinical trials in pediatric patients. Both the patient/family and clinician should consider the potential benefits and risks of these approaches. (See 'Trials of GLP-1 agonists' above and 'Trials of SGLT2 inhibitors' above.)
For individuals who do not tolerate metformin, another option is to treat with a combination of basal insulin, a GLP-1 agonist, and an SGLT2 inhibitor (empagliflozin or dapagliflozin [where available]). Such a regimen may have benefits for cardiovascular and renal outcomes, as suggested by studies in adults with T2DM.
Dosing of insulin, GLP-1 agonist, or SGLT2 inhibitor
●Adding insulin – When initiating basal insulin therapy for patients who fail metformin monotherapy, we administer insulin glargine (U-100 or U-300), detemir, or degludec (U-100 or U-200) at bedtime with a starting dose of 0.2 units/kg per day (up to a maximum of 1.5 units/kg/day). We choose a long-acting insulin analog to minimize the risk of nocturnal hypoglycemia compared with intermediate-acting insulin (NPH [neutral protamine hagedorn]). In addition, use of longer-acting insulin analogs, such as degludec and U-300 glargine, can aid patients who have challenges with the timely administration of injection therapy because these insulins allow for greater flexibility in timing due to their longer duration of action. The dose is then adjusted as needed to achieve targets for blood glucose and A1C (FPG <130 or sometimes <100 mg/dL; A1C <7 percent) (see 'Goals for glycemic control' above). Insulin therapy for T2DM is discussed in more detail in a separate topic review. (See "Insulin therapy in type 2 diabetes mellitus".)
If a patient on metformin alone develops an acute decompensation of glycemic control (eg, severe hyperglycemia [eg, plasma glucose ≥250 mg/dL (13.9 mmol/L) or A1C >8.5 percent] or ketoacidosis), we include multiple daily rapid-acting insulin injections in the regimen, rather than basal insulin alone, as described above. Metformin should be held during periods of acute metabolic decompensation, such as ketoacidosis, or when A1C exceeds 12 percent. (See 'Insulin' above.)
If a patient on dual therapy with metformin and basal insulin fails to achieve glycemic targets, one option is to add prandial doses of insulin (rapid-acting insulin given before each meal). Adding extended-release exenatide or liraglutide is a reasonable alternative to prandial insulin.
●Adding a GLP-1 agonist – A GLP-1 agonist (daily liraglutide, extended-release exenatide, or dulaglutide) can be added as a second agent for patients who fail monotherapy with metformin or as a third agent for those who fail combination therapy with metformin and insulin.
We suggest the following approach to dosing, similar to the protocols used in pediatric clinical trials (see 'Trials of GLP-1 agonists' above):
•Exenatide (extended-release formulation) dosing is 2 mg once weekly; it was managed without titration in the clinical trial.
•Dulaglutide is started at a dose of 0.75 mg subcutaneously once weekly. If additional glycemic control is needed, the dose may be increased to 1.5 mg once weekly (maximum dose 1.5 mg for age <18 years).
•Liraglutide is started at a dose of 0.6 mg subcutaneously once daily for at least one week. Liraglutide is dispensed in a pen, allowing for ease of use and dosing.
The liraglutide dose is increased by 0.6 mg increments until fasting glucose targets are achieved to a maximum of 1.8 mg/day. To minimize side effects, we suggest advancing the dose of liraglutide slowly (eg, increasing the dose at two-week intervals or longer), in contrast to the weekly schedule of dose advancement that was done during the ELLIPSE trial described above.
•If the patient is on insulin, the insulin dose should be reduced by 20 percent when the GLP-1 agonist is started. After initiating exenatide or completing the dose titration for liraglutide, the insulin can be increased if needed.
Gastrointestinal symptoms (nausea or vomiting) are common (25 to 30 percent of patients), typically occurring during the first two months of therapy. GLP-1 agonists appear to have some weight loss benefits. The safety and efficacy of these agents was shown in the clinical trials described above. (See 'Trials of GLP-1 agonists' above.)
Rarely, severe acute pancreatitis or thyroid cancer have been reported in patients on GLP-1 agonists. We do not generally check calcitonin levels or pancreatic enzymes prior to starting these drugs [49]. These drugs should not be used for patients with severe renal insufficiency, a history of pancreatitis, or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Contraindications and precautions'.)
●Adding an SGLT2 inhibitor – Empagliflozin is started at 10 mg orally once daily. After 12 weeks of therapy, the dose is titrated up to 25 mg if needed to achieve glycemic goals (A1C <7 percent). Dapagliflozin (where available) is started at 5 mg once daily, then increased after 12 weeks if needed to achieve glycemic goals.
Other measures — In youth treated with dual or triple therapy who fail to achieve glycemic targets, concerted efforts should be made to ensure medication adherence, improve diet, increase physical activity, and reduce body weight. If the patient appears to be adherent to the current regimen, options include:
●Intensification of insulin therapy. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Titrating dose'.)
●Consideration of weight loss surgery. The efficacy of weight loss surgery for T2DM is discussed briefly in the following section, and the indications and outcomes are discussed separately in detail. (See 'Surgical therapy' below and "Surgical management of severe obesity in adolescents".)
We do not recommend glucose-lowering agents other than metformin, insulin, or approved GLP-1 agonists or SGLT2 inhibitors in adolescent patients, except in the context of a clinical trial. No other hypoglycemic agents are approved or generally used in pediatric patients due to lack of clinical trial data and safety concerns. A number of ongoing clinical trials are evaluating the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and other SGLT2 inhibitors in adolescent patients. (See 'Pharmacologic agents' above.)
SCREENING FOR COMORBIDITIES — Comorbidities and complications of T2DM include hypertension, dyslipidemia, nonalcoholic fatty liver disease, microvascular disease (eg, retinopathy, nephropathy, and neuropathy), and cardiovascular disease. Diagnosis and management of these disorders is an essential component of the complete care of adolescents and adults with T2DM. Details are discussed in a separate topic review. (See "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus".)
PREGNANCY PREVENTION AND RISK — Teens and young women with T2DM are at risk for adverse pregnancy outcomes, as reported in the TODAY study [13]. Of 53 pregnancies, over 53 percent resulted in either pregnancy loss, still birth, prematurity, or a major congenital anomaly. It is noteworthy that only 4.8 percent of pregnant participants practiced contraception before pregnancy despite recurrent reminders during the clinical trial. These findings highlight the importance of emphasizing adequate contraception as well as providing pregnancy planning to optimize pregnancy outcomes when caring for teens and young women with youth-onset T2DM. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management" and "Contraception: Issues specific to adolescents".)
Management of T2DM during pregnancy is discussed separately. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)
SURGICAL THERAPY — Individuals with T2DM who have moderate or severe obesity are candidates for weight loss surgery (gastric bypass, sleeve gastrectomy, or adjustable banding). Eligibility for weight loss surgery includes a body mass index (BMI) >35 kg/m2, or if less than age 18, ≥120 percent of the 95th percentile of BMI for age, with T2DM or other severe comorbidity. Weight loss surgery should be particularly considered for those patients with uncontrolled glycemia and/or serious comorbidities despite intensive lifestyle and pharmacologic intervention [14,15]. (See "Surgical management of severe obesity in adolescents", section on 'Patient selection'.)
These individuals are likely to benefit from the increased insulin sensitivity and weight reduction that follows weight loss surgery. Seventy to 85 percent of adults with T2DM experience remission after gastric bypass [50,51]. Moreover, the frequency of remission seems to be inversely related to age at the time of surgery, duration of diabetes, and severity of disease [52-54]. These observations support earlier surgical intervention. (See "Outcomes of bariatric surgery", section on 'Diabetes mellitus' and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Bariatric (metabolic) surgery'.)
Weight loss surgery is occasionally employed to treat severe obesity in adolescents, and outcomes from programs with the most experience show good efficacy and safety. T2DM usually remits after surgery [53,55,56]. As an example, in a report of 29 adolescents with severe obesity and T2DM, the diabetes resolved after weight loss surgery in 95 percent and remained in remission at three years follow-up [55]. Five-year outcomes for a subset of this group documented that T2DM remained in remission in 90 percent of participants [57]. An analysis of glycemic outcomes in an age-, sex-, and BMI-matched sample of patients in Teen-LABS with participants in the TODAY study demonstrated superior glycemic control among those treated with bariatric surgery compared with medical therapy alone [58]. There were substantially more acute complications in the surgery group. The experience with weight loss surgery in adolescents is limited but growing. Selection criteria for this age group are based on an evolving understanding of the special risks and benefits of surgery for this age group, as discussed separately. There are no long-term data comparing durability of the bariatric surgery on glycemic control and other health outcomes. (See "Surgical management of severe obesity in adolescents" and "Outcomes of bariatric surgery".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in children" and "Society guideline links: Hyperglycemic emergencies".)
SUMMARY AND RECOMMENDATIONS
●Goals and rationale – Goals for management of pediatric type 2 diabetes mellitus (T2DM) include maintenance of near-normal glycemic control and treatment of comorbidities (hypertension, dyslipidemia, and nonalcoholic fatty liver diseases), with the expectation that this will reduce the risk of long-term vascular sequelae. (See 'Goals' above and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus".)
●Glycemic targets – We recommend a goal of strict glycemic control for children and adolescents with T2DM (Grade 1B). Our ideal goal for strict glycemic control is maintenance of hemoglobin A1c (A1C) below 7 percent and fasting plasma glucose (FPG) below 130 mg/dL (7.2 mmol/L). Although traditionally reported as percent, A1C is increasingly reported as mmol/mol (calculator 1). (See 'Goals for glycemic control' above.)
●Initial treatment approach – Available data indicate that optimal glycemic control is best achieved in most patients by a combination of nonpharmacologic therapy (lifestyle changes) combined with pharmacologic therapy (algorithm 1). Initial steps are:
•Nonpharmacologic – Essential lifestyle changes include reduction of excess weight by decreasing caloric intake while increasing physical activity and decreasing sedentary behaviors (eg, screen time) (table 2). (See 'Nonpharmacologic therapy' above.)
•Pharmacologic
-For most adolescents with T2DM and moderate dysglycemia (A1C 7 to 8.5 percent), we suggest initiating treatment with metformin monotherapy (Grade 2B). Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine concentrations should be measured before beginning metformin. Most patients will have an initial response to metformin, and approximately 50 percent of patients will have a durable response. (See 'Metformin' above and 'TODAY study' above.)
-For patients with severe hyperglycemia (plasma glucose ≥250 mg/dL [13.9 mmol/L] or A1C >8.5 percent) or mixed features of T2DM and type 1 diabetes mellitus (T1DM), we recommend insulin therapy in combination with metformin (Grade 1B). For patients with ketosis or ketoacidosis, insulin monotherapy should be used initially, and metformin should be added after the ketosis is cleared and blood glucose values have returned to normal or near-normal concentrations. (See 'Insulin' above.)
●Monitoring – Body weight, body mass index (BMI), and A1C should be measured every three months. For the occasional more stable patient, this interval can be extended to four to six months. Blood glucose self-monitoring also should be performed fasting and two hours postprandial daily and more frequently when changing therapy or dosing or when glycemic control is poor. (See 'Monitoring therapy' above.)
●Intensification of therapy – Patients who do not meet or make progress toward attaining goals for glycemic control should be managed by optimizing nonpharmacologic therapy and intensification of pharmacotherapy.
•For patients initially treated with metformin monotherapy (at maximal tolerated dosing) who do not achieve glycemic targets, either a glucagon-like peptide 1 (GLP-1) agonist (extended-release exenatide, dulaglutide, or liraglutide) or basal insulin analog (glargine [U-100 or U-300], detemir, or degludec [U-100 or U-200]) may be added as a second therapeutic agent. The choice depends on patient and clinician preference. Insulin has the advantage of considerable clinical experience in adolescents and adults; it has the disadvantages of weight gain, need for frequent monitoring and dose adjustment, and risk of hypoglycemia. A GLP-1 agonist may promote weight loss and also offers ease of dose titration but may be more costly than insulin. For selected patients, a sodium-glucose cotransporter 2 (SGLT2) inhibitor is a reasonable alternative, especially for patients who strongly prefer an oral therapy. (See 'Indications for dual or triple therapy' above.)
•For youth who are already on combination therapy with metformin and basal insulin and still fail to achieve glycemic control, we suggest adding a GLP-1 agonist or an SGLT2 inhibitor as a third agent rather than adding prandial rapid-acting insulin (Grade 2C). Adjunctive therapy with a GLP-1 agonist or SGLT2 inhibitor improves glycemic control and is generally well tolerated, as shown in clinical trials in adolescents. (See 'Indications for dual or triple therapy' above and 'Trials of GLP-1 agonists' above and 'Trials of SGLT2 inhibitors' above.)
•Weight loss surgery may be considered for selected adolescents with T2DM and moderate or severe obesity, particularly if the diabetes is not adequately controlled with pharmacologic intervention. (See 'Surgical therapy' above and "Surgical management of severe obesity in adolescents".)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
