Approach
Type 2 diabetes mellitus (T2DM) is a progressive disease, and prompt initiation and maintenance of treatment modalities to achieve and maintain normoglycemia is critical. Goals of treatment are to promote weight loss, increase exercise capacity, normalize glycemia and maintain hemoglobin A1c (HbA1c) at <7% (<53 mmol/mol), decrease acanthosis nigricans, and prevent or control comorbidities such as hypertension and dyslipidemia. More stringent HbA1c targets (such as <6.5% [<48 mmol/mol]) may be appropriate for selected individual patients and will minimize the risk of long‑term complications.[1] Appropriate patients include those with short duration of diabetes and lesser degrees of beta-cell dysfunction and patients who achieve significant weight improvement when treated with lifestyle or metformin only.[1] Less stringent targets (e.g., HbA1c 7.5% [58 mmol/mol]) may be suitable for patients at increased risk of hypoglycemia.[1]
Treatment varies depending on the clinical presentation, initial blood glucose values and HbA1c, and the presence or absence of acidosis and/or ketosis.[1][63] Therapy should therefore be individualized, and ideally initiated by specialist pediatric diabetes teams.
Patients with new-onset diabetes should be tested for pancreatic autoantibodies to exclude a diagnosis of type 1 diabetes.[1] Results of pancreatic autoantibody testing may not always be available at the initiation of treatment. Treatment will need to be adjusted if patients are positive for pancreatic autoantibodies and a diagnosis of type 1 diabetes is confirmed; insulin therapy should be initiated or continued and metformin discontinued. See Type 1 diabetes mellitus.
If insulin therapy is required in a nonacute setting, patients must self-monitor blood glucose to avoid hypoglycemia, the most serious complication of insulin treatment, and to allow adjustment of doses to achieve optimal HbA1c.
Acute management of ketoacidosis or hyperosmolar hyperglycemic nonketotic syndrome
Ketoacidosis may be present in 5% to 25% of children with type 2 diabetes at presentation.[64] Stressful events such as illness, trauma, and surgery may also cause a decline in glycemic control and precipitate ketoacidosis.[1]
Hyperosmolar hyperglycemic nonketotic syndrome (HHNS) may form part of the initial presentation of type 2 diabetes in up to 2% of children.[64] Stressful events such as illness, trauma, and surgery may also cause a decline in glycemic control and precipitate HHNS.[1] Children and adolescents presenting with severe hyperglycemia (blood glucose ≥600 mg/dL [≥33.3 mmol/L]) should be assessed for HHNS.[1]
Any child who presents in ketoacidosis with volume depletion or HHNS should be admitted and placed on intravenous insulin and fluids.[64] Typically used fluids include full-strength (0.9%) or half-strength (0.45%) normal saline, depending on hydration status, serum sodium concentrations, and osmolality.[64] Serum potassium concentrations need to be closely monitored during treatment and replaced as necessary. Deficits in phosphate and magnesium may also need to be addressed.[64] In general, deficits of potassium, phosphate, and magnesium are greater in HHNS than ketoacidosis.[64] Fluid replacement should begin before starting insulin therapy.[64] Differences in treatment strategy between HHNS and ketoacidosis include the volume of fluid administered and the timing of insulin administration: in ketoacidosis the rates of fluid infusion are substantially lower than for HHNS; in ketoacidosis insulin administration can begin at least 1 hour after starting fluid replacement, while in HHNS insulin should be started when plasma glucose decreases by <50 mg/dL (3 mmol/L) per hour with fluids alone.[64] Mixed presentation of ketoacidosis and HHNS - where children meet criteria for both ketoacidosis and have hyperosmolality - is frequently unrecognized.[64] In these circumstances, treatment must account for potential complications of both ketoacidosis and HHNS; mental status should be monitored and frequent reassessment of circulatory status and fluid balance is necessary to guide therapy.[64]
Once ketoacidosis or HHNS has resolved, patients should be switched from intravenous insulin to subcutaneous basal-bolus insulin, and metformin should be initiated.[1] Suitable long-acting basal insulins include insulin glargine, insulin degludec, and insulin detemir. The intermediate-acting insulin neutral protamine Hagedorn (NPH) is also available but is used less commonly. Short-acting bolus insulins include insulin lispro, insulin aspart, and insulin glulisine.
Once fasting and postprandial blood glucose values are restored to normal or near-normal levels (<80-130 mg/dL [<4.4 to 7.2 mmol/mol] fasting and <180 mg/dL [<10.0 mmol/mol] postprandial), it may be appropriate to consider discontinuing insulin therapy in selected patients.
Lifestyle modifications
All children require dietary modifications, exercise, counseling, and diabetes education.[1][63][66][67] Weight loss with its concomitant decrease in insulin resistance should be the primary goal for every individual.
Effective treatment requires a motivated and informed family who are willing to engage in lifestyle modifications that involve the entire family, not just the affected child. It may be beneficial to include a psychologist or a social worker early in the disease, as behavioral changes and motivation are key requirements in the treatment of T2DM. Peer support interventions have been found to be useful in some studies.[68]
Referral to an experienced dietitian is highly recommended and often cost-efficient. Dietary guidance to address children's overconsumption of energy-dense, nutrient-poor foods and beverages, physical activity patterns, the impact of school meals on children's diets, and the roles of parents and caregivers in influencing the development of healthy eating behaviors should be provided to every family.[48] Children with type 2 diabetes with overweight/obesity should aim for at least a 7% to 10% decrease in excess weight.[1] Calories need to be restricted to achieve recommended weight loss. Nutrition advice needs to be tailored to the needs of each individual patient, preferably offering diverse food choices to ensure compliance, with an optimal mix of carbohydrate, fats, and protein. Protein intake should not exceed the recommended daily allowance of 0.8 g/kg/day.[1]
Low-carbohydrate diets are popular and theoretically promising for the management of type 2 diabetes in children, but evidence is currently insufficient to support their widespread use, according to a 2023 report by the American Academy of Pediatrics’ Committee on Nutrition.[69] There is no standard definition of a low-carbohydrate diet, but in general moderate carbohydrate restriction can be defined as 26% to 44% of total calorie intake, low carbohydrate as below 26% of total calories, and very low-carbohydrate as 20-50 g of carbohydrate per day.[69] In one retrospective study of 20 children (mean age 14.5 years) who followed a ketogenic, very-low-calorie diet for an average of 60 days, mean HbA1c fell from 8.8% to 7.4%, mean BMI fell from 43.5 kg/m² to 39.3 kg/m², and all but one child was able to discontinue insulin and metformin.[70] However, these potential benefits need to be weighed against the risks of carbohydrate restriction for children with diabetes, notably growth deceleration, nutritional deficiencies, poor bone health, nutritional ketosis that cannot be distinguished from ketosis resulting from insulin deficiency, and disordered eating behaviors.[69] Rather than focusing purely on carbohydrate restriction, the Committee on Nutrition recommends:[69]
Increase dietary fiber; reduce consumption of nutrient-poor carbohydrates, particularly processed foods with high amounts of refined grains and added sugars.
Eliminate sugar-sweetened beverages: this significantly improves blood glucose and weight management.
For patients in whom weight loss or maintenance is medically indicated, a reduced-energy diet, irrespective of carbohydrate content, is most important for achieving weight loss.
Consider following a healthy dietary pattern strategy (i.e., Mediterranean diet, Dietary Guidelines for Americans) and strive for 60 minutes per day of moderate to vigorous aerobic activity to reduce obesity, improve diabetes-related health outcomes, and promote optimal glycemic and cardiometabolic outcomes.
Regular medical follow-up of patients who do choose to follow a low-carbohydrate diet.
At least 60 minutes of moderate to vigorous aerobic exercise daily, and strength training on at least 3 days per week should be implemented to help improve glycemic control, assist with weight maintenance, and reduce comorbidities (e.g., cardiovascular risk).[1][71][72][73][74][75] Studies have shown that both school- and family-based approaches to exercise are effective for children at risk for T2DM.[73] School-based lifestyle intervention programs result in decreased indexes of adiposity for children.[33]
A smoking history should be taken at initial and follow-up appointments. All children and adolescents should be advised not to smoke, including electronic cigarettes, or encouraged to quit if they already smoke.[1] Smoking cessation counseling should be included as a routine component of diabetes care.
While lifestyle modification is intuitively the most important intervention for children and youth with T2DM, there are no studies to support a specific approach as being effective.[76]
Patients with HbA1c <8.5% and no acidosis or ketosis
Initial pharmacotherapy: metformin
Metformin is the first-line pharmacotherapy for all children diagnosed with type 2 diabetes who are metabolically stable with normal renal function.[1] Metformin improves hyperglycemia primarily through its suppression of hepatic glucose production, especially hepatic gluconeogenesis. It also causes anorexia and a modest amount of weight loss.
The recommendation for initial treatment with metformin is supported by the TODAY study, which showed that metformin monotherapy provided durable glycemic control in approximately 50% of the participating children and adolescents.[77]
A low dose should be given to begin with, then the dose should be increased every 1-2 weeks according to response and if no gastrointestinal (GI) adverse effects have occurred.[78]
An extended-release formulation is available in some countries and can be given once daily. The extended-release formulation is preferred over the immediate-release formulation due to less frequent GI adverse effects; however, safety and efficacy of the extended-release preparation has not been established in children.
Metformin is also available in a solution for children unable to swallow tablets.
Subsequent pharmacotherapy: glucagon-like peptide 1 (GLP-1) receptor agonist or sodium-glucose cotransporter-2 (SGLT2) inhibitor (in children ages 10 years or older).
Patients with new-onset diabetes should be tested for pancreatic autoantibodies to exclude a diagnosis of type 1 diabetes.[1]
In individuals who are negative for autoantibodies, if the <7% HbA1c goal (<53 mmol/mol) (or other individualized target) is not achieved with the maximum dose of metformin therapy, addition of a GLP-1 receptor agonist or a SGLT2 inhibitor is recommended.[1]
GLP-1 receptor agonists
Liraglutide, exenatide, and dulaglutide are the only GLP-1 receptor agonists approved for use in children ages ≥10 years with type 2 diabetes.
Liraglutide is administered as a once-daily subcutaneous injection, whereas exenatide extended-release and dulaglutide are administered once weekly.
A randomized controlled trial (RCT) of liraglutide plus metformin, with or without basal insulin, improved glycemic control compared with placebo in children and adolescents with type 2 diabetes.[79] Similar impacts on glycemic control were reported in RCTs of exenatide and dulaglutide.[80][81]
GI adverse effects are the most common adverse effect associated with GLP-1 receptor agonists.
GLP-1 receptor agonists are contraindicated in those with a past medical history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2.
Note that basal insulin may be considered as an alternative to a GLP-1 receptor agonist in some patients (e.g., those who do not meet criteria for a GLP-1 receptor agonist).[1]
SGLT2 inhibitors
SGLT2 inhibitors are approved for use in children in some countries, offering a new class of drugs for the management of type 2 diabetes in children.
Empagliflozin (either alone or in combination with other therapies) is approved in the US and Europe as an adjunct to diet and exercise to improve glycemic control in children ages ≥10 years. The safety and efficacy of empagliflozin in children were studied in a double-blind, randomized, placebo-controlled trial in patients ages 10 to 17 years with inadequately controlled type 2 diabetes.[82] The trial found that, at week 26, treatment with empagliflozin was superior in reducing HbA1c compared to placebo (0.84% HbA1c decrease with empagliflozin as compared to placebo).[82] Common adverse effects in children treated with empagliflozin were generally similar to those reported in adults, except there was a higher risk of hypoglycemia, regardless of whether they were taking other therapies for diabetes. However, no severe hypoglycemia cases were reported.[82]
Subsequent pharmacotherapy: triple therapy
If the <7% HbA1c goal (<53 mmol/mol) (or other individualized target) is not achieved after the addition of a GLP-1 receptor agonist or SGLT2 inhibitor to metformin, addition of the third drug (either a GLP-1 receptor agonist or SGLT2 inhibitor, whichever was not used yet) is recommended before initiating insulin therapy.[1]
Subsequent pharmacotherapy: insulin
If the <7% HbA1c goal (<53 mmol/mol) (or other individualized target) is not achieved after the addition of both, a GLP-1 receptor agonist and SGLT2 inhibitor to metformin therapy, basal insulin is recommended if not already used.[1]
If glycemic targets are not met on escalating doses of basal insulin, addition of bolus insulin should be considered (i.e., with multiple injections of prandial insulin, or insulin pump therapy).[1]
When choosing glucose-lowering medications for youth with type 2 diabetes and overweight or obesity, consider the effects of medications and medication-taking behavior on their weight.[1]
Patients with HbA1c ≥8.5% with no acidosis with or without ketosis (pancreatic autoantibodies negative or unknown)
Initial pharmacotherapy: insulin plus metformin
Individuals with marked hyperglycemia (HbA1c ≥8.5% [≥69 mmol/mol] or blood glucose ≥250 mg/dL [≥13.9 mmol/L]), polyuria, polydipsia, nocturia, and/or weight loss should be treated with basal insulin while metformin is initiated and titrated.[1]
If glycemic targets are not met on escalating doses of basal insulin, addition of bolus insulin should be considered (i.e., with multiple injections of prandial insulin, or insulin pump therapy).[1]
Subsequent pharmacotherapy: GLP-1 receptor agonist and/or SGLT2 inhibitor
Patients with new-onset diabetes should be tested for pancreatic autoantibodies to exclude a diagnosis of type 1 diabetes.[1]
In individuals who are negative for autoantibodies, if the <7% HbA1c goal (<53 mmol/mol) (or other individualized target) is not achieved on basal or basal-bolus insulin plus metformin, addition of either a GLP-1 receptor agonist or SGLT2 inhibitor should be considered.[1]
If the goal is still not met, addition of the fourth drug (either a GLP-1 receptor agonist or SGLT2 inhibitor, whichever was not used yet) is recommended before intensifying insulin therapy.[1]
Designing an insulin regimen
The choice of insulin regimen and dose depends on the severity of hyperglycemia, as well as the patient's school, mealtime, and sleeping schedule.
Suitable long-acting basal insulins include insulin glargine, insulin degludec, and insulin detemir. The intermediate-acting insulin neutral protamine Hagedorn (NPH) is also available but is used less commonly. The Endocrine Society recommends using a long-acting insulin rather than NPH insulin for patients on basal insulin who are at a high risk of hypoglycemia.[83] Suitable short-acting bolus insulins include insulin lispro, insulin aspart, and insulin glulisine.
A basal-bolus regimen consists of a long-acting basal insulin (e.g., glargine, degludec, or detemir) at bedtime plus a short-acting insulin bolus (e.g., lispro, aspart, or glulisine) before each meal. Patients on basal-bolus insulin can learn to count carbohydrates and cover what they eat with bolus insulin in addition to covering elevated blood glucose, to achieve better glycemic control.
An intermediate-acting insulin such as NPH may also be given in combination with a short-acting insulin, either mixed by the patient or in a premixed proprietary formulation. Patients on this regimen must eat at scheduled times to avoid hypoglycemia at times of insulin peaks.
Motivated patients may be considered for correction-dose insulin treatment. Insulin sensitivity, which determines the sliding scale, is calculated for each patient as: 1800/total daily dose of insulin. This rule estimates the milligram per deciliter drop in blood glucose for every unit of rapid-acting insulin taken. Patients are taught to administer the appropriate fast-acting insulin dose based on the blood glucose values and food intake.
In general, the American Diabetes Association recommends starting basal insulin at 0.5 units/kg/day and titrating the dose every 2-3 days based on blood glucose values.[1]
In children initially treated with insulin and metformin who are meeting glucose targets according to blood glucose monitoring values or continuous glucose monitoring (CGM), insulin can be tapered over a period of 2 to 6 weeks by decreasing insulin dose by 10% to 30% every few days.[1]
In patients in whom basal-bolus insulin is indicated, an insulin pump may be considered as an alternative to a regimen of multiple daily injections if the individual is able to manage the device safely.[1]
The UK Medicines and Healthcare products Regulatory Agency warns of cases of diabetic ketoacidosis in patients with type 2 diabetes on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued.[84]
Metabolic surgery
Metabolic surgery, also known as bariatric surgery, may be appropriate for adolescents with class 2 obesity or higher (BMI >35 kg/m² or 120% of 95th percentile for age and sex, whichever is lower) and uncontrolled glycemia and/or serious comorbidities despite pharmacotherapy and lifestyle modifications.[1] Sleeve gastrectomy and Roux-en-Y gastric bypass are the most commonly performed bariatric procedures in adolescents.[85][86] Such surgery is generally safe and effective in adolescents, with short-term studies showing that it is comparable to metabolic surgery in adults in terms of major complications, readmissions, and mortality.[85][86]
The World Gastroenterology Organisation and International Federation for the Surgery of Obesity and Metabolic Diseases note that bariatric surgery is the most effective treatment for severe obesity in adolescents.[85]
Further, studies have found that metabolic surgery may lead to type 2 diabetes remission in over 95% of adolescents. Other beneficial effects include improvements in cardiometabolic risk factors such as dyslipidemia and hypertension.[87][88]
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