Approach

Type 2 diabetes mellitus (T2DM) is a progressive disease, and prompt initiation and maintenance of treatment modalities to achieve and maintain normoglycaemia is critical. Goals of treatment are to promote weight loss, increase exercise capacity, normalise glycaemia and maintain haemoglobin A1c (HbA1c) at <48 mmol/mol (<6.5%), for most patients, and prevent or control comorbidities such as hypertension and dyslipidaemia.[1]​ This HbA1c goal of <48 mmol/mol (<6.5%) is lower than the goal of <53 mmol/mol (<7%) recommended in type 1 diabetes mellitus (T1DM); this is justified by a lower risk of hypoglycaemia and higher risk of micro- and macrovascular complications in youth with T2DM.[1]​ Less stringent targets may be suitable for patients at increased risk of hypoglycaemia.[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][2]​​​​​ Therapy should therefore be individualised and ideally initiated by specialist paediatric diabetes teams.

Patients with new-onset diabetes should be tested for pancreatic autoantibodies to exclude a diagnosis of T1DM.[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 T1DM is confirmed; insulin therapy should be initiated or continued and metformin discontinued. See Type 1 diabetes.

If insulin therapy is required in a non-acute setting, patients must self-monitor blood glucose to avoid hypoglycaemia, the most serious complication of insulin treatment, and to allow adjustment of doses to achieve optimal HbA1c.

Acute management of ketoacidosis or hyperglycaemic hyperosmolar state (HHS)

Ketoacidosis may be present in 5% to 25% of children with T2DM at presentation.[4]​​ Stressful events such as illness, trauma, and surgery may also cause a decline in glycaemic control and precipitate ketoacidosis.[1]​​

​HHS may form part of the initial presentation of T2DM in up to 2% of children.[4]​ Stressful events such as illness, trauma, and surgery may also cause a decline in glycaemic control and precipitate HHS.[1]​ Children and adolescents presenting with severe hyperglycaemia (blood glucose ≥33.3 mmol/L [≥600 mg/dL]) should be assessed for HHS.[1]​​

​Any child who presents in ketoacidosis with volume depletion or HHS should be admitted and placed on intravenous insulin and fluids.[4]​ Typically used fluids include full-strength (0.9%) or half-strength (0.45%) normal saline, depending on hydration status, serum sodium concentrations, and osmolality.[4]​ 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.[4]​ In general, deficits of potassium, phosphate, and magnesium are greater in HHS than ketoacidosis.[4]​ Fluid replacement should begin before starting insulin therapy.[4]​ Differences in treatment strategy between HHS 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 HHS; in ketoacidosis insulin administration can begin at least 1 hour after starting fluid replacement, while in HHS insulin should be started when plasma glucose decreases by <3 mmol/L (50 mg/dL) per hour with fluids alone.​[4]​ Mixed presentation of ketoacidosis and HHS - where children meet criteria for both ketoacidosis and have hyperosmolality - is frequently unrecognised.[4]​ In these circumstances, treatment must account for potential complications of both ketoacidosis and HHS; mental status should be monitored and frequent reassessment of circulatory status and fluid balance is necessary to guide therapy.[4]

​Once ketoacidosis or HHS 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 and insulin degludec. 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 (<4.4 to 7.2 mmol/mol [<80-130 mg/dL] fasting and <10.0 mmol/mol [<180 mg/dL] postprandial), it may be appropriate to consider discontinuing insulin therapy in selected patients.

Lifestyle modifications

All children require dietary modifications, exercise, counselling, and diabetes education.​[1][2]​​​​​​​​[76]​​​​​​​ Weight loss with its concomitant decrease in insulin resistance should be the primary goal for every individual with overweight or obesity.

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 behavioural changes and motivation are key requirements in the treatment of T2DM. Peer support interventions have been found to be useful in some studies.[77]

Referral to an experienced dietician is highly recommended and often cost-efficient. Dietary guidance to address children's over-consumption 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 carers in influencing the development of healthy eating behaviours should be provided to every family.[56]​​​ Children with T2DM with overweight/obesity should aim for at least a 7% to 10% decrease in excess weight.[1]

Low-carbohydrate diets are popular and theoretically promising for the management of T2DM 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.[78]​ 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.[78]​ 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.[79]​ 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 behaviours.[78]​ Rather than focusing purely on carbohydrate restriction, the Committee on Nutrition recommends:[78]

  • Increase dietary fibre; 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 (e.g., 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 glycaemic and cardiometabolic outcomes.

  • Regular medical follow-up of patients who do choose to follow a low-carbohydrate diet.

The American Diabetes Association (ADA) makes similar recommendations, advising that nutrition for young people with pre-diabetes and T2DM, like for all children and adolescents, should focus on key nutrition principles (i.e., eat more non-starchy vegetables, whole fruits, legumes, whole grains, nuts and seeds, and low-fat dairy products, and eat less meat, sugar-sweetened beverages, sweets, refined grains, and processed or ultraprocessed foods).​[1]

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 glycaemic control, assist with weight maintenance, and reduce comorbidities (e.g., cardiovascular risk).[1]​​[80][81][82][83][84]​​​​​ Children should also be advised to decrease sedentary recreational screen time.[1][2]​ Studies have shown that both school- and family-based approaches to exercise are effective for children at risk for T2DM.[82] School-based lifestyle intervention programmes result in decreased indexes of adiposity for children.[29]

A smoking history should be taken at initial and follow-up appointments. All children and adolescents should be advised not to smoke, including vaping and electronic cigarettes, or encouraged to quit if they already smoke.[1]​ Smoking cessation counselling should be included as a routine component of diabetes care. Patients should also be screened for substance and alcohol use at diagnosis and regularly thereafter.[1]​ As alcohol use has implications for glycaemic management and safety in young people with diabetes, patients should be educated about the risks and advised to reduce alcohol use if appropriate. All patients should be advised not to use cannabis recreationally in any form.[1]

Inadequate sleep is associated with insulin resistance in children and adolescents and contributes to T2DM development.[2]​ Sleep timing, duration, and quality should be discussed with young people and their families, and advice given on how to optimise sleep routines. This includes: encouraging adequate sleep duration according to age (9-11 hours for children aged 5-13 years and 8-10 hours for adolescents); encouraging consistent bed and wake up times and avoiding naps; and reducing use of electronic devices prior to going to sleep.[2]

While lifestyle modification is intuitively the most important intervention for children and youths with T2DM, there are no studies to support one particular approach as being effective.[85]

Patients with HbA1c <69 mmol/mol (<8.5%) and no acidosis or ketosis

Initial pharmacotherapy: metformin

  • Metformin is the first-line pharmacotherapy for all children diagnosed with T2DM who are metabolically stable with normal renal function.[1]​​ Metformin improves hyperglycaemia 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 achieved initial glycaemic control in over 90% of the participating children and adolescents, and durable glycaemic control (>2 years) in approximately 50%.[86]

  • A low dose should be given to begin with, and the dose should be increased every 1 to 2 weeks according to response and if no gastrointestinal (GI) adverse effects have occurred.[87]

  • 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 aged 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 <48 mmol/mol (<6.5%) HbA1c goal (or other individualised 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 aged ≥10 years with T2DM.

  • Liraglutide is administered as a once-daily subcutaneous injection, whereas exenatide extended-release and dulaglutide are administered once weekly.

  • GLP-1 receptor agonists have been shown to be safe and effective for decreasing HbA1c and have the added advantage of promoting weight loss at higher doses approved for obesity (note: GLP-1 receptor agonists are only approved for use in children ≥12 years for the management of obesity).[1]

  • A randomised controlled trial (RCT) of liraglutide plus metformin, with or without basal insulin, improved glycaemic control compared with placebo in children and adolescents with T2DM.[88]​ Similar impacts on glycaemic control were reported in RCTs of exenatide and dulaglutide.[89][90]​​​

  • GI adverse effects are the most common adverse effect associated with GLP-1 receptor agonists. Patients should be counselled about potential for ileus.[1]

  • 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.[1]

  • 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 T2DM 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 glycaemic control in children aged ≥10 years. The safety and efficacy of empagliflozin in children were studied in a double-blind, randomised, placebo-controlled trial in patients aged 10-17 years with inadequately controlled T2DM.[91]​ 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).[91]​ Common adverse effects in children treated with empagliflozin were generally similar to those reported in adults, except there was a higher risk of hypoglycaemia, regardless of whether they were taking other therapies for diabetes. However, no severe hypoglycaemia cases were reported.[91]

  • ​ Dapagliflozin (either alone or in combination with other therapies) is also approved in the US and Europe as an adjunct to diet and exercise for the treatment of insufficiently controlled T2DM in children aged ≥10 years. The European approval of dapagliflozin was based on the findings of one small phase 3 trial that enroled patients aged 10-24 years who were receiving standard of care for T2DM (metformin alone, insulin alone, or metformin plus insulin).[92]​ Compared with placebo, the addition of dapagliflozin did not result in a significant difference in HbA1c after 24 weeks in the intention-to-treat population.[92]​ However, a pre-specified sensitivity analysis did show a significant difference between groups, favouring dapagliflozin.[92]​ The most common adverse events reported with dapagliflozin were headache, nasopharyngitis, and vitamin D deficiency.[92]​ The US approval of dapagliflozin was based on another randomised trial in adolescents aged 10-17 years, where dapagliflozin reduced HbA1c by 1.03 percentage points compared with placebo.[93]​ Non-serious headaches were more common in participants treated with dapagliflozin compared with placebo.[93]

Subsequent pharmacotherapy: triple therapy

  • If the <48 mmol/mol HbA1c goal (<6.5%) (or other individualised 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 therapy

  • If the <48 mmol/mol (<6.5%) HbA1c goal (or other individualised 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 glycaemic 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 drugs for youth with T2DM and overweight or obesity, consider the effects of these drugs and drug-taking behaviour on their weight.[1]

Patients with HbA1c ≥69 mmol/mol (8.5%) and no acidosis with or without ketosis (pancreatic autoantibodies negative or unknown)

Initial pharmacotherapy: insulin plus metformin

  • Individuals with marked hyperglycaemia (HbA1c ≥69 mmol/mol [≥8.5%] or blood glucose ≥13.9 mmol/L [≥250 mg/dL]), polyuria, polydipsia, nocturia, and/or weight loss should be treated with basal insulin while metformin is initiated and titrated.[1]​​

  • If glycaemic 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 T1DM.[1]

  • In individuals who are negative for autoantibodies, if the <48 mmol/mol (<6.5%) HbA1c goal (or other individualised 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 the severity of hyperglycaemia, as well as the patient's school, mealtime, and sleeping schedule. Insulin regimens include:

  • Suitable long-acting basal insulins include insulin glargine and insulin degludec. 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 hypoglycaemia.[94]​ 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 or degludec) 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 glycaemic 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 pre-mixed proprietary formulation. Patients on this regimen must eat at scheduled times to avoid hypoglycaemia 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 milligrams per decilitre 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 ADA recommends starting basal insulin at 0.5 units/kg/day and titrating the dose every 2 to 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]​​

  • Continuous subcutaneous insulin infusion (CSII) may be of benefit for children with T2DM, but studies so far have only included small numbers of individuals.[95]

  • The UK Medicines and Healthcare products Regulatory Agency (MHRA) warns of cases of diabetic ketoacidosis in patients with T2DM on a combination of a GLP-1 receptor agonist and insulin who had doses of concomitant insulin rapidly reduced or discontinued.[96]

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 glycaemia 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.[97][98]​​​ 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.[97][98]

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.[97]

Further, studies have found that metabolic surgery may lead to T2DM remission (defined as an HbA1c level of <48 mmol/mol (<6.5%) which remains at that level for at least 3 months without continuation of the usual antihyperglycaemic agents) in over 95% of adolescents.[99][100][101]​​ Other beneficial effects include improvements in cardiometabolic risk factors such as dyslipidaemia and hypertension.[100][101]

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