pediatrics
Diabetes Mellitus in Children and Adolescents
Treatment of Diabetes in Children and Adolescents
Diet and exercise For type 1 diabetes,insulin For type 2 diabetes,metforminand sometimesinsulinorliraglutide (For recommendations about treatment, see also the American Diabetes Association's2022 standards of medical care in diabetes for children and adolescentsand the International Society for Pediatric and Adolescent Diabetes' (ISPAD)2018 guidelines for diabetes in children and adolescents.) Intensive education and treatment in childhood and adolescence may help achieve treatment goals, which are to normalize blood glucose levels while minimizing the number of hypoglycemic episodes and to prevent or delay the onset and progression of complications. Poor glycemic control and increased hospitalization rates are associated with certain socioeconomic factors. In spite of advances in diabetes technology that have improved quality of care and glycemic control, not all patients have benefited, and low-income and non-Hispanic Black children remain at higher risk of complications and adverse outcomes because of poor glycemic control. Social determinants of health (eg, socioeconomic status, neighborhood and physical environment, food environment, health care, social context) may impact the ability to maintain optimal glycemic control in children with type 1 diabetes. Lifestyle modifications that benefit all patients include Eating regularly and in consistent amounts Limiting intake of refined carbohydrates and saturated fats Increasing physical activity In general, the termdietshould be avoided in favor ofmeal planorhealthy food choices. The main focus is on encouraging heart-healthy diets low in cholesterol and saturated fats. Intype 1 diabetes,the popularity of basal–bolus regimens and the use of carbohydrate counting (parents estimate the amount of carbohydrate in an upcoming meal and use that amount to calculate the preprandialinsulindose) has changed meal plan strategies. In this flexible approach, food intake is not rigidly specified. Instead, meal plans are based on the child's usual eating patterns rather than on a theoretically optimal diet to which the child is unlikely to adhere, andinsulindose is matched to actual carbohydrate intake. Theinsulin:carbohydrate ratio is individualized but varies with age, activity level, pubertal status, and length of time from initial diagnosis. Technologic advances have allowed for greater precision and customization ofinsulindoses. A good rule of thumb for age is Birth to 5 years: 1 unitinsulinper 30 g carbohydrate 6 to 12 years: 1 unitinsulinper 15 g carbohydrate Adolescence: 1 unitinsulinper 5 to 10 g carbohydrate Intype 2 diabetes,patients should be encouraged to lose weight and thus increaseinsulinsensitivity. A good rule of thumb to determine the amount of calories needed by a child age 3 to 13 years is 1000 calories + (100 × child's age in years). Simple steps to improve the diet and manage caloric intake include Eliminating sugar-containing drinks and foods made of refined, simple sugars (eg, processed candies and high fructose corn syrups) Discouraging skipping meals Avoiding grazing on food throughout the day Controlling portion size Limiting high-fat, high-calorie foods in the home Increasing fiber intake by eating more fruits and vegetables ( see Table: Glucose and HbA1c Target Levels in Children and Adolescents with Type 1 Diabetes ) are established to balance the need to normalize glucose levels with the risk of hypoglycemia. Patients beyond the honeymoon phase (ie, patients who no longer have residual beta-cell function) should try to have ≥ 50% of blood glucose levels in the normal range (70 to 180 mg/dL [3.9 to 10 mmol/L]) and < 10% below range. Treatment goals should be individualized based on patient age, diabetes duration, access to diabetes technology (eg,insulinpumps, continuous monitoring systems), comorbid conditions, and psychosocial circumstances. The risk of hypoglycemia in children who have hypoglycemia unawareness or lack the maturity to recognize the symptoms of hypoglycemia can limit aggressive attempts to achieve treatment goals. A less stringent HbA1c target level (< 7.5% [< 58 mmol/mol]) should be considered for such patients, whereas a more stringent target level (< 6.5% [< 48 mmol/mol]) should be reserved for select patients in whom it can be achieved without significant hypoglycemia and without negative impacts on well-being. HbA1c target levels for type 1 diabetesin children and adolescents have been lowered over time in an effort to reduce complications—lower HbA1c levels during adolescence and young adulthood are associated with a lower risk of vascular complications. An HbA1c target level of < 7% (< 53 mmol/mol) is appropriate for most children, but many children and adolescents do not meet this target. An increased frequency of self-monitoring of blood glucose levels (up to 6 to 10 times per day) or use of a continuous glucose monitoring (CGM) system can improve HbA1c levels because patients are better able to adjustinsulinfor meals, have an improved ability to correct hyperglycemic values, and are potentially able to detect hypoglycemia earlier, which prevents overcorrection (ie, excessive carbohydrate intake as treatment for hypoglycemia, resulting in hyperglycemia). When used properly, intermittently scanned CGM in conjunction withinsulintherapy can be used to replace self-monitoring of blood glucose. regimen in combination with HbA1c level. A 10% change in time-in-range corresponds to about a 0.8 percentage point change in HbA1c. For example, a time-in-range of 80% corresponds to an HbA1c level of 5.9% (41 mmol/mol), 70% corresponds to 6.7% (50 mmol/mol), 60% corresponds to 7.5% (58 mmol/mol), and 40% time-in-range corresponds to an HbA1c level of 9% (75 mmol/mol) ( Treatment reference ). In addition to time-in-range, CGM provides information related to average sensor glucose, time-above-range (> 180 mg/dL [> 10 mmol/L]) and time-below-range (< 70 mg/dL [< 3.9 mmol/L]), glycemic variability, glucose management indicator, and information related to adherence (eg, active CGM time, days worn). CGM metrics derived from use over the most recent 14 days are recommended to be used in conjunction with HbA1c level. CGM data can be reported in a standardized format. The ambulatory glucose profile (AGP) is a standardized report of the mean glucose, time-in-range, and time-below-range. When using the AGP to monitor glycemia, a goal of time-in-range of > 70% with a time-below-range of < 4% may be used as a glycemic control goal along with the goal of an HbA1c target of < 7% (< 53 mmol/mol). Another report is the glucose management indicator, which provides an estimated HbA1c from mean CGM glucose levels, preferably from ≥ 14 days of data. HbA1c target levels for type 2 diabetesin children and adolescents are similar to targets in type 1 diabetes, ie < 7% (< 53 mmol/mol). Similar to type 1 diabetes, target fasting glucose levels in type 2 diabetes should be < 130 mg/dL (7.2 mmol/L). Children who fail to meet HbA1c and/or fasting glucose targets are candidates for intensified therapy (eg, withinsulin,liraglutide). More stringent targets for HbA1c (< 6.5% [< 48 mmol/mol]) and fasting blood glucose (< 110 mg/dL [6.1 mmol/L]) may be considered in patients with shorter duration of diabetes and in those treated with lifestyle interventions ormetforminalone who achieve significant weight reduction. formulations are similar to those used in adults ( see Table: Onset, Peak, and Duration of Action of Human Insulin Preparations* ). Types ofinsulinregimensinclude Multiple daily injections (MDI) regimen using basal-bolus regimen Insulinpump therapy Fixed forms of MDI regimen or premixedinsulinregimen (less common) Most people with type 1 diabetes should be treated with MDI regimens (3 to 4 injections per day of basal and prandialinsulin) orinsulinpump therapy as part of intensiveinsulinregimens with the goal of improving metabolic control. Abasal-bolus regimenis typically the preferred MDI regimen. In this regimen, children are given a daily baseline dose ofinsulinthat is then supplemented by doses of short-actinginsulinbefore each meal based on anticipated carbohydrate intake and on measured glucose levels. The basal dose can be given as a once-a-day injection (sometimes every 12 hours for younger children) of a long-actinginsulin(glargine,detemir, or degludec), with supplemental boluses given as separate injections of rapid-actinginsulin(usually aspart or lispro). Glargine, degludec, or detemir injections are typically given at dinner or bedtime and must not be mixed with short-actinginsulin. Ininsulinpump therapy,the basalinsulinis delivered at a fixed or variable rate by a continuous subcutaneous infusion of rapid-actinginsulin(CSII) through a catheter placed under the skin. Mealtime and correction boluses also are delivered via theinsulinpump. The basal dose helps keep blood glucose levels in range between meals and at night. Using aninsulinpump to deliver the basal dose allows for maximal flexibility; the pump can be programmed to give different rates at different times throughout the day and night. Insulinpump therapy is increasingly being used in children because of the potential benefits of glycemic control, safety, and patient satisfaction compared to MDI regimens. This therapy is typically preferred for younger children (toddlers, preschoolers) and overall offers an added degree of control to many children. Others find wearing the pump inconvenient or develop sores or infections at the catheter site. Children must rotate their injection and pump sites to avoid developing lipohypertrophy. Lipohypertrophy is an accumulation of lumps of fatty tissue under the skin. The lumps occur atinsulininjection sites that have been overused and can cause variation in blood glucose levels because they can preventinsulinfrom being absorbed consistently. Morefixed formsof MDI regimens are less commonly used. They can be considered if a basal-bolus regimen is not an option (eg, because the family needs a simpler regimen, the child or parents have a needle phobia, lunchtime injections cannot be given at school or daycare). In this regimen, children usually receive neutralprotamineHagedorn (NPH)insulinbefore eating breakfast and dinner and at bedtime and receive rapid-actinginsulinbefore eating breakfast and dinner. Because NPH and rapid-actinginsulincan be mixed, this regimen provides fewer injections than the basal-bolus regimen. However, this regimen provides less flexibility, requires a set daily schedule for meals and snack times, and has been largely supplanted by the analog insulins glargine and detemir because of the lower risk of hypoglycemia. Premixedinsulinregimensuse preparations of 70/30 (70%insulinaspartprotamine/30% regularinsulin) or 75/25 (75%insulinlisproprotamine/25%insulinlispro). Premixed regimens are not a good choice but are simpler and may improve adherence because they require fewer injections. Children are given set doses twice daily, with two thirds of the total daily dose given at breakfast and one third at dinner. However, premixed regimens provide much less flexibility with respect to timing and amount of meals and are less precise than other regimens because of the fixed ratios. Clinicians should use the most intensive management program children and their family can adhere to in order to maximize glycemic control and thus reduce the risk of long-term vascular complications. Hypoglycemia None 1 mg IM is usually used if neuroglycopenic symptoms (eg, behavioral changes, confusion, difficulty thinking) prevent eating or drinking. If untreated, severe hypoglycemia can cause seizures or even coma or death. Real-time continuous glucose monitoring devices can help children with hypoglycemia unawareness because they sound an alarm when glucose is below a specified range or when glucose declines at a rapid rate (see Monitoring glucose and HbA1c levels ). Ketonuria/ketonemiais most often caused by intercurrent illness but also can result from not taking enoughinsulinor from missing doses and can be a warning of impending DKA. Because early detection of ketones is crucial to prevent progression to DKA and minimize need for emergency department or hospital admission, children and families should be taught to check for ketones in the urine or capillary blood using ketone test strips. Blood ketone testing may be preferred in younger children, those with recurrent DKA, andinsulinpump users or if a urine sample is difficult to obtain. Ketone testing should be done whenever the child become ill (regardless of the blood sugar level) or when the blood sugar is high (typically > 240 mg/dL [13.3 mmol/L]). The presence of moderate or large urine ketone levels or blood ketone levels > 1.5 mmol/L can suggest DKA, especially if children also have abdominal pain, vomiting, drowsiness, or rapid breathing. Small urine ketone levels or blood ketone levels 0.6 to 1.5 mmol/L also must be addressed. When ketones are present, children are given additional short-actinginsulin, typically 10 to 20% of the total daily dose, every 2 to 3 hours until ketones are cleared. Also, additional fluid should be given to prevent dehydration. This program of measuring ketones and giving additional fluid andinsulinduring illness and/or hyperglycemia is called sick-day management. Parents should be instructed to call their health care provider or go to the emergency department if ketones increase or do not clear after 4 to 6 hours, or if the clinical status worsens (eg, respiratory distress, continued vomiting, change in mental status). As in type 1 diabetes, lifestyle modifications, with improved nutrition and increased physical activity, are important. Insulinis started in children who present with more severe diabetes (HbA1c > 9% [> 75 mmol/mol] or with DKA); glargine, detemir, or premixedinsulincan be used. If acidosis is not present,metforminis usually started at the same time.Insulinrequirements may decline rapidly during the initial weeks of treatment as endogenousinsulinsecretion increases;insulinoften can be stopped several weeks after regaining acceptable metabolic control. sensitizer and is the only oral antihyperglycemic drug approved for patients < 18 years of age. Other Oral Antihyperglycemic Medications may benefit some adolescents, but they are more expensive, and there is limited evidence for their use in youth. Liraglutideand extended-releaseexenatideareglucagon-like peptide-1 (GLP-1) receptor agonists approved for use in children > 10 years of age with type 2 diabetes and can help reduce HbA1c levels. These injectable noninsulin antihyperglycemic drugs enhance glucose-dependentinsulinsecretion and slow gastric emptying.Liraglutideis started at 0.6 mg subcutaneously once a day and may be increased weekly by 0.6 mg until control is adequate up to 1.8 mg once a day. Extended-releaseexenatidedose is 2 mg subcutaneously once/week, which may improve patient adherence. Both drugs promote weight loss, likely through the effect of delayed gastric emptying and appetite reduction. The most common adverse effects of GLP-1 agonists are gastrointestinal, especially nausea and vomiting.Liraglutideandexenatidecan be used ifmetforminis not tolerated or added on if HbA1c target levels are not achieved withmetforminalone within 3 months.Liraglutideandexenatidecan be used in place of or in combination withinsulinas part of intensive treatment of type 2 diabetes. Management of monogenic diabetes is individualized and depends on subtype. The glucokinase subtype generally does not require treatment because children are not at risk of long-term complications. Most patients with hepatic nuclear factor 4-alpha and hepatic nuclear factor 1-alpha types are sensitive to sulfonylureas, but some ultimately requireinsulin. Other oral hypoglycemics such asmetforminare typically not effective. Routine monitoring involves Multiple daily glucose checks by fingerstick or continuous glucose monitoring HbA1c measurements every 3 months Intype 1 diabetes,blood glucose levels should be monitored 6 to 10 times per day by using a glucose meter or a continuous glucose monitoring (CGM) system to optimize control. Traditionally, glucose levels should be measured using a fingerstick sample before all meals and before a bedtime snack. Levels also should be checked during the night (around 2 to 3 AM) if nocturnal hypoglycemia is a concern (eg, because of hypoglycemia or vigorous exercise during the day, or when aninsulindose is increased). Because exercise can lower glucose levels for up to 24 hours, levels should be checked more frequently on days when children exercise or are more active. To prevent hypoglycemia, children may increase carbohydrate intake or lowerinsulindosing when they anticipate increased activity. Sick-day management should be used with hyperglycemia or illness. Parents should keep detailed daily records of all factors that can affect glycemic control, including blood glucose levels; timing and amount ofinsulindoses, carbohydrate intake, and physical activity; and any other relevant factors (eg, illness, late snack, missedinsulindose). Patients withtype 2 diabetesusually self-monitor blood glucose levels less frequently than patients with type 1 diabetes, but frequency varies depending on the type of drug therapy used. Children and adolescents taking multiple dailyinsulininjections, those who are ill, and those with suboptimal control should monitor glucose levels at least 3 times a day. Those who are on stable regimens ofmetforminand only long-actinginsulin, who are meeting their targets without hypoglycemia, can monitor less frequently, typically twice a day (fasting and 2 hours postprandial). Children and adolescents with type 2 diabetes oninsulinregimens with multiple daily injections sometimes use continuous glucose monitoring systems. Intype 2 diabetes,blood glucose levels should be measured regularly but typically less often than in type 1 diabetes. The frequency of self-monitoring of blood glucose should be individualized based on the patient's fasting and postprandial glucose levels, the degree of glycemic control deemed achievable, and the available resources. The frequency of monitoring should increase if glycemic control targets are not being met, during illness, or when symptoms of hypoglycemia or hyperglycemia are felt. Once targets are achieved, home testing is limited to a few fasting and postprandial blood glucose measurements per week. HbA1c levelsshould be measured every 3 months in type 1 diabetes and in type 2 diabetes ifinsulinis being used or metabolic control is suboptimal. Otherwise, in type 2 diabetes, levels can be measured twice a year, although every 3 months is optimal. Continuous glucose monitoring(CGM) systems are a common method (> 60% of children use one) of monitoring blood glucose levels and can replace routine self-monitoring of blood glucose for some patients. They are a more sophisticated and effective approach to monitoring that uses a subcutaneous sensor to measure interstitial fluid glucose levels every 1 to 5 minutes and then translate the measurements into blood glucose values, thus more closely detecting glucose fluctuations that can then be acted upon in real time. CGM systems transmit results wirelessly to a monitoring and display device that may be built into aninsulinpump or may be a stand-alone device. By identifying times of consistent hyperglycemia and times of increased risk of hypoglycemia, CGM systems can help patients with type 1 diabetes more safely reach glycemic goals. Two types of CGM systems are currently available: real-time CGM and intermittently scanned CGM. Real-time CGM can be used in children ≥ 2 years of age. The system automatically transmits a continuous stream of glucose data to the user in real time, provides alerts and active alarms, and also transmits glucose data to a receiver, smartwatch, or smartphone. Real-time CGM should be used as close to daily as possible for maximal benefit. Intermittently scanned CGM can be used in children ≥ 4 years of age. It provides the same type of glucose data as real-time CGM but requires the user to purposely scan the sensor to obtain information and does not have alerts and alarms. Intermittently scanned CGM should be used frequently, a minimum of once every 8 hours. Children using CGM devices need to be able to measure blood glucose by fingerstick to calibrate their monitor and/or to verify readings if they are discordant from symptoms. Compared to intermittent monitoring, CGM systems can help lower HbA1c levels, increase the percentage of time-in-range, and lower the risk of hypoglycemia. Although CGM devices can be used with any regimen, they are typically worn byinsulinpump users. When used in conjunction with aninsulinpump, the combination is known as sensor-augmented pump therapy. This therapy requires manual adjustment ofinsulindoses based on CGM results. Other CGM systems are integrated with a pump and can also suspend the basal rate for up to 2 hours when glucose levels drop below a set threshold. This integration can reduce the number of hypoglycemic events, even when compared to sensor-augmented pump therapy. Closed-loopinsulinpumps can be used in children ≥ 2 years of age. These hybrid closed-loop systems automate blood glucose management through sophisticated computer algorithms that are on a smartphone or similar device and link a CGM sensor to aninsulinpump to determine blood glucose levels and controlinsulindelivery. Delivery is controlled by suspending, increasing, or decreasing basalinsulinin response to CGM values. Current hybrid closed-loop systems are not truly automated because they require users to administer a bolus for meals and snacks. These systems help more tightly controlinsulindosing and limit hyperglycemic and hypoglycemic episodes. A fully automated closed-loop system, sometimes known as a bihormonal (insulinandglucagon) artificial pancreas, continues to be evaluated and is not commercially available. Patients are screened regularly for complications depending on the type of diabetes ( see Table: Screening Children for Complications of Diabetes ). If complications are detected, subsequent testing is done more frequently. /creatinine ratio 30 to 300 mg/g) on repeat samples or with persistently Hypertension in Children (> 90th to 95th percentiles for age or ≥ 130/80 mm Hg for adolescents) who do not respond to lifestyle interventions typically require antihypertensive therapy, most commonly using an angiotensin-converting enzyme inhibitor. For children with dyslipidemia, if low-density lipoprotein (LDL) cholesterol remains > 160 mg/dL (4.14 mmol/L) or > 130 mg/dL (3.37 mmol/L) and one or more cardiovascular risk factors remain despite lifestyle interventions, statins should be considered in children > 10 years, although long-term safety is not established. 1.Beck RW, Bergenstal RM, Cheng P, et al: The relationships between time in range, hyperglycemia metrics, and HbA1c.Diabetes Technol Ther13(4):614–626, 2019. doi: 10.1177/1932296818822496 