Type 2 Diabetes in Children and Adolescents - The Next Epidemic?

Eva M. Vivian

Disclosures

Curr Med Res Opin. 2006;22(2):297-306. 

In This Article

Pharmacologic Therapy

Oral Agents

Often, non-pharmacologic measures are not adequate to achieve the desired glycemic goals.[36] Asymptomatic patients with type 2 diabetes with blood glucose levels > 126mg/dL and < 250mg/dL should be started on oral antidiabetic agents. Patients who present with blood glucose levels > 250 mg/dL, or with signs of hyperglycemia or ketosis, should be started on insulin therapy (Figure 1). As blood glucose levels normalize, the insulin dose may be reduced and oral antidiabetic agents can be initiated. Strict glycemic control has been shown to delay the progression of diabetes-related complications, such as retinopathy, renal disease, or neuropathy.[37,38]

Figure 1.

Treatment algorithm for type 2 diabetes in children[40,45,56]. FPG = fasting plasma glucose; NPH = neutral protamine

The Diabetes Control and Complication trial (DCCT)[37] and United Prospective Diabetes Study (UKPDS 33)[38] reported that tight glycemic control can delay the progression of microvascular complications. Although these studies were conducted in adults with diabetes, every attempt should be made to achieve an HbA1c goal of less than 7% in children and adolescents with diabetes.[28]

Currently, metformin is the only oral antidiabetic agent approved for use by the Federal Drug Administration (FDA) in pediatric patients 10 years of age or older.[28] Jones et al..[39] evaluated the safety and efficacy of metformin in reducing blood glucose levels in 82 children with type 2 diabetes, aged 10-16 years, for 16 weeks. Patients were randomized to receive metformin (≤ 2000 mg daily) or placebo for 16 weeks. At the end of the study, patients who received metformin had a mean change in fasting plasma glucose, from baseline, of -42.9mg/dL compared with a +21.4mg/dL increase for the placebo group ( p < 0.001). Mean HbAvalues were significantly lower for the metformin group compared with the placebo group (7.5 vs. 8.6%, respectively; p < 0.001).[39]

Metformin decreases hepatic glucose production and enhances muscle insulin sensitivity, but does not stimulate insulin secretion; therefore there is no risk of hypoglycemia when it is used as monotherapy. Metformin use can result in weight loss and reduction in low density lipoprotein (LDL) cholesterol and triglyceride levels. Treatment with metformin may stabilize ovulatory abnormalities in girls. Metformin is contraindicated in patients with renal insufficiency and should be discontinued with the administration of radiocontrast material.[40,41]

Monotherapy with metformin is recommended as the first line, unless contraindicated. The recommended starting dose of metformin in pediatric patients is 500 mg, given twice a day with meals. Dosage increases should be made in increments of 500mg weekly up to a maximum dose of 2000 mg daily.[41]

The various different classes of oral agents used to treat type 2 diabetes target different defects in the pathophysiology of diabetes. Therefore they may be used in combination to complement each other if monotherapy fails to achieve desired glycemic goals. The sulfonylureas (glyburide, glipizide or glimepiride) or thiazolidinediones (pioglitazone and rosiglitazone) are most frequently used in combination with metformin. Sulfonylureas stimulate insulin secretion and reduce HbA1c levels by 1–2%. Sulfonylureas may cause weight gain and are associated with the highest incidence of hypoglycemia among the oral antidiabetic agents. The nonsulfonylureas produce short-term promotion of glucose stimulated insulin secretion (repaglinide and nateglinide). In common with the sulfonylureas, the nonsulfonylureas may cause hypoglycemia and weight gain. Glucosidase inhibitors slow the hydrolysis of complex carbohydrates and carbohydrate absorption (acarbose and miglitol). The glucosidase inhibitors reduce HbA1c by 0.5−0.9%. These agents may cause flatulence and gastrointestinal discomfort. The thiazolidinediones improve peripheral insulin sensitivity and reduce HbA1c by 0.5−1.5% The thiazolidinediones do not cause hypoglycemia when used as monotherapy, but may cause edema and weight gain. The sulfonylureas, nonsulfonylureas, glucosidase inhibitors, and thiazolidinediones have not received approval by the FDA for use in the pediatric population.[28,40,42]

Insulin Therapy

Insulin therapy is indicated for children or adolescents with type 2 diabetes who have a consistently elevated fasting plasma glucose (FPG) level of ≥ 250mg/dL and the presence of ketonemia, ketonuria, and/or polyuria, polydipsia, and weight loss. Patients who fail to achieve glycemic control with combination antidiabetic agents should also be initiated on insulin therapy. Insulin therapy is also warranted when oral antidiabetic agents are contraindicated (e.g., renal failure, liver failure or chronic heart failure) (Figure 1).[28,42]

Several insulin preparations are available for the treatment of diabetes. All preparations of insulin are equally effective in lowering blood glucose levels. The features that distinguish the different insulins are the onset, peak and duration of action ( Table 3 ).[43]

These preparations include rapid-acting insulin (lispro, aspart, and glulisine insulin), short-acting preparations (regular insulin), intermediate acting insulin preparation (neutral protamine hagedorn [NPH]), and long acting insulin (glargine). The short and rapid forms are used to mimic a bolus release of insulin, and the intermediate and long acting types are designed to mimic basal release of insulin from the pancreas.[43,44]

A single or bedtime dose of insulin can be given to children or adolescents with type 2 diabetes who have failed to achieve glycemic control on two oral agents. The oral agents should be continued at the same dose. The use of metformin or a sulfonylurea, in combination with insulin, may actually lower the insulin requirement.[43,45] Thiazolidinediones should be used with caution in combination with insulin due to the increased risk of weight gain, pulmonary edema, and heart failure.[46,47]

There is a risk of hypoglycemia in patients with type 2 diabetes with bedtime insulin. Patients should be told to check their blood glucose levels before retiring and to eat a snack, consisting of 15-30 g of carbohydrates, if their blood glucose levels are less than 120 mg/dL.[46,47]

Many patients will fail to achieve their glycemic goals with once daily insulin because the therapy is initiated so late in the disease progression that there is little beta-cell function left.[43,44,47] Patients who require additional coverage during the day may be given a conventional insulin-therapy that consists of 2 insulin injections daily. Intermediate acting NPH insulin may be given twice a day. The morning injection will cover basal glucose production during the day and the dinner injection will inhibit nocturnal hepatic glucose production. A rapid or short-acting insulin, combined with an intermediate form, may be given at breakfast and dinner. The rapid or short-acting insulin will serve as a prandial insulin for breakfast or dinner, and the intermediate acting NPH insulin will provide the necessary basal coverage. Another alternative would be the administration of premixed insulin (either 70% NPH, 30% regular, or 75% neutral protamine lispro, 25% lispro) at breakfast and dinner. The premixed insulins are not recommended until a patient's insulin requirements have been determined as they limit the patient's ability to alter the dose of either insulin.[43,44]

Short acting (regular) or rapid acting (lispro or aspart) insulin can be used before breakfast, lunch, and dinner; a long acting basal insulin (glargine) is used at breakfast. This regimen, often referred to as 'the poor man's pump', is ideal because it mimics the natural physiologic response to a glucose load. The basal insulin dose is usually 40-55% of the total insulin requirement. The prandial insulin doses are usually titrated to maintain postprandial blood glucose levels between 120 mg/dL and 140 mg/dL. The prandial insulin dose may vary based on the carbohydrate content of each meal.[43,44,47] The use of insulin glargine during insulin combination therapy in patients with type 2 diabetes offers some advantages, compared to intermediate insulin, because it is associated with less nocturnal hypoglycemia and better glycemic control.[43,44,47]

Education is an important component in achieving treatment goals. Children, adolescents, and caregivers should receive extensive training on the proper administration and storage of insulin, medical nutrition therapy, treatment of hypoglycemia, and other aspects of diabetes self-management prior to initiating insulin therapy. Many children are afraid of needles and have apprehensions about injecting themselves. However, the needles used for insulin injections are fine 31 gauge needles. Children often prefer the insulin pen as it is more convenient to use at school and at social functions. The insulin pen is also an alternative for children who have difficulty drawing up and mixing insulin. Patients should also receive education about other aspects of diabetes self-management such as glucometer training, treating hypoglycemia, and carbohydrate counting.[42]

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