Medication Summary
In general, the treatment of type 2 diabetes in children follows the same rationale as does treatment for the disease in adults. The safety and efficacy of most noninsulin hypoglycemic therapies in children and adolescents with type 2 diabetes have not been established; however, physicians have prescribed drugs typically used in adults to treat children and adolescents. Among all of the noninsulin drugs currently in use to treat type 2 diabetes in adults, the US Food and Drug Administration (FDA) has approved metformin, liraglutide, and exenatide extended-release for use in children with type 2 DM.
Biguanides
Class Summary
These agents reduce hepatic glucose production; they also increase peripheral insulin sensitivity. Metformin rarely induces hypoglycemia. Because of its anorexigenic effects, many treated children maintain or lose weight. Since metformin can lead to ovulatory cycles and resumption of regular menses in patients with PCOS, appropriate counseling should be provided to sexually active adolescents.
Kooy et al found improved body weight, glycemic control, and insulin requirements when metformin was added to insulin in type 2 diabetes mellitus. No improvement of an aggregate of microvascular and macrovascular morbidity and mortality was observed; however, risk reduction of macrovascular disease was evident after a follow-up period of 4.3 years. Because of these sustained beneficial effects, the policy to continue metformin treatment after the introduction of insulin in type 2 diabetes mellitus should be followed unless contraindicated. [54]
Metformin (Glucophage, Glumetza, Riomet)
Metformin use frequently results in weight loss and mild improvement of all aspects of the lipid profile. It cannot be used in renal or hepatic insufficiency or decompensated congestive heart failure requiring pharmacologic therapy (due to an increased risk for lactic acidosis).
Metformin can be used as monotherapy or with sulfonylureas, glitazones, or insulin. It reduces hepatic glucose output, may decrease intestinal absorption of glucose, and may increase glucose uptake in peripheral tissues. It is a major drug used in obese patients with type 2 diabetes.
Because of adverse gastrointestinal (GI) effects from metformin, titrate the drug slowly and have patients take the medication during (rather than before) meals. Many patients tolerate metformin best if it is administered in the middle or at the end of the meal. The drug is available in immediate-release (IR) or extended-release (ER) form. Only the IR form has been approved for children.
Sulfonylureas
Class Summary
These agents promote insulin release from the pancreas.
Chlorpropamide
Chlorpropamide may increase insulin secretion from pancreatic beta cells.
Glipizide (Glucotrol, Glucotrol XL)
Glipizide is a second-generation sulfonylurea that stimulates the release of insulin from pancreatic beta cells.
Glyburide (DiaBeta, Glynase, PresTab)
Glyburide is a second-generation sulfonylurea. It may be started at a high dose in patients with severe hyperglycemia and in those with symptoms, if home glucose monitoring and close follow-up can be arranged.
Tolbutamide
Tolbutamide increases insulin secretion from pancreatic beta cells.
Meglitinides
Class Summary
These agents promote short-term insulin secretion from the pancreas and are designed to be taken immediately before meals.
Repaglinide (Prandin)
Stimulates insulin release from pancreatic beta cells.
Nateglinide (Starlix)
Nateglinide is an amino acid derivative that stimulates insulin secretion from the pancreas (within 20 minutes of oral administration), which, in turn, reduces blood glucose levels. The drug's action depends on functional beta cells in pancreatic islets. Nateglinide interacts with the adenosine triphosphate (ATP) ̶ sensitive potassium channel on pancreatic beta cells.
Alpha-glucosidase inhibitors
Class Summary
These agents lower postprandial glucose by slowing glucose absorption and delaying the hydrolysis of ingested complex carbohydrates and disaccharide. They must be taken immediately before meals.
Acarbose (Precose)
Acarbose delays the hydrolysis of ingested complex carbohydrates and disaccharides and the absorption of glucose. It inhibits the metabolism of sucrose to glucose and fructose.
Miglitol (Glyset)
Miglitol delays glucose absorption in the small intestine and lowers postprandial hyperglycemia.
Thiazolinediones (glitazones)
Class Summary
The first of this class, troglitazone, was removed from the US market due to fatal hepatic necrosis. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by enhancing insulin sensitivity. The drug is a potent, highly selective agonist for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and use, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. [55, 56]
A meta-analysis reported an increased risk of myocardial infarction and heart-related death in patients treated with rosiglitazone. The report prompted the FDA to issue an alert on May 21, 2007, to patients and healthcare professionals, enjoining patients to discuss the issue with their physician in order to make individualized decisions regarding their care. A large-scale phase IV trial specifically designed to study cardiovascular outcomes of rosiglitazone is under way. Whether this warning also applies to the other thiazolidinediones (eg, pioglitazone) is unknown.
As of September 2010, the FDA was requiring a restricted access program to be developed for rosiglitazone under a risk evaluation and mitigation strategy (REMS). Patients currently taking rosiglitazone and benefiting from the drug will be able to continue if they choose to do so. Rosiglitazone will only be available to new patients if they are unable to achieve glucose control on other medications and are unable to take pioglitazone, the only other thiazolidinedione.
Results from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) trial indicated that the use of rosiglitazone for type 2 diabetes mellitus increases the risk of heart failure. In the study, cardiovascular outcomes were assessed after adding rosiglitazone to metformin or sulfonylurea regimens for type 2 diabetes mellitus. [57] The study was a multicenter, open-label trial that included 4447 patients with mean HbA1c of 7.9%. Follow-up of the 2 combinations took place over 5-7 years.
No difference was observed between the 2 groups for cardiovascular death, myocardial infarction, and stroke; 61 patients who received rosiglitazone experienced heart failure that caused either hospital admission or death compared with 29 patients in the active control group.
Noncardiovascular adverse effects in the study included increased upper and distal lower limb fracture rates, particularly in women. At 5 years, mean HbA1c was lower in the rosiglitazone group compared with the active control group. In addition to finding that the use of rosiglitazone for type 2 diabetes mellitus increases the risk of heart failure, the study found that the drug increases the risk for select fractures, particularly in women.
For more information, see the FDA’s Safety Alert on Avandia. The online meta-analysis is titled " Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. " Additionally, responses to the controversy can be viewed at the Heartwire news (theheart.org from WebMD) including the following articles:
- " Rosiglitazone increases MI and CV death in meta-analysis. "
- " The rosiglitazone aftermath: Legitimate concerns or hype? "
- " RECORD interim analysis of rosiglitazone safety: No clear-cut answers. "
Rosiglitazone (Avandia)
Rosiglitazone is available only via a restricted access program. It is an insulin sensitizer with a major effect in the stimulation of glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels and is used to treat type 2 diabetes associated with insulin resistance.
Pioglitazone (Actos)
Pioglitazone improves target cell response to insulin without increasing insulin secretion from the pancreas. It decreases hepatic glucose output and increases insulin-dependent glucose use in skeletal muscle and, possibly, in liver and adipose tissue.
Glucagon-like Peptide-1 (GLP-1) Receptor Agonists
Class Summary
GLP-1 receptor agonists are incretin mimetics that enhance glucose-dependent insulin secretion by the pancreatic beta-cells by stimulating G-protein, suppress inappropriately elevated glucagon secretion, and slow gastric emptying. These agents also increase intracellular cyclic adenosine monophosphate (AMP), leading to insulin release in the presence of elevated glucose concentrations.
Liraglutide (Victoza)
Approved by the FDA as an adjunct to diet and exercise for treatment of T2DM in adults and children aged 10 y and older.
Exenatide injectable suspension (Bydureon, Bydureon BCise)
Approved by the FDA as an adjunct to diet and exercise for treatment of T2DM in adults and children aged 10 y and older.
Amylin analogue
Class Summary
This agent is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. It is indicated to treat type 1 and type 2 diabetes in combination with insulin. This agent is administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. It helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1C levels), compared with insulin alone. Less insulin use and a reduction in body weight are also observed.
Pramlintide (Symlin)
Pramlintide is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. The drug is indicated to treat type 1 and type 2 diabetes in combination with insulin. It is administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. Pramlintide helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1C levels), compared with insulin alone. Less insulin use and a reduction in body weight are also observed.
Dipeptidyl peptidase IV (DPP-4) inhibitors
Class Summary
These agents block the action of DDP-4, which is known to degrade incretin. DDP-4 inhibitors have not yet gained FDA approval for use in children.
Linagliptin (Tradjenta)
Linagliptin increases and prolongs incretin hormone activity, which is inactivated by the DPP-4 enzyme. It is indicated, along with diet and exercise, for adults with type 2 diabetes mellitus, to lower blood sugar. Linagliptin may be used as monotherapy or in combination with other common antidiabetic medications, including metformin, sulfonylurea, and pioglitazone. It has not been studied in combination with insulin.
Sitagliptin (Januvia)
Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. It increases concentrations of active intact incretin hormones (GLP-1, GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for type 2 diabetes as monotherapy or is combined with metformin or with a PPAR-gamma agonist (eg, thiazolidinediones).
Saxagliptin (Onglyza)
Saxagliptin blocks DPP-4, which is known to degrade incretin hormones, increasing concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Antidiabetics, Insulins
Class Summary
Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.
Insulin degludec (Tresiba)
Ultra-long-acting insulin that is the only insulin product approved by the FDA to improve glycemic control in pediatric patients aged ≥1 y with type 2 DM. It usually takes 3-4 days for insulin degludec to reach steady state, peak plasma time is 9 h and the duration of action is at least 42 h. It is highly protein bound, and following SC administration, the protein-binding provides a depot effect.
Insulin degludec is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached.
Insulin regular human (Humulin R, Humulin R U-500, Myxredlin)
Indicated for diabetes mellitus. Recommended use in children and adolescents 10 years and older. Regular insulin has a short onset of action, 0.5 hour. Its peak effect occurs within 2-4 hours, and its usual duration of action is 5-8 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular human insulin (eg, Novolin 70/30 and Humulin 70/30) are available, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use.
Hypoglycemia Antidotes
Class Summary
Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis.
Glucagon (GlucaGen, Gvoke)
Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract. Available as a powder for reconstitution. It is also available as a ready-to-use SC solution in prefilled syringes or an autoinjector.
Glucagon intranasal (Baqsimi)
Activates hepatic glucagon receptors that stimulate cAMP synthesis. This action accelerates hepatic glycogenolysis and gluconeogenesis, causing an increase in blood glucose levels. Preexisting hepatic glycogen stores necessary to be effective in treating hypoglycemia. It is indicated for severe hypoglycemic reactions in adults and children aged 4 y or older with diabetes.
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Simplified scheme for the pathophysiology of type 2 diabetes mellitus.
