Pediatric Type 2 Diabetes Mellitus Medication
- Author: Alba Morales Pozzo, MD; Chief Editor: Stephen Kemp, MD, PhD more...
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 oral hypoglycemic therapy 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 drugs currently in use to treat type 2 diabetes in adults, the US Food and Drug Administration (FDA) has approved only metformin and insulin for use in children.
The FDA has issued an early communication to health care practitioners regarding 4 published observational studies that describe the possible association of insulin glargine (Lantus) with an increased risk of cancer.[44] Insulin glargine is a long-acting human insulin analogue approved for once-daily dosing.
The observational studies evaluated large patient databases, and all reported some association between insulin glargine and other insulin products with various types of cancer. The duration of the observational studies was shorter than that which is considered necessary to evaluate for drug-related cancers. Additionally, findings were inconsistent within and across the studies, and patient characteristics differed across treatment groups. These issues raise further questions about the actual risk of using insulin glargine and, therefore, concerns about the drug warrant further evaluation.
The FDA states that patients should not stop taking insulin without consulting their physician. An ongoing review by the FDA will continue to update the medical community and consumers with additional information as it emerges. Statements from the American Diabetes Association and the European Association for the Study of Diabetes called the findings conflicting and inconclusive and cautioned against overreaction.
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.[45]
Metformin (Glucophage, Glumetza, Riomet, Fortamet)
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.[46, 47]
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.[48] 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 (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.[46, 47]
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
Exenatide enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
Exenatide (Byetta)
Exenatide is an incretin mimetic agent that mimics glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. It improves glycemic control in patients with type 2 diabetes mellitus by enhancing glucose-dependent insulin secretion by pancreatic beta cells. It also suppresses inappropriately elevated glucagon secretion and slows gastric emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin, glucagonlike peptide-1. Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin or a sulfonylurea but who have not achieved glycemic control.
Liraglutide (Victoza)
Liraglutide is an incretin mimetic agent that elicits glucagonlike peptide-1 (GLP-1) receptor agonist activity. It activates the GLP-1 receptor by stimulating G-protein in pancreatic beta cells. Liraglutide increases intracellular cyclic adenosine monophosphate (AMP), leading to insulin release in the presence of elevated glucose concentrations. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. The drug has not been studied in combination with insulin.
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.
Alberti G, Zimmet P, Shaw J, Bloomgarden Z, Kaufman F, Silink M. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care. Jul 2004;27(7):1798-811. [Medline].
Morales AE, Rosenbloom AL. Death caused by hyperglycemic hyperosmolar state at the onset of type 2 diabetes. J Pediatr. Feb 2004;144(2):270-3. [Medline].
Ten S, Maclaren N. Insulin resistance syndrome in children. J Clin Endocrinol Metab. Jun 2004;89(6):2526-39. [Medline].
Hillier TA, Pedula KL. Complications in young adults with early-onset type 2 diabetes: losing the relative protection of youth. Diabetes Care. Nov 2003;26(11):2999-3005. [Medline].
Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. Sep 1999;104(6):787-94. [Medline].
Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. UK Prospective Diabetes Study (UKPDS) Group. Diabet Med. Apr 1998;15(4):297-303. [Medline].
Gungor N, Arslanian S. Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr. May 2004;144(5):656-9. [Medline].
Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. Feb 1999;22(2):345-54. [Medline].
Wei JN, Sung FC, Li CY, et al. Low birth weight and high birth weight infants are both at an increased risk to have type 2 diabetes among schoolchildren in taiwan. Diabetes Care. Feb 2003;26(2):343-8. [Medline].
Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care. May 1995;18(5):611-7. [Medline].
Young TK, Martens PJ, Taback SP, et al. Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native canadians. Arch Pediatr Adolesc Med. Jul 2002;156(7):651-5. [Medline].
Mayer-Davis EJ, Dabelea D, Lamichhane AP, D'Agostino RB Jr, Liese AD, Thomas J. Breast-feeding and type 2 diabetes in the youth of three ethnic groups: the SEARCh for diabetes in youth case-control study. Diabetes Care. Mar 2008;31(3):470-5. [Medline].
Type 2 diabetes in children and adolescents. American Diabetes Association. Pediatrics. Mar 2000;105(3 Pt 1):671-80. [Medline].
Dabelea D, Bell RA, D'Agostino RB Jr, et al. Incidence of diabetes in youth in the United States. JAMA. Jun 27 2007;297(24):2716-24. [Medline].
Urakami T, Kubota S, Nitadori Y, Harada K, Owada M, Kitagawa T. Annual incidence and clinical characteristics of type 2 diabetes in children as detected by urine glucose screening in the Tokyo metropolitan area. Diabetes Care. Aug 2005;28(8):1876-81. [Medline].
Ehtisham S, Hattersley AT, Dunger DB, Barrett TG,. First UK survey of paediatric type 2 diabetes and MODY. Arch Dis Child. Jun 2004;89(6):526-9. [Medline].
Kadiki OA, Reddy MR, Marzouk AA. Incidence of insulin-dependent diabetes (IDDM) and non-insulin-dependent diabetes (NIDDM) (0-34 years at onset) in Benghazi, Libya. Diabetes Res Clin Pract. May 1996;32(3):165-73. [Medline].
Chan JC, Cheung CK, Swaminathan R, Nicholls MG, Cockram CS. Obesity, albuminuria and hypertension among Hong Kong Chinese with non-insulin-dependent diabetes mellitus (NIDDM). Postgrad Med J. Mar 1993;69(809):204-10. [Medline].
Ramachandran A, Snehalatha C, Satyavani K, Sivasankari S, Vijay V. Type 2 diabetes in Asian-Indian urban children. Diabetes Care. Apr 2003;26(4):1022-5. [Medline].
Sayeed MA, Hussain MZ, Banu A, Rumi MA, Azad Khan AK. Prevalence of diabetes in a suburban population of Bangladesh. Diabetes Res Clin Pract. Jan 1997;34(3):149-55. [Medline].
Braun B, Zimmermann MB, Kretchmer N, Spargo RM, Smith RM, Gracey M. Risk factors for diabetes and cardiovascular disease in young Australian aborigines. A 5-year follow-up study. Diabetes Care. May 1996;19(5):472-9. [Medline].
McGrath NM, Parker GN, Dawson P. Early presentation of type 2 diabetes mellitus in young New Zealand Maori. Diabetes Res Clin Pract. Mar 1999;43(3):205-9. [Medline].
Eppens MC, Craig ME, Jones TW, Silink M, Ong S, Ping YJ. Type 2 diabetes in youth from the Western Pacific region: glycaemic control, diabetes care and complications. Curr Med Res Opin. May 2006;22(5):1013-20. [Medline].
Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr. May 2000;136(5):664-72. [Medline].
Grinstein G, Muzumdar R, Aponte L, et al. Presentation and 5-year follow-up of type 2 diabetes mellitus in African-American and Caribbean-Hispanic adolescents. Horm Res. 2003;60(3):121-6. [Medline].
Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA. Jul 26 2006;296(4):421-6. [Medline].
Yokoyama H, Okudaira M, Otani T, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int. Jul 2000;58(1):302-11. [Medline].
Maahs DM, Snively BM, Bell RA, Dolan L, Hirsch I, Imperatore G. Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes: the SEARCH for Diabetes in Youth study. Diabetes Care. Oct 2007;30(10):2593-8. [Medline].
Dart AB, Sellers EA, Martens PJ, Rigatto C, Brownell MD, Dean HJ. High Burden of Kidney Disease in Youth-Onset Type 2 Diabetes. Diabetes Care. Mar 19 2012;[Medline].
Krakoff J, Lindsay RS, Looker HC, et al. Incidence of retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes. Diabetes Care. Jan 2003;26(1):76-81. [Medline].
American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes Care. Mar 2000;23(3):381-9. [Medline].
Palmert MR, Gordon CM, Kartashov AI, et al. Screening for abnormal glucose tolerance in adolescents with polycystic ovary syndrome. J Clin Endocrinol Metab. Mar 2002;87(3):1017-23. [Medline].
Pinhas-Hamiel O, Standiford D, Hamiel D, et al. The type 2 family: a setting for development and treatment of adolescent type 2 diabetes mellitus. Arch Pediatr Adolesc Med. Oct 1999;153(10):1063-7. [Medline].
[Guideline] Diagnosis and classification of diabetes mellitus. Diabetes Care. Jan 2004;27 Suppl 1:S5-S10. [Medline].
Management of dyslipidemia in children and adolescents with diabetes. Diabetes Care. Jul 2003;26(7):2194-7. [Medline].
Bennett WL, Maruthur NM, Singh S, Segal JB, Wilson LM, Chatterjee R, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. May 3 2011;154(9):602-13. [Medline].
Bennett WL, Maruthur NM, Singh S, et al. Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations. Ann Intern Med. May 3 2011;154(9):602-13. [Medline].
[Best Evidence] Loimaala A, Groundstroem K, Rinne M, Nenonen A, Huhtala H, Parkkari J, et al. Effect of long-term endurance and strength training on metabolic control and arterial elasticity in patients with type 2 diabetes mellitus. Am J Cardiol. Apr 1 2009;103(7):972-7. [Medline].
McGavock J, Sellers E, Dean H. Physical activity for the prevention and management of youth-onset type 2 diabetes mellitus: focus on cardiovascular complications. Diab Vasc Dis Res. Dec 2007;4(4):305-10. [Medline].
Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. Dec 12 2006;114(24):2710-38. [Medline].
The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. Aug 2004;114(2 Suppl 4th Report):555-76. [Medline].
[Guideline] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. Feb 2011;42(2):517-84. [Medline].
[Best Evidence] International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care. Jul 2009;32(7):1327-34. [Medline]. [Full Text].
US Food and Drug Administration. Early Communication About Safety of Lantus (insulin Glargine). [Full Text].
[Best Evidence] Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. Mar 23 2009;169(6):616-25. [Medline].
Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, et al. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N Engl J Med. Jul 5 2007;357(1):28-38. [Medline].
McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf. Jul 2007;16(7):711-25. [Medline].
[Best Evidence] Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. Jun 20 2009;373(9681):2125-35. [Medline].
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