Strange and Schafermeyer's Pediatric Emergency Medicine, Fourth Edition (Strange, Pediatric Emergency Medicine), 4th Ed.

CHAPTER 121. Oral Anti-Diabetic Agents

Kimberly  Barker

Donna  Seger

HIGH YIELD FACTS

• Oral anti-diabetic drugs function by either increasing insulin secretion or by modulating blood glucose concentrations through a variety of mechanisms other than the increase of blood insulin concentration.

• Significant poisoning is associated with sulfonylureas and metformin only.

• Sulfonylurea overdose can produce life-threatening hypoglycemia, and the antidote of choice is octreotide.

• It is inadvisable to administer prophylactic intravenous dextrose to normoglycemic children with sulfonylurea ingestion because this may mask and prolong the appearance of sulfonylurea-induced hypoglycemia.

• Asymptomatic, euglycemic young children presenting with a history of sulfonylurea ingestion require 8 hours of observation and no prophylactic intravenous dextrose therapy.

• Metformin overdose can result in life-threatening lactic acidosis that may require hemodialysis.

There are 18.8 million people in the United States diagnosed with Type II diabetes (T2DM).1 The mainstay of T2DM treatment is oral anti-diabetic therapy, and pediatric exposures may result from the significant number of homes with these medications. However, not all oral anti-diabetic agents produce hypoglycemia in overdose. Biguanides, thiazolidinediones, and alpha-glucosidase inhibitors help to maintain euglycemia in the body but do not cause hypoglycemia. Sulfonylureas, meglitinides, and to a lesser extent dipeptidyl peptidase (DPP)-IV inhibitors increase pancreatic insulin and may cause hypoglycemia following overdose. Although a single sulfonylurea tablet may produce symptomatic hypoglycemia in a toddler, noteworthy sequelae have not been reported. Larger overdoses are associated with significant morbidity and mortality in older children and adults.2 Many oral anti-diabetic agents are prescribed in combination forms or in extended release forms. History should include careful questioning to determine all active ingredients in the product as well as release form. Both biguanides and thiazolidinediones may be prescribed in adolescents for treatment of diabetes. Chronic toxicity seen with these agents includes lactic acidosis (biguanides) and hepatotoxicity (thiazolidinediones). A summary of the expected toxicity from each class of oral anti-diabetic drugs is found in Table 121-1.

TABLE 121-1

Oral Anti-Diabetic Drugs

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INSULIN SECRETAGOGUES

image SULFONYLUREAS

Pharmacology Sulfonylureas stimulate pancreatic beta cells to release insulin.3 (Figure 121-1). Second-generation sulfonylureas (glimepiride, glipizide, and glyburide) are more commonly prescribed than the first generation (tolbutamide and chlorpromide). All of the second-generation agents are rapidly absorbed, have a duration of action of approximately 24 hours, and a single dose may produce mild symptomatic hypoglycemia in a young child.

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FIGURE 121-1. Site of action for insulin secretagogues. (Reproduced with permission from Brunton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc.;2011 All rights reserved.)

Toxic Dose Case reports, prospective case series, and a retrospective review document mild to moderate hypoglycemia following reported single-dose sulfonylurea ingestions.46 There are no reports of deaths or permanent sequelae in young children after unintentional ingestion of these drugs.

Clinical Presentation Signs and symptoms of hypoglycemia include dizziness, diaphoresis, anxiety, headache, confusion, fatigue, slurred speech, coma, and seizures. Delayed onset of toxicity has been reported, but this is seen in patients receiving parenteral dextrose administered to euglycemic patients with the intent of preventing hypoglycemia.

Management Duration of observation of asymptomatic young children presenting with the history of sulfonylurea ingestion is problematic because of reports of delayed onset of hypoglycemia. Recommendations vary from 8–24 hours. Since delayed hypoglycemia occurred in children receiving prophylactic intravenous dextrose, this practice should be avoided. A 2005 literature review4 and a 1997 prospective multi-center observational series in 185 children7 both recommend 8 hours of observation. A 2011 retrospective medical record review of 93 children admitted to a single institution recommended 16 hours of observation.6 The median time for hypoglycemia was 4.0–5.5 hours with the longest interval 13.0 hours. However there was no mention of whether or not parenteral dextrose was administered. A 1996 retrospective poison center review of 93 children recommended 24 hours of observation.8Fifty-three of the 93 children received parenteral dextrose, and hypoglycemia beyond 4 hours was documented in only four (at 11, 12, 12 and 16 hours). All four were being treated with parenteral dextrose.

Therefore, asymptomatic young children presenting with the history of sulfonylurea ingestion should not be treated with prophylactic intravenous dextrose. They should receive hourly point of care blood sugar measurements and may be discharged from the emergency department if 8 hours of euglycemia is documented.

If the patient presents less than 1.0 hour after the ingestion of potentially toxic sulfonylurea, consider the administration of activated charcoal. If hypoglycemia occurs, administer an intravenous bolus of 0.5 g/kg of 25% dextrose followed by a 5% or 10% dextrose infusion. This often reverses the hypoglycemia of mild sulfonylurea poisoning. Unfortunately, dextrose is a secretagogue for sulfonylurea-sensitized beta cells resulting in insulin release. Thus, hypoglycemia may be refractory to supplemental dextrose administration. Glucagon and corticosteroids, because of their hyperglycemic actions, may be considered for sulfonylurea-poisoned patients resistant to dextrose therapy. However, these interventions are ineffective because they also stimulate insulin secretion.

Octreotide, a synthetic analogue of somatostatin, is indicated in all sulfonylurea-poisoned patients unresponsive to parenteral dextrose. Octreotide inhibits pituitary release of growth hormone and inhibits glucagon and insulin release.9 Although there are limited data, animal models of SU overdose indicate that octreotide reduces the number of refractory hypoglycemic episodes.10,11 Case series indicate that octreotide decreases the need for supplemental glucose and the number of hypoglycemic events.11,12 There are reports of octreotide being used in children with sulfonylurea poisoning.1315 When used in acute overdose, complications of this antidote are infrequent and include nausea, vomiting, abdominal pain, and diarrhea.11 Consider administering 1–1.25 μg/kg if hypoglycemia occurs despite dextrose infusion. Octreotide may be administered intravenously or subcutaneously. If additional octreotide doses are required, consider a continuous infusion. Diazoxide also blocks insulin secretion and is effective for sulfonylurea-induced hypoglycemia,2 but the intravenous preparation is no longer available.

Disposition Children who remain asymptomatic and euglycemic for 8 hours without parenteral dextrose administration may be discharged from the emergency department. If hypoglycemia is documented, initiate treatment and admit to hospital.

image MEGLITINIDES

Pharmacology Currently available meglitinides include repaglinide and nateglinide. Although structurally different from sulfonylureas, these drugs also stimulate insulin secretion (Figure 121-1) and can produce hypoglycemia.3,16Peak plasma concentrations of each occur within 1 hour and elimination half-life is approximately 1–1.5 hours. Meglitinides are not approved for use in children. Pediatric dosing is not available, and there are no reports of pediatric overdose. Since therapeutic doses have caused hypoglycemia in non-diabetic adult patients, any dose in pediatric patients may potentially cause hypoglycemia.17

Management There is no overdose experience in children and negligible experience in adults. Because of their shorter duration of action, they are expected to cause less severe hypoglycemia than sulfonylureas. If hypoglycemia is documented, follow the sulfonylurea management.

image DPP-IV INHIBITORS

Currently available DPP-IV inhibitors include linagliptin, sitagliptin, and saxagliptin. DPP-IV is an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This stimulates insulin release and inhibits glucagon secretion (Figure 121-1).3,18 The release of insulin stimulated by GLP-1 and GIP is glucose dependent and should only occur in the setting of high or normal glucose. Thus, the development of significant hypoglycemia is not expected. Peak plasma concentrations generally occur within 1–4 hours with a variable half-life depending on the agent. DPP-IV inhibitors are not approved for use in children, and there are no case reports of overdose in children. While not as potent hypoglycemic agents as the sulfonylureas, hypoglycemia may occur following ingestion. The only reported adult overdose occurred in an 86-year-old female who ingested 1700 mg of sitagliptin (17 times recommended therapeutic dose) who was treated with intravenous dextrose for 11 hours following ingestion and did not develop hypoglycemia.19

Management For children presenting with overdose of one of these drugs, hourly point of care blood sugar measurements for 4–6 hours should suffice. Administer parenteral dextrose only if hypoglycemia is documented. Significant hypoglycemia is not expected.

NON-INSULIN SECRETAGOGUES

image BIGUANIDES

Pharmacology Metformin is the only biguanide currently available in the United States. It decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization via activation of AMP-dependent protein kinase (AMPK).3,20 In high concentrations, metformin inhibits hepatic lactate uptake and conversion of lactate to glucose. This is most likely to occur with chronic dosing in the setting of renal impairment.21 Metformin does not produce hypoglycemia and does not increase release of insulin.

Toxicity and Toxic Dose Acute metformin overdose is rare in children. However significant toxicity has been documented in teenagers and adults. The concern is not for hypoglycemia; rather, it is for lactic acidosis. Although this is usually seen in patients with renal impairment, it can occur in patients with normal renal function.2224 The toxic dose is unknown. Ingestions of 1–2 tablets by a child <6 years old or less than 5.0 g in a teenager are not expected to produce toxicity.

Clinical Presentation Asymptomatic children without evidence of lactic acidosis should be observed for 4–6 hours (8 hours for ingestion of extended release tablets) and discharged from the ED if no toxicity develops. Early symptoms include abdominal pain, nausea, malaise, myalgia, and dizziness.25 As acidosis develops, altered mental status, respiratory depression, hypotension, and hyperglycemia may be seen.

Treatment If the patient presents within 1 hour after the ingestion of a potentially toxic dose of metformin, consider administration of activated charcoal. Treatment of metformin poisoning is aimed at correcting acidosis. Use of high-dose sodium bicarbonate infusions may be required. As the majority of the drug is eliminated by glomerular filtration and tubular secretion, renal insufficiency increases the severity of the acidosis. Because of its large volume of distribution, hemodialysis is unlikely to significantly enhance elimination. However significant lactic acidosis, particularly if there is renal impairment, is an indication for hemodialysis. This corrects the acidosis as well as the fluid and electrolyte abnormalities and removes some metformin although exact clearance rates are unknown.26

Disposition Asymptomatic patients can be discharged after 6 hours of observation. Patients with lactic acidosis require admission to hospital. Severe cases require prompt consultation with an intensivist and a nephrologist.

image THIAZOLIDINEDIONE DERIVATIVES

Pharmacology Currently available thiazolidinedione derivatives (TZD) include pioglitazone and rosiglitazone. These drugs decrease peripheral and hepatic insulin resistance resulting in increased glucose breakdown and decreased hepatic glucose output.3,27,28 They do not produce hypoglycemia and do not increase release of insulin. Peak plasma concentrations are achieved within 2 hours and elimination half ranges from 3–7 hours for parent compounds.

Management Acute overdoses of TZD are not expected to produce hypoglycemia. Common adverse effects in therapeutic doses in adults include upper respiratory tract infections, sinusitis, and pharyngitis.27,28 Management is symptomatic and supportive.

image ALPHA-GLUCOSIDASE INHIBITORS

Currently available agents include acarbose and miglitol. Alpha-glucosidase inhibitors are complex oligosaccharides that inhibit the digestion of complex carbohydrates to glucose and other monosaccharides in the small intestine.3,29This limits post-prandial blood sugar concentrations. These drugs do not increase insulin secretion and do not lead to hypoglycemia. They lack significant oral absorption since the primary site of action is within the gastrointestinal tract.

Management Significant toxicity is not expected. Management is symptomatic and supportive.

image SODIUM–GLUCOSE CO-TRANSPORTER 2 (SGLT2) INHIBITORS

The newest oral anti-diabetic agents are the SGLT2 inhibitors, such as canagliflozin, approved by the FDA in March 2013. SGLT2 inhibitors work in the proximal tubule to decrease glucose reabsorption following renal filtration.30Therapeutic dosing of canagliflozin in adults is 100–300 mg daily. Dosing in pediatrics has not been evaluated. Hypoglycemia is not expected to occur following overdose. Further experience with these agents is needed to make recommendations on potential toxic dose, observation, or treatment following overdose.

REFERENCES

1. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed February 15, 2013.

2. Palatnick W, Meatherall RC, Tenenbein M. Clinical spectrum of sulfonylurea overdose and experience with diazoxide therapy. Arch Intern Med. 1991;151:1859–1862.

3. Powers AC, DAlessio D. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In: Chabner BA, Brunton LL, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011, Chapter 43.

4. Little GL, Boniface KS. Are one or two dangerous? Sulfonylurea exposures in toddlers. J Emerg Med. 2004;28(3):305–310.

5. Szlatenyi CS, Capes KF, Wang RY. Delayed hypoglycemia in a child after ingestion of a single glipizide tablet. Ann Emerg Med. 1998;31: 773–776.

6. Levine M, Ruha AM, LoVecchio F, et al. Hypoglycemia after accidental pediatric sulfonylurea ingestions. Pediatr Emerg Care. 2011;27:846–849.

7. Spiller HA, Villalobos D, Krenzelok EP, et al. Prosective multicenter study of sulfonylurea ingestion in children. J Pediatr. 1997;131:141–146.

8. Quadrani DA, Spiller HA, Widder P. Five year retrospective evaluation of sulfonylurea ingestion in children. J Toxicol Clin Toxicol. 1996; 34(3):267–270.

9. Lheureux PER, Zahir S, Penaloza A, et al. Bench-to-bedside review: antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide. Crit Care. 2005;9:543–549.

10. Gul M, Cander B, Girsgin S, et al. The effectiveness of various doses of octreotide for sulfonylurea-induced hypoglycemia after overdose. Adv Ther. 2006;23:878–884.

11. Boyle PJ, Justice K, Krentz AJ, et al. Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses. J Clin Endocrinol Metabl. 1993;76:752–756.

12. Fasano CJ, O’Malley G, Dominici P, et al. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med. 2008; 51:400–406.

13. Mordel A, Sivilotti MLA, Old AC, et al. Octreotide for pediatric sulfonylurea poisoning. J Toxicol Clin Toxicol. 1998;36:437.

14. Kent DA, Main BA, Friesen MS. Use of octreotide in sulfonylurea poisoning in a child. J Toxicol Clin Toxicol. 2003;41:669.

15. Spiller HA. Management of sulfonylurea ingestions. Pediatr Emerg Care. 1999;15:227–230.

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17. Hirshberg B, Skarulis MC, Pucino F, et al. Repaglinide-induced factitious hypoglycemia. J Clin Endocrinol Metab. 2001;86:475–477.

18. National Library of Medicine. Januvia package insert. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=9f4e2f54-274a-4ecd-9f42-c16437018fdb#nlm34089-3. Accessed January 24, 2013.

19. Furukawa S, Kumagi T, Miyake T, et al. Suicide attempt by an overdose of sitagiptin, an oral hypoglycemic agent: a case report and review of the literature. Endocr J. 2012;59(4):329–333.

20. National Library of Medicine. Glucophage package insert. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4a0166c7-7097-4e4a-9036-6c9a60d08fc6#nlm34067-9. Accessed January 24, 2013

21. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Systematic Review. 2010;April.

22. Heaney D, Majid A, Junor B. Bicarbonate hemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant. 1997;12:1046–1047.

23. Lacher M, Hermanns-Clausen M, Haeffner K, et al. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr. 2005;164:362–365.

24. Suchard JR, Grotsky TA. Fatal metformin overdose presenting with progressive hyperglycemia. West J Emerg Med. 2008;9:160–164.

25. Bosse GM. Antidiabetics and hypoglycemic. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al., eds. Goldfrank’s Toxicologic Emergencies. 8th ed. New York McGraw-Hill; 2006:749–763.

26. Gan S, Barr J, Arieff A, et al. Biguanide-associated lactic acidosis. Arch Intern Med. 1992;152:2333–2336.

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