Chapter 121: Oral Anti-Diabetic Agents

• 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.

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.

Toxic Dose

Case reports, prospective case series, and a retrospective review document mild to moderate hypoglycemia following reported single-dose sulfonylurea ingestions.^4–6 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.⁸ Fifty-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/kgof 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 octreotidedecreases 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.^13–15 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.

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.^3,16 Peak 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.

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.

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.^22–24 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.

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.

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.^3,29 This 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.

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.³⁰ Therapeutic 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.