The Pre-brief
A 62-year-old male is brought to the emergency department (ED) for hypoglycemia. Prior to arrival, he was given “an amp of dextrose” for a blood glucose of 50 mg/dL. The patient’s blood glucose on arrival to the ED is 85 mg/dL; however, a repeat measurement a short time later reveals a blood glucose of 45 mg/dL, requiring more dextrose. Upon further investigation, the patient has a past medical history of diabetes. Glyburide, a sulfonylurea anti-diabetic agent, was found when reviewing his medication list. Due to his recurring hypoglycemia and requiring multiple rounds of dextrose, octreotide is considered in addition to intravenous (IV) dextrose in the management of the patient’s hypoglycemic events due to possible sulfonylurea toxicity.
Sulfonylureas – Antidiabetic Agents
Sulfonylureas are common medications used in the management of type II diabetes and include agents such as, but not limited to, glimepiride, glipizide, and glyburide. The major side effect of sulfonylureas is hypoglycemia. Toxicity presents as recurrent hypoglycemia and may be the result of overdose, drug-drug interactions via inhibition of CYP2C9, decreased drug metabolism, or decreased drug excretion. Hypoglycemia may be delayed for up to 12 hours and persist for days after overdose (lasting up to 72 hours with one report of refractory hypoglycemia lasting 27 days in a 2-year-old child who ingested glibenclamide).
Sulfonylureas work by enhancing the release of insulin from pancreatic islet beta cells in response to glucose. These medications bind to the sulfonylurea receptor type 1 (SUR1) on the pancreatic beta-cell membrane, which is associated with ATP-dependent potassium channels. This binding inhibits potassium channel activity, preventing potassium efflux, and ultimately results in membrane depolarization. As a consequence, voltage-dependent calcium channels are opened, resulting in an influx of calcium and an increase in intracellular calcium, triggering insulin release via exocytosis.
More Dextrose More Problems
Hypoglycemic episodes are managed by IV dextrose; however, excessive IV dextrose administration resulting in hyperglycemia may stimulate endogenous insulin production from the pancreas, contributing to subsequent hypoglycemia. Re-administration of dextrose leads to a vicious cycle of repeated dextrose boluses and rebound hypoglycemic events. This, in combination with an extended duration of action from the sulfonylurea itself, creates the need for frequent blood glucose monitoring and high dextrose requirements.
Octreotide in Sulfonylurea Overdos
Octreotide, a long-acting synthetic analogue of somatostatin, is used as an antidote to counteract the hypoglycemic effects of sulfonylureas. Octreotide has the ability to inhibit the secretion of insulin, glucagon, and other insulin counterregulatory hormones, making it a rational choice for the treatment of poisoning due to sulfonylureas. Octreotide binds to specific somatostatin subtype 2 membrane receptors on pancreatic beta cells “downstream” from where sulfonylureas bind. It inhibits cellular cyclic adenosine monophosphate production and calcium influx through a voltage-gated calcium channel via G-protein-coupled receptors. This prevents the influx of calcium and results in decreased calcium conductance, decreasing intracellular calcium concentrations, resulting in pancreatic cell hyperpolarization and inhibition of insulin secretion.
A retrospective review by McLaughlin and colleagues aimed to determine whether treatment with octreotide decreased the glucose requirements and the number of hypoglycemic episodes in patients with sulfonylurea-induced hypoglycemia. The dosing of octreotide varied widely from a single subcutaneous dose of 40 mcg to an IV infusion of 125 mcg/hr. There was a significant reduction in the number of episodes of hypoglycemia; 29 (mean 3.2 per patient) pre-octreotide and 2 (mean 0.2 per patient) post-octreotide administration (P = 0.008). Also, there was a reduction in the number of ampules of dextrose 50% (25 g) administered; 27 ampules pre-octreotide (mean 2.9 per patient) and 2 ampules (mean 0.2 per patient) post-octreotide (P = 0.004). The authors concluded that octreotide seems to be safe and effective in preventing rebound hypoglycemia and should be considered as first-line therapy in combination with IV dextrose for the treatment of sulfonylurea-induced hypoglycemia.
A prospective, double-blind, placebo-controlled trial by Fasano et. al. compared standard of care (1 ampule of 50% dextrose IV and oral carbohydrates) and placebo (1 mL normal saline subcutaneously) versus standard of care plus 1 dose of octreotide 75 mcg subcutaneously. Forty patients were included in the study: 22 patients in the octreotide group and 18 in the placebo group. Serum glucose values in the octreotide group were higher when compared to the placebo group during the first eight hours but then showed no difference in subsequent hours (drug/time interaction, P<0.0001). Ten patients in the octreotide group (45%) experienced recurrent hypoglycemia (no patient experienced multiple episodes) compared to six (33%) in the control group (13 episodes with 3 patients experiencing multiple hypoglycemic events). More patients in the placebo group experienced multiple hypoglycemic events. The authors concluded there was a significant increase in mean glucose level in patients receiving octreotide versus placebo, and this was more pronounced in the first 4 – 8 hours after administration of octreotide. Recurrent hypoglycemic events were more likely to occur in the placebo group versus those who received octreotide. No adverse events were reported within the first 72 hours after octreotide administration.
Various case reports also demonstrate that the use of octreotide appears to reduce the number of hypoglycemic episodes and glucose requirements with no reported associated adverse events.
Administration and Dosing
Octreotide may be dosed at 50 – 100 mcg subcutaneous or IV every six to 12 hours in adult patients and 1 – 2 mcg/kg (max 50 mcg) subcutaneous or IV every six to 12 hours in pediatric patients. It should be administered as needed based on glucose concentrations. Due to the relatively short half-life of octreotide (88 – 100 minutes) and long duration of action of sulfonylurea medications (12 – 24 hours and even longer), repeat administration may be warranted. Absorption via subcutaneous administration is rapid and complete with a bioavailability of 100%.
The subcutaneous route is preferred as the IV route is more expensive and more difficult to prepare and administer.
There is no evidence that the IV route is superior or necessary for this indication. Subcutaneous administration sites should be rotated. Serum glucose concentrations should be monitored closely (initially, approximately every 15 – 60 minutes) during treatment with octreotide and IV dextrose. Adverse effects include burning pain at the injection site, hyperglycemia, nausea, abdominal pain, flatulence, and diarrhea.
The Debrief
- Sulfonylureas are a common medication class that may be used in the management of type II diabetes
- Sulfonylurea toxicity is characterized by recurrent hypoglycemia and may be due to overdose, drug-drug interactions, decreased metabolism, or decreased excretion
- Monotherapy with IV dextrose may not be suitable as multiple boluses of dextrose may produce endogenous insulin release, contributing to hypoglycemic events
- Octreotide may be an effective adjunct to IV dextrose in managing refractory hypoglycemia due to sulfonylurea toxicity
- Octreotide may be administered as 50 – 100 mcg subcutaneously or IV every six to 12 hours in adults and 1 – 2 mcg/kg up to 50 mcg subcutaneously or IV in pediatric patients every six to 12 hours as needed
- Call the Poison Center at 1-800-222-1222 when these patients present
References
- Klein-Schwartz W, Stassinos G, Isbister G. Treatment of sulfonylurea and insulin overdose. Br J Clin Pharmacol. 2016; 81(3): 496 – 504.
- Dougherty P, Klein-Schwartz W. Octreotide’s role in the management of sulfonylurea-induced hypoglycemia. J Med Toxicol. 2010; 6: 199 – 206.
- Rowden A, Fasano C. Emergency management of oral hypoglycemic drug toxicity. Emerg Med Clin N Am. 2007; 25: 347 – 356.
- Hayes B. Chapter 156: Octreotide. Critical Care Toxicology. 2017. Pp: 2897 – 2905.
- McLaughlin S, Crandall C, McKinney P. Octreotide: an antidote for sulfonylurea- induced hypoglycemia. Ann Emerg Med. 2000; 36(2): 133 – 138.
- Carr R, Zed P. Octreotide for sulfonylurea-induced hypoglycemia following overdose. Ann Pharmacother. 2002; 36: 1727 – 1732.
- Glatstein M, Scolnik D, Bentur Y. Octreotide for the treatment of sulfonylurea poisoning. Clinical Toxicology. 2012; 50: 795 – 804.
- Marraffa J, Cohen V, Howland M. Antidotes for toxicological emergencies: a practical review. Am J Health-Syst Pharm. 2012; 69:199 – 212.
- Fasano C, O’Malley G, Dominici P, Aguilera E, Latta D. Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea-induced hypoglycemia. Ann Emerg Med. 2008; 51: 400 – 406.
- Gunaratne K, Austin E, Wu P. Unintentional sulfonylurea toxicity due to a drug–drug interaction: a case report. BMC Res Notes. 2018; 11(331): 1 – 3.
