by Kavita Babu
In 1999, a toddler encountered glipizide during an exploratory ingestion. When he wouldn’t wake up from a nap, the family called the EMTs, who found a fingerstick blood sugar of 13 mg/dL. He received several D25 boluses – each time his sugar would respond appropriately, then fall. His care team started an infusion of D5, then escalated to D10, and then D12.5. The ping-pong sugars continued, and a central line was considered to allow for even more concentrated dextrose infusions. Enter Dr. Rick Wang, toxicology attending – who gently and sagaciously pointed out that we were doing it wrong. What the patient needed was octreotide, he said, producing the literature that made the case. The sugars stabilized, the central line was averted, and the patient was discharged home looking perfect. And, as a fourth-year medical student rotating on toxicology, my career path was cemented. That curly-haired, big-eyed toddler is now of legal drinking age, but the use of octreotide as the antidote for sulfonylurea-induced hypoglycemia is still not universal.
The sulfonylurea compounds were serendipitously found to cause hypoglycemia during trials of sulfonamide antibiotics in the 1940s for the treatment of typhoid fever. This discovery led to the development of the modern sulfonylureas (e.g. chlorpropramide, glipizide, glimepiride, tolazamide, and tolbutamide) as mainstays in the treatment of diabetes mellitus. Sulfonylureas produce hypoglycemic adverse events in approximately 1% of patients. The majority of these events will be minimally symptomatic with rapid and total resolution after administration of glucose; however, a minority of patients will progress to seizures, coma, brain injury, or death.
In the setting of a sulfonylurea-associated hypoglycemic event (symptoms + blood sugar less than 60 mg/dL), the immediate management priority is getting sugar in. In an alert patient with minimal symptoms, enteral sugar administration (like orange juice and a sandwich) may be sufficient. In an altered patient, D50 administration is the mainstay. And the blood sugar will typically improve. But we know (on a theoretical and experiential level) that rebound hypoglycemia occurs. Sulfonylureas accentuate insulin release in response to a glucose load. As a result, repeated bolus dextrose administration causes the rapidly oscillating hypoglycemic -> hyperglycemic->euglycemic-> hypoglycemic pattern seen during a sulfonylurea overdose.
Enter octreotide, a somatostatin analog. You remember somatostatin (the master of euhormonemia) which inhibits the secretion of growth hormone, glucagon, and insulin? Octreotide is rapidly and completely absorbed after subcutaneous injection, reaching peak concentrations within approximately 30 minutes. Octreotide has an elimination half-life of almost 2 hours, which can be prolonged in patients with renal impairment or advanced liver disease (Sandostatin® package insert). The demonstrated euglycemic effect of octreotide lasts approximately 8 hours after a 75 mcg subcutaneous dose (Fasano 2008 PMID: 17764782). Dosing strategies vary. Historically, the literature contains data regarding sc dosing; however, it is difficult to find a clear pharmacokinetic advantage over iv administration. One recommended regimen was put forth by Glatstein et al (Glatstein 2012 PMID: 23046209).
- In children, octreotide 1–1.5 μg/kg IV or SC, followed by 2–3 more doses 6 hours apart
- In adults, octreotide 50 μg SC or IV, followed by three 50 μg doses every 6 hours
In many cases though, a single dose of octreotide will be sufficient to prevent further hypoglycemia (Fasano 2008 PMID: 17764782). Continuous octreotide infusions are often necessitated by pediatric sulfonylurea exposures, massive overdoses, and for those cases where recurrent hypoglycemia develops after adequate bolus octreotide administration. The downside of administering octreotide? Gastrointestinal upset is reported as the major adverse effect, but patients tolerate the small doses used for hypoglycemia well. And a single 100 mcg vial costs $6.50-12.37.
The diffusion of glucose into pancreatic beta-islet cells increases the ATP:ADP ratio, resulting in closure of the ATP-dependent K channel. Sulfonylureas potentiate this depolarizing effect of ATP, preventing potassium efflux. The resulting rise in intracellular potassium leads to opening of calcium channels. The subsequent calcium entry leads to exocytosis of insulin. Take home: sulfonylurea + glucose load ⇒ more insulin secretion.
Octreotide binds to G protein-coupled somatostatin receptors, leading to decreased calcium entry into the cell via L-type calcium channels (the same culprits that produce hyperglycemia in calcium channel blocker toxicity). Take home: octreotide + beta-islet cell ⇒ less insulin secretion.
In this fashion, octreotide acts through a non-competitive mechanism that counteracts sulfonylurea effect, and a is a true sulfonylurea antidote. Antidotes are awesome. Applying an antidote that is cheap, safe, and evidence-based is even better.
Octreotide is not FDA-approved for the treatment of sulfonylurea-associated hypoglycemia. Urban legend says that octreotide’s effectiveness in preventing hypoglycemia in patients with insulinoma led to its discovery as a treatment for sulfonylurea toxicity. Since the 1980s, several investigations have supported the use of octreotide to prevent recurrent hypoglycemia after sulfonylurea exposure or overdose. In one study, eight healthy volunteers received 1.45 mg/kg of glipizide. Comparison arms included dextrose infusion (D20) and octreotide infusion (30 ng/kg/min). Hyperinsulinemia was reversed by octreotide infusion. Moreover, when compared to dextrose infusion alone, octreotide minimized or eliminated the need for supplemental dextrose administration (Boyle 1993 PMID: 8445035). In a time-based analysis of cases between 1995 and 1998 in which patients with sulfonylurea-associated hypoglycemia received octreotide, the risk of recurrent hypoglycemia was 27 times higher before octreotide administration (McLaughlin 2000 PMID:10918104).
This evidence most closely mirrors overdose scenarios, where toxicologists would agree that octreotide has an essential role in treatment. But what about the (much more common) therapeutic misadventure? There is the most rare of evidence-based birds, a toxicologic RCT, that addresses this subject.
In 2008, Fasano et al (Fasano 2008 PMID: 17764782) conducted a prospective, double-blind, placebo-controlled trial of patients presenting to an ED for hypoglycemia in the setting of sulfonylurea use. The trial arms included 1) standard treatment (with D50 and oral carbohydrates), or 2) standard treatment + 75 mcg of subcutaneous octreotide. The results? In the placebo group, hypoglycemic events occurred in six of 18 patients had a total of 13 recurrent hypoglycemic episodes. Patients in the octreotide arm had higher serum glucose values for the first 8 hours after treatment, and fewer in-hospital hypoglycemic events. So we have the holy grail of toxicologic literature supporting the use of octreotide to prevent recurrent hypoglycemia in the setting of therapeutic misadventures with sulfonylureas. There is also case literature suggesting that octreotide may be of benefit in the setting of insulin overdose among both diabetics and non-diabetics (Dewaal 2017 PMID: 29202888, Groth 2013 PMID: 23669130).
Overall, I support the routine use of octreotide once a patient has demonstrated sulfonylurea-associated hypoglycemia. Some authors opine that patients should not receive octreotide after a single episode of sulfonylurea-induced hypoglycemia including some toxicologists that I really respect (here’s looking at you @toxicologist12). In my algebra, patient safety in hypoglycemia is perched on the serial and accurate assessment of serum blood glucose levels. While I find the literature compelling, I am even more persuaded by the idea that the diagnosis and response to hypoglycemia is an all too human endeavor with multiple moving parts. You don’t have to wait for a second hypoglycemic episode to give the octreotide, especially if you are planning on an admission anyway. Administration of octreotide is an indication to watch the patient for an additional 12-24 hours from the last dose.
So, the next time you treat a patient with a hypoglycemic episode and a sulfonylurea on her medication list, fix their hypoglycemia first. Then remember you have an antidote, the evidence from a toxicologic RCT, and the support of at least one hound when you reach for octreotide.
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis, Part II - August 14, 2020
- Tox and Hound – Fellow Friday – Whence the Protons of Lactic Acidosis? - July 24, 2020
- The Dantastic Mr. Tox & Howard – S03E03 – Inside Out - July 6, 2020