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By Richard A. Harrigan, MD, FAAEM
There currently are three generations of sulfonylurea (SU) agents available for the treatment of type 2 diabetes mellitus (DM) (see Table). These agents commonly are encountered in the practice of emergency medicine, especially the second- (glipizide, glyburide) and third- (glimepiride) generation drugs. The most common serious toxicity associated with the SUs is hypoglycemia, which occurs in adult and pediatric patients—usually due to accidental ingestion in the latter group. In adults, SU-associated hypoglycemia may be intentional, as in overdose scenarios, or unintentional. Kidney and liver disease, alcohol use, polypharmacy, poor nutrition, and advanced age are factors that have been associated with increased risk of SU-associated hypoglycemia.1,2 Hypoglycemia recognition usually is not difficult, nor is the initial treatment: glucose administration. But what if your patient continues to be hypoglycemic after two amps of D50? Recurrent or refractory hypoglycemia due to SU poisoning poses a therapeutic challenge; effective management requires a working knowledge of the pharmacology of both the SU agents and the pharmacologic adjuncts used to treat hypoglycemia. After briefly reviewing the pharmacology of SUs, the following discussion will focus on the emergence of octreotide as an attractive supplement to glucose in persistent hypoglycemia secondary to SU toxicity.
Time to Peak (hours)
Duration of Action (hours)
|Glyburide||Miconase, DiaBeta, Glynase||2-6||12-24|
SUs increase the secretion, and amplify the effect, of insulin. In the pancreas, they stimulate insulin release, a mechanism that is enhanced in the presence of glucose. They decrease hepatic insulin clearance; the elevated circulating levels of insulin that result then suppress production of glucose by the liver. SUs also may decrease insulin resistance peripherally and thereby enhance its action.3,4
All SUs feature a relatively long duration of action—an attractive attribute from a treatment perspective, but a hindrance to treatment in a poisoning setting (see Table). Delays in time-to-peak effect may create an illusion of wellness at the time of initial emergency department (ED) evaluation, especially if the patient presents in the first hour or two after an intentional ingestion. All SUs undergo hepatic metabolism; thus, the presence of hepatic disease (or competition for hepatic metabolism by other drugs) may lead to a protracted duration of action. Chlorpropamide, glyburide, and glimepiride undergo renal excretion of either the parent drug (chlorpropamide) or active metabolites (glyburide and glimepiride [the significance with the latter drug is still unclear]); therefore, concomitant renal insufficiency portends prolonged toxicity. Chlorpropamide, glyburide, and the extended-action formulation of glipizide are the most likely to cause sustained hypoglycemia.5 (See Table.) Glyburide recently was found to be the responsible drug in all study patients who developed protracted hypoglycemia from SUs in a retrospective investigation restricted to a population of end-stage renal disease patients.6
As discussed above, hypoglycemia refractory to simple glucose administration may develop in cases of SU ingestion confounded by hepatic impairment, renal insufficiency (with some agents), or massive ingestion. In such cases, consideration of adjuncts to glucose is necessary.
Octreotide, a somatostatin analog, is appealing mechanistically due to its ability to suppress the secretion of numerous endogenous hormones—one of which is insulin. It enjoys experimental and clinical data support for use in SU-induced hypoglycemia. Boyle and associates compared octreotide to diazoxide and glucose in a small (8 patients), simulated, sub-toxic glipizide overdose model using healthy non-diabetic volunteers.7 The octreotide arm demonstrated significantly less need for supplemental glucose than the diazoxide and glucose arms; indeed, 50% of octreotide patients did not need any supplemental glucose.
Since that time, a number of case reports have attested to octreotide’s clinical efficacy. These cases demonstrate successful use of octreotide in adults8-12 and a child,13 and include a wide variety of culprit SU agents. A uniformly diminished need for supplemental glucose is evident after octreotide administration (oftentimes no further need); four cases in which insulin levels were measured showed a profound drop in serum insulin levels (elevated due to SU ingestion and glucose administration) after administration of octreotide.8-10,13 Paradoxically, it should be noted that the glucose that is administered to combat SU-induced hypoglycemia (secondary to SU-induced hyperinsulinism) "feeds the fire," in that glucose also is a potent insulin secretagogue.8,9,14
A recent retrospective case series involving nine patients demonstrated a significant reduction in the need for D50 and in the number of hypoglycemic events after octreotide administration.14 The risk for recurrent hypoglycemia in the pre-octreotide phase was 27 times that of the risk in the post-octreotide period.14
Data thus far have not demonstrated toxicity with short-term use. Octreotide has been administered both subcutaneously and intravenously, and it has been given successfully via continuous infusion.8-14 Ideal dosing is yet to be determined; adult dosing thus far has ranged from 40 mcg to 100 mcg/dose;8-12,14 the lone pediatric case utilized a dose of 25 mcg subcutaneously in a 20 kg 5-year-old.13 Octreotide has been administered safely in other pediatric scenarios at 1-10 mcg/kg.15 Intravenous infusions in adults have been administered up to 100-125 mcg/hr.12,14 Case series data reflect variable dosing quantities and intervals.14
Glucagon, which works by mobilizing hepatic glycogen stores and inducing gluconeogenesis, is a less-than-optimal supplement to glucose in the treatment of SU-induced hypoglycemia. First, its success is at least partially dependent upon the existence of adequate glycogen reserves in the liver. Furthermore, glucagon—at least theoretically—worsens the hyperinsulinemic state of SU poisoning in that it, too, stimulates insulin release.15 It is a reasonable temporizing alternative to glucose if intravenous access is delayed, and thus has a role in the prehospital situation. However, it lacks the advantages of octreotide as a first-line supplement.
Historically important as a potent vasodilator used in the treatment of hypertensive crisis, diazoxide has long been used in the treatment of SU-associated hypoglycemia due to its ability to raise the blood sugar.15 In the study by Boyle and colleagues, it was outperformed by octreotide; of note, diazoxide did not suppress insulin levels in that model, and thus lacks the mechanistic appeal of octreotide.
Octreotide has been touted as a true antidote for SU-induced hypoglycemia. Recent case report and case series data suggest it is rapid-acting, highly efficacious, and well-tolerated. While clinical experience is still mounting, and optimal dosing guidelines are yet to be established, it appears to be a first-line supplement to glucose in the patient with refractory hypoglycemia due to SU poisoning.
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