Toxicology/original research
Comparison of Octreotide and Standard Therapy Versus Standard Therapy Alone for the Treatment of Sulfonylurea-Induced Hypoglycemia

Presented as preliminary data at the Society for Academic Emergency Medicine annual meeting, May 2006, San Francisco, CA.
https://doi.org/10.1016/j.annemergmed.2007.06.493Get rights and content

Study objective

This study is designed to test the hypothesis that the administration of octreotide acetate (Sandostatin; Novartis Pharmaceuticals) in addition to standard therapy will increase serum glucose level measured at serial intervals in patients presenting to the emergency department (ED) with sulfonylurea-induced hypoglycemia compared with standard therapy alone.

Methods

This study was a prospective, double-blind, placebo-controlled trial. All adult patients who presented to the ED with hypoglycemia (serum glucose level ≤60 mg/dL) and were found to be taking a sulfonylurea or a combination of insulin and sulfonylurea were screened for participation in the study. Study participants were randomized to receive standard treatment (1 ampule of 50% dextrose intravenously and carbohydrates orally) and placebo (1 mL of 0.9% normal saline solution subcutaneously) or standard treatment plus 1 dose of octreotide 75 μg subcutaneously. Subsequent treatment interventions were at the discretion of the inpatient internal medicine service.

Results

A total of 40 patients (18 placebo; 22 octreotide) were enrolled. The mean serum glucose measurement at presentation was placebo 35 mg/dL and octreotide 39 mg/dL. The mean glucose values for octreotide patients compared with placebo were consistently higher during the first 8 hours but showed no difference in subsequent hours. Mean glucose differences approached statistical significance from 1 to 3 hours and were significant from 4 to 8 hours after octreotide or placebo administration.

Conclusion

The addition of octreotide to standard therapy in hypoglycemic patients receiving treatment with a sulfonylurea increased serum glucose values for the first 8 hours after administration in our patients. Recurrent hypoglycemic episodes occurred less frequently in patients who received octreotide compared with those who received placebo.

Introduction

Hypoglycemia is a common presenting sign in emergency department (ED) patients.1 Sulfonylureas are a widely prescribed class of oral medications for the treatment of diabetes (Table 1). Sulfonylureas are believed to stimulate insulin release from pancreatic β cells through a complex mechanism culminating in calcium influx and release of stored insulin from secretory granules within the pancreas.1 A frequent and well-reported adverse reaction of sulfonylurea administration is persistent hypoglycemia, often necessitating hospital admission for serial glucose determinations.2

The American Association of Poison Control Centers reported 4,285 sulfonylurea exposures, resulting in 1,334 adverse outcomes, including 11 deaths, in 2005. Octreotide was reportedly used as an antidote 203 times.3 The true incidence of sulfonylurea-induced hypoglycemia is higher because poisoning and overdose are frequently underreported. Whereas insulin-dependent diabetic patients are usually discharged home after establishing normal blood glucose levels, hospital admission is recommended for hypoglycemic patients taking oral sulfonylureas because of the long duration of effect, delayed clearance of the drugs and their metabolites, and subsequent high likelihood of recurrent hypoglycemic episodes.2

Several case reports and 1 prospective study in healthy volunteers have demonstrated the safety and efficacy of octreotide administration for the treatment of sulfonylurea-induced hypoglycemia.4, 5, 6, 7 Many toxicologists suggest that administration of octreotide be considered in treatment of patients after intentional or unintentional ingestion of a sulfonylurea with recurrent hypoglycemia.8, 9

To our knowledge, this is the first prospective, placebo-controlled investigation of octreotide in sulfonylurea-induced hypoglycemia. Before this investigation, the use of octreotide for the treatment of sulfonylurea-induced hypoglycemia had never been compared to placebo, nor had it been evaluated prospectively in actual ED patients. Authors have called for prospective, randomized, controlled clinical trials to confirm or disprove any potential benefit of octreotide in this population.10

The primary goal of this study was to compare the effect of octreotide on serial mean serum glucose concentrations in actual hypoglycemic ED patients. A secondary goal of this investigation was to quantify the potential decrease in hypoglycemic episodes among those patients who received octreotide compared to placebo.

Section snippets

Study Design

The study was a prospective, randomized, double-blind, placebo-controlled trial. The study was approved by the institutional review board at our institution.

Setting

The study was conducted at an urban, community teaching hospital with 74,000 ED visits annually. Trained physician research assistants familiar with the protocol, research methodology, and the informed consent process staff the ED 24 hours per day.

Selection of Participants

All adult (>18 years old) nonpregnant patients presenting to the ED with hypoglycemia (serum

Characteristics of Study Subjects

A total of 358 hypoglycemic patients were screened for participation. Two hundred forty-two were excluded because they did not meet inclusion criteria. Of those patients not meeting inclusion criteria, 216 were found not to be taking a sulfonylurea, and an additional 20 had a serum glucose level greater than 60 mg/dL. Three patients were previously enrolled, and an additional 3 patients did not meet inclusion criteria, because the class of oral hypoglycemic medication could not be verified

Limitations

Our inclusion criteria allowed for a wide range of subjects with comorbidity. We did not control for physiologic or pathologic differences among the subjects, and the study was not powered to do subgroup analysis.

No distinction was made between different sulfonylureas (Table 1). It is conceivable that patients ingesting first-generation sulfonylureas with longer elimination half-lives would have a higher potential for recurrent hypoglycemia compared with patients ingesting the second- or

Discussion

Octreotide is a somatostatin analog that is known to suppress several hormones, including insulin.11 Dextrose itself induces insulin secretion, theoretically contributing to rebound hypoglycemia when used to treat low blood sugar.1, 11 Octreotide is thought to lower insulin levels that result from either dextrose or a sulfonylurea medication.1 We believe our study to be the first prospective, randomized investigation of octreotide in sulfonylurea-induced hypoglycemia.

Several case reports and 1

References (15)

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    Standard treatment for sulfonylurea-induced hypoglycemia includes administration of oral or intermittent i.v. dextrose. Octreotide, which acts downstream from the sulfonylurea receptor to inhibit insulin release, can be used as adjunct therapy to prevent ongoing hypoglycemia (1,3,5,8−11). However, severe hypoglycemia with neurologic sequelae can be refractory to standard therapies, and management of these cases is not well established.

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    Therapy with octreotide is now favored over glucagon and diazoxide to counteract hypoglycemia due to increased adverse effects associated with the latter two agents (Table 3).42,67,68 A randomized, double-blind, placebo-controlled study of 40 patients compared standard treatment of sulfonylurea-induced hypoglycemia (50% IV glucose and oral carbohydrates) to standard treatment combined with one dose of 75 µg octreotide given subcutaneously.68 Serum glucose values 4 to 8 h after initiating treatment were significantly higher and recurrent hypoglycemia was less frequent for patients receiving octreotide.68

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    Most patients received octreotide at doses ranging from 40 to 100 μg given as a single dose or every 6−12 h, with the exception of 1 patient who received an infusion of 125 μg/h for 9 h (11). There are two published prospective trials looking at the use of octreotide for sulfonylurea-induced hypoglycemia, however, neither trial included cases of acute overdose (25,26). The first was a randomized, double-blind, placebo-controlled trial in patients presenting to the ED hypoglycemic with a sulfonylurea listed as a home medication.

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Supervising editor: Richard C. Dart, MD, PhD

Author contributions: CJF and GO conceived the study and designed the trial. CJF, PD, EA, and DRL supervised the conduct of the trial and data collection. CJF, PD, EA, and DRL undertook recruitment of patients and managed the data, including quality control. GO, PD, and DRL provided statistical advice on study design and data analysis. CJF drafted the article, and all authors contributed substantially to its revision. CJF takes responsibility for the paper as a whole.

Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that may create any potential conflict of interest. The authors have stated that no such relationships exist. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement.

Publication dates: Available online August 30, 2007.

Earn CME Credit: Continuing Medical Education for this article is available at: www.ACEP-EMedHome.com.

Reprints not available from the authors.

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