10 minute read
Materia Medica
by TEAM
Treating Insulin-Induced Hypoglycemia with Confidence: Dasiglucagon (Zegalogue®)
KaRen m. FanCheR, PhaRmD, BCOP
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Type 1 diabetes mellitus (T1DM), once known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin.1 When the body does not have enough insulin or cannot use it properly, glucose accumulates in the blood and can result in a variety of short- and long-term health complications.2 Approximately 1.6 million Americans have T1DM, including about 200,000 youth (under 20 years of age) and 1.4 million adults.3 Up to five million people in the United States are expected to have T1DM by 2050, including nearly 600,000 youth.
As pancreatic β-cell function declines in patients with T1DM, exogenous insulin is required to achieve glycemic control.4 Administration of exogenous insulin is central to the management of T1DM, but hypoglycemia often occurs; it is estimated that 30-40% of patients with T1DM experience one to three episodes of severe hypoglycemia per year. Severe hypoglycemia requires prompt medical intervention to prevent potentially life-threatening complications such as seizure, loss of consciousness and coma.5 Further, multiple hypoglycemic episodes may have negative longterm consequences on growth and development in pediatric patients.
Patients with T1DM who experience severe hypoglycemia are typically treated with glucagon, a wellestablished first-line treatment.5,6 The American Diabetes Association treatment guidelines recommend that glucagon is prescribed for all individuals at increased risk for clinically significant hypoglycemia, and pediatric guidelines recommend that an unexpired glucagon rescue kit be readily accessible to all patients and their caregivers.5,7,8 However, native glucagon is unstable and rapidly degrades in aqueous solutions, and therefore commercially available glucagon emergency kits contain a lyophilized powdered glucagon that must be reconstituted using multiple complex steps prior to injection. The reconstitution process represents a significant barrier to timely, accurate and effective administration of this emergency product.5,6,9 Therefore, a stable ready-to-use formulation is of great interest.4
Dasiglucagon (Zegalogue®) is a glucagon analogue with improved solubility and stability in aqueous liquid. Dasiglucagon was approved by the United States Food and Drug Administration in March 2021 for the treatment of severe hypoglycemia in adult patients with diabetes and in pediatric patients with diabetes who are six years of age or older.6,10
Dasiglucagon
Dasiglucagon is a novel peptide analogue of human glucagon. It acts as a glucagon receptor agonist, increasing the release of glucose from the liver and stimulating glycogen breakdown. This anti-hypoglycemic effect is dependent on hepatic glycogen stores.6,11
Dasiglucagon is comprised of 29 amino acids, with seven substitutions compared to native glucagon.4 The substitutions result in increased solubility and stability while maintaining specificity for the glucagon receptor.6,9 In addition, it has a higher absorption rate and longer plasma elimination half-life than traditional reconstituted glucagon.12
Clinical Studies
The efficacy of dasiglucagon for the treatment of severe hypoglycemia in patients with T1DM was demonstrated in a randomized, double-blind, phase III trial.9 In this study, 170 adult patients with T1DM were randomized 2:1:1 to receive subcutaneous dasiglucagon, reference glucagon (GlucaGen®) or placebo during controlled insulininduced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The median time to plasma glucose recovery was 10
minutes with dasiglucagon compared with 40 minutes for placebo (p < 0.001); the corresponding result with reference glucagon was 12 minutes. After 10 minutes, 65% of patients in the dasiglucagon group had recovered, compared with 49% of patients in the reference glucagon group. After 15 minutes, 99% of dasiglucagon patients had recovered their plasma glucose compared to 2% of placebo patients; this difference was statistically significant (p < 0.001). Similar outcomes were observed at other timepoints, including 10, 20 and 30 minutes after dosing.
A second randomized, doubleblind, phase III trial of dasiglucagon was conducted in 45 adult patients with T1DM.13 This study enrolled patients aged 18-70 years with a glycosylated hemoglobin <10% who had been receiving insulin for one year or more. Patients were randomized to dasiglucagon or placebo in a 3:1 ratio, with the primary endpoint of median time to plasma glucose recovery, defined as an increase in plasma glucose of ≥20 mg/dL from baseline after induction of hypoglycemia. The median time to plasma glucose recovery was significantly shorted with dasiglucagon than with placebo (10 minutes vs 35 minutes, p < 0.0001). In addition, significantly more dasiglucagon recipients experience plasma glucose recovery within 10 minutes compared to placebo recipients (62 vs 0%, p ≤ 0.001). The increase in plasma glucose from baseline was also significantly higher with dasiglucagon than with placebo at all time points (p ≤ 0.001).
In pediatric patients, dasiglucagon was compared to placebo and reconstituted glucagon in a randomized, controlled, phase III trial.5 In this study, 42 patients aged 6-17 years with T1DM were randomly allocated in a 2:1:1 ratio to dasiglucagon, reconstituted glucagon or placebo during insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose recovery, defined as an increase of ≥20 mg/ dL from baseline without rescue intravenous glucose, in dasiglucagon vs placebo; reconstituted glucagon was used as a reference. The median time to plasma glucose recovery was statistically significantly shorter in the dasiglucagon group compared to the placebo group (10 minutes vs 30 minutes, p < 0.001). The median time to plasma glucose recovery in the reference glucose group was also 10 minutes, but this time did not include the time taken to reconstitute the lyophilized powder. Plasma glucose recovery occurred within 20 minutes in 100% of patients who received dasiglucagon, compared to 18% of patients who received placebo.
Adverse Effects
Dasiglucagon was generally well-tolerated in all clinical trials.10 In adults, adverse effects occurring with 12 hours of administration were nausea (57%), vomiting (25%), headache (11%), diarrhea (5%), and injection site pain (2%). In trials in pediatric patients, the most common adverse effects included nausea (65%), vomiting (50%), headache (10%), and injection site pain (5%). However, it should be noted that administration of glucagon products is known to cause nausea and vomiting, so these adverse effects are not surprising. Other adverse effects that occurred within 12 hours of treatment included hypertension, hypotension, bradycardia, presyncope, palpitations and orthostasis. There were no serious drug-related adverse effects noted in clinical trials, and no adverse effects leading to treatment discontinuation were reported.6
As will all therapeutic peptides, dasiglucagon is potentially immunogenic. In clinical trials, <1% of patients developed treatmentemergent anti-drug antibodies (ADAs). No safety or efficacy concerns were noted in these patients, although it is currently unknown whether these ADAs affect pharmacokinetics, pharmacodynamics, safety and/or efficacy of dasiglucagon.10,12
Practical Considerations
Dasiglucagon is available as a solution for subcutaneous injection in a single-use autoinjector or prefilled syringe. 6,10 The recommended dose is 0.6 mg administered into the outer upper arm, lower abdomen, buttock or thigh. If no response is observed after 15 minutes, a second dose of 0.6 mg may be administered from a new device.
Dasiglucagon can be stored in the refrigerator for up to three years or can be kept at room temperature between 68o and 77o Fahrenheit for up to one year.10 The product should be stored in the provided protective case and protected from light. The product is provided in a single package that contains two devices of 0.6 mg each; it should be clearly explained to patients and caregivers that the full dose is provided in one device.
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Due to dasiglucagon’s effect on liver glycogen, patients with starvation, adrenal insufficiency, or chronic hypoglycemia may not have sufficient liver glycogen levels for dasiglucagon to be effective.12 Patients with these conditions should be treated with glucose.10,11 Additionally, since glucagon products stimulate the release of catecholamines from tumors, dasiglucagon should not be used in patients with pheochromocytomas or insulinomas.
Several drug-drug interactions have been noted and may be clinically significant.10 Patients taking betablockers may experience a transient increase in pulse and blood pressure when given dasiglucagon; patients should be monitored and treated as clinically indicated. Similarly, patients who are taking warfarin should be frequently monitored, as dasiglucagon may increase warfarin’s anticoagulant effects. In patients taking indomethacin, dasiglucagon may lose its ability to raise blood glucose or may even produce hypoglycemia. Careful observation of glucose levels and appropriate intervention is recommended in this scenario.
Zealand Pharma ConnectedCare is a commercial patient support program that is available through the product manufacturer.14 The program can assist patients with determining insurance coverage, co-pay savings, and home delivery of the product. The program is available at to both patients and healthcare providers at https://www. zegalogue.com/savings-and-support/ .
Future Directions
There are several ongoing clinical trials of dasiglucagon in various phases and clinical settings:5,15 • A phase III extension study examining the long-term safety and efficacy of dasiglucagon in children aged six weeks to thirteen years with congenital hyperinsulinemia who completed one of two lead-in trials. • A phase II/III trial is investigating the efficacy and safety of dasiglucagon in children under the age of one year with congenital hyperinsulinism. • A phase II trial is evaluating the efficacy, safety and feasibility of low dose dasiglucagon to prevent or treat episodes of mild hypoglycemia in patients with T1DM who use an insulin pump • Two other phase II trials are examining the use of dasiglucagon for the treatment postprandial hypoglycemia after Roux-en-Y gastric bypass surgery.
Summary
Dasiglucagon is a novel peptide analog of human glucagon, which can effectively rescue insulin-induced severe hypoglycemia.12 Three phase III trials have demonstrated the superiority of dasiglucagon over placebo in the time to plasma glucose recovery in adult and pediatric patients with T1DM who experienced hypoglycemia. Although no significant difference existed in the time of plasma glucose recovery for hypoglycemia between dasiglucagon and marketed glucagon in these studies, the readyto-use formulation of dasiglucagon potentially decreases time to blood glucose rescue and likely increases the user or caregiver’s confidence in proper administration.9 Adverse effects are similar between dasiglucagon and marketed glucagon, with the most commonly reported events of gastrointestinal nature and in short duration.4,9 The reliability, safety and convenience of this product represents an advance in the management of patients with T1DM and may result in fewer cases of severe hypoglycemia that require additional medical intervention.
Dr. Fancher is an Associate Professor of Pharmacy Practice at Duquesne University School of Pharmacy. She also serves as a Clinical Pharmacy Specialist in Oncology at the University of Pittsburgh Medical Center at Passavant Hospital. She can be reached at fancherk@duq.edu or (412) 396-5485.
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