Abstract
Dasiglucagon, a glucagon analogue developed by Zealand Pharma, offers a groundbreaking solution for managing severe hypoglycemia, particularly in Type 1 diabetes patients. Approved by the FDA in 2021, Dasiglucagon has demonstrated rapid and reliable increases in plasma glucose levels, making it a vital tool for hypoglycemia rescue. Its enhanced solubility and stability in aqueous solutions set it apart from conventional glucagon, offering ease of administration via autoinjector or prefilled syringe. Clinical trials have highlighted its efficacy not only in hypoglycemia management but also in future applications such as congenital hyperinsulinism and bihormonal artificial pancreas systems. Despite mild adverse events such as nausea and injection site pain, Dasiglucagon has shown a promising safety profile. This review delves into its pharmacodynamics, pharmacokinetics, clinical efficacy, and safety, positioning Dasiglucagon as a pivotal agent in the evolving landscape of diabetes management.
Keywords: Dasiglucagon， Severe hypoglycemia， Type 1 diabetes， Glucagon analogue， Congenital hyperinsulinism
Introduction to Dasiglucagon: Revolutionizing Hypoglycemia Management
Dasiglucagon is a novel glucagon analogue developed by Zealand Pharma to address the critical need for rapid hypoglycemia treatment, particularly for patients with Type 1 diabetes mellitus (T1DM). Severe hypoglycemia is a life-threatening condition that requires immediate intervention to restore blood glucose levels. Traditional glucagon therapies, while effective, present challenges such as poor stability in aqueous solutions and the need for reconstitution, which can delay treatment. Dasiglucagon’s key innovation lies in its enhanced stability and solubility, allowing it to be administered quickly via a prefilled syringe or autoinjector without prior preparation.
In March 2021, Dasiglucagon received its first FDA approval for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes aged six years and older. This approval marked a significant milestone in the management of diabetes, offering patients and healthcare providers a more reliable and efficient solution for hypoglycemic emergencies. In addition to its use in severe hypoglycemia, Dasiglucagon is being explored for its potential in other conditions, including congenital hyperinsulinism, where it could provide a safer and more effective means of managing persistent hypoglycemia in affected children.
Unlike traditional glucagon formulations, Dasiglucagon is provided in a ready-to-use liquid form, making it particularly advantageous in emergency settings where time is of the essence. This formulation minimizes the risk of user error and reduces delays in glucose rescue. Furthermore, its rapid onset of action, demonstrated in several clinical trials, has positioned Dasiglucagon as a leading therapy in the management of severe hypoglycemia.
In addition to its approved indications, ongoing research into Dasiglucagon’s role in bihormonal artificial pancreas systems further highlights its potential to revolutionize glucose control for patients with diabetes.
Mechanism of Action: How Dasiglucagon Restores Blood Glucose
Dasiglucagon is a synthetic glucagon analogue designed to mimic the natural hormone’s role in counteracting hypoglycemia by stimulating hepatic glucose production. As a glucagon receptor agonist, Dasiglucagon binds to specific receptors located in the liver, activating a cascade that results in glycogenolysis—the breakdown of glycogen stored in the liver into glucose, which is subsequently released into the bloodstream. This process rapidly increases blood glucose levels, effectively reversing the dangerous effects of severe hypoglycemia.
The structure of Dasiglucagon consists of 29 amino acids, similar to native glucagon, but with key substitutions that enhance its physicochemical properties. These modifications improve its solubility and stability in aqueous solutions, making it more suitable for immediate use in emergencies. Unlike traditional glucagon, which requires reconstitution before administration, Dasiglucagon is available in a prefilled, ready-to-use format, reducing the potential for user error and facilitating quicker glucose recovery.
Pharmacodynamically, Dasiglucagon exhibits a rapid onset of action, with glucose levels typically rising within minutes of subcutaneous administration. This makes it highly effective for treating severe hypoglycemia in both pediatric and adult patients. Studies have shown that Dasiglucagon produces a rapid and dose-dependent increase in plasma glucose concentrations, with similar potency to native glucagon at the glucagon receptor. However, due to its enhanced stability, Dasiglucagon offers greater convenience and reliability in clinical settings.
The efficacy of Dasiglucagon is closely tied to the availability of hepatic glycogen stores, as the drug stimulates glycogenolysis to raise blood glucose levels. This mechanism underlines its role as an emergency treatment for hypoglycemia, particularly in Type 1 diabetes, where insulin therapy can sometimes lead to dangerously low blood sugar levels.
Pharmacokinetics and Administration: Fast, Reliable, and Easy-to-Use
Dasiglucagon is rapidly absorbed following subcutaneous administration, providing a fast and effective response in patients experiencing severe hypoglycemia. The pharmacokinetics of Dasiglucagon have been well characterized in both adult and pediatric populations. After subcutaneous injection, Dasiglucagon reaches its peak plasma concentration (Tmax) in approximately 35 minutes, with a half-life (T1/2) of about 30 minutes. This rapid absorption and short half-life make it an ideal treatment for acute hypoglycemic events, ensuring prompt glucose recovery.
The volume of distribution for Dasiglucagon ranges from 47 to 57 liters, indicating extensive tissue distribution. Its elimination occurs through proteolytic degradation, primarily in the blood, liver, and kidneys, following similar pathways to that of native glucagon. The pharmacokinetic profile of Dasiglucagon has been shown to be consistent across different age groups, including pediatric patients, where the pharmacodynamics remain comparable to those observed in adults.
Dasiglucagon is available as a ready-to-use solution for subcutaneous injection, either in a single-use autoinjector or a prefilled syringe. The recommended dose is 0.6 mg, administered into the outer upper arm, lower abdomen, buttocks, or thigh. In clinical practice, this immediate availability without the need for reconstitution is a significant advantage over conventional glucagon, which requires mixing before use, leading to potential delays in critical situations. If no response is observed within 15 minutes of the initial injection, a second 0.6 mg dose from a new device can be administered while awaiting emergency assistance.
Dasiglucagon’s ease of administration and rapid pharmacokinetic profile enhance its utility in both home and clinical settings, providing a reliable solution for managing hypoglycemia in Type 1 diabetes and other conditions requiring glucose rescue.
Clinical Efficacy and Safety: A Proven Solution for Hypoglycemia
Dasiglucagon has undergone extensive clinical trials to establish its efficacy and safety in treating severe hypoglycemia, particularly in patients with Type 1 diabetes mellitus (T1DM). In multiple Phase III randomized, double-blind trials, Dasiglucagon demonstrated a rapid and effective increase in plasma glucose levels, surpassing placebo and comparable to traditional glucagon. For instance, in a key Phase III study, the median time to glucose recovery was 10 minutes with Dasiglucagon, compared to 40 minutes with placebo, and similar to the response time for commercial glucagon (12 minutes). These trials confirmed Dasiglucagon’s efficacy in both adult and pediatric populations, highlighting its reliability in emergency hypoglycemia treatment.
In pediatric trials, Dasiglucagon showed comparable efficacy across different age groups, including children as young as six years old. Clinical studies also highlighted Dasiglucagon’s potential in other applications, such as bihormonal artificial pancreas systems, where it effectively maintained glucose levels by delivering small, precise doses alongside insulin. This development represents a significant advancement in diabetes management by preventing hypoglycemic episodes and reducing the time spent in hypoglycemia.
Regarding safety, Dasiglucagon has shown a favorable safety profile with most adverse events being mild and transient. Common side effects include nausea, vomiting, headache, and injection site pain, all of which are consistent with those observed in traditional glucagon therapies. Importantly, Dasiglucagon was not associated with serious adverse events related to immune responses, with a very low incidence of anti-drug antibodies (ADAs) reported in clinical trials.
Dasiglucagon’s robust efficacy and safety profile support its use as an essential treatment for severe hypoglycemia, particularly for individuals who require fast and reliable glucose recovery in life-threatening situations.
Summary: Dasiglucagon’s Role in the Future of Diabetes Care
Glucagon is well established as a first-line pharmaceutical emergency treatment for severe (level 3) hypoglycemia in people with diabetes. Rescue glucagon can be carried by patients or caregivers, providing them with a valuable safety measure. As the only prescription treatment for severe hypoglycemia that is not limited to dosing by health care professionals, glucagon has been recommended in the most recent American Diabetes Association treatment guidelines to be prescribed for all individuals at increased risk of level 2 hypoglycemia, defined as blood glucose <54 mg/dL (<3.0 mmol/L), so it is available if needed. Caregivers, school personnel, or family members of these individuals are advised that they should know where glucagon treatment is stored and when and how to administer it.
Despite these recommendations, glucagon is underused for the treatment of severe hypoglycemia in individuals with diabetes, even when available to well-informed patients and caregivers. This underuse may be at least partly attributable to the fact that the majority of glucagon for prescription use is provided in glucagon emergency kits (Glucagon for Injection, Eli Lilly and Company; GlucaGen HypoKit, Novo Nordisk) that require multistep reconstitution before subcutaneous or intramuscular injection. The complexity of the multistep reconstitution process is a known barrier to timely, accurate, and effective administration of glucagon, often resulting in both delays and inaccurate dosing and the potential for total failure in dose administration. More recently, ready-to-use glucagon products for subcutaneous injection (Gvoke; formulation in the organic solvent DMSO) and intranasal dry powder administration (Baqsimi) have become available. These newer products have unique benefit-risk profiles because of the characteristics of drug formulation and/or mode of administration.
The next-generation glucagon analog dasiglucagon is the first glucagon product to be provided in a ready-to-use, aqueous formulation. Like endogenous glucagon, dasiglucagon is composed of 29 amino acids, but with seven amino acid substitutions compared with endogenous glucagon to increase the physical and chemical stability in aqueous media. Aqueous formulation is thereby enabled, eliminating the need for reconstitution before injection. Dasiglucagon maintains specificity for the glucagon receptor and has potency comparable to that of native glucagon. Overall, Dasiglucagon represents a significant advancement in the management of hypoglycemia, offering fast, effective, and convenient glucose rescue for patients with diabetes, particularly in life-threatening situations.