Chemistry:Dasiglucagon

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Short description: Medication
Dasiglucagon
Clinical data
Trade namesZegalogue
AHFS/Drugs.comMonograph
MedlinePlusa621022
License data
Routes of
administration		Subcutaneous
Drug classGlucagon receptor agonist
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC152H222N38O50
Molar mass3381.664 g·mol−1
3D model (JSmol)

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.[1][2]

The most common side effects include nausea, vomiting, headache, diarrhea, and injection site pain.[3]

Dasiglucagon was approved for medical use in the United States in March 2021.[1][4][5][6]

Medical uses

Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.[1][4]

Contraindications

Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.[1]

Pharmacodynamics

Dasiglucagon elevates blood glucose levels in normal and hypoglycemic conditions.[7] In adult patients with type 1 diabetes, the average increase in glucose levels at 90 minutes after dasiglucagon administration was 168 mg/dL. For pediatric patients aged seven to 17 years with type 1 diabetes, the mean glucose increase at 60 minutes post-administration was 162 mg/dL.[8] A study conducted on Danish patients with type 1 diabetes (T1DM) compared the pharmacological effects of dasiglucagon with glucagon. Dasiglucagon reached its maximum plasma concentration later than glucagon (35 minutes vs. 20 minutes) across different doses. The time for patients to recover glycemic levels above 70 mg/dL was similar between dasiglucagon (≥0.3 mg) and glucagon (0.5 mg and 1 mg) groups.[9] Dasiglucagon rapidly increased plasma glucose (PG) levels in a dose-dependent manner, reaching a maximum concentration in approximately 50-90 minutes. The glycokinetic response of dasiglucagon was 2-4 times higher than that of glucagon.[10] Dasiglucagon had a higher overall effect than GlucaGen at certain dose levels. In children with T1DM (7 to 17 years old), dasiglucagon showed a faster increase in blood glucose levels by 160 mg/dL or more from baseline at an earlier time (about 30 min) than in adults.[11] Due to the limited number of patients aged 65 years and older enrolled in phase 3 trials, it was impossible to determine if these patients' responses differed from those of young adults. Dasiglucagon demonstrates pharmacological effects consistent with glucagon, except for the freezing deficiency observed in rats (specific to rats and occurring simultaneously with glucagon and dasiglucagon) and the accumulation of liver glycogen in non-diabetic animals with obvious hyperglycemia and hyperinsulinemia.[12]

Pharmacokinetics

Dasiglucagon rapidly enters the bloodstream upon administration, resulting in a dose-dependent increase in plasma levels within approximately 15 minutes.[13][10] The maximum concentration of dasiglucagon in the bloodstream is typically attained around 35 minutes after administration, with a half-life (t1/2) of approximately 0.5 hours. Following the time to maximum concentration (tmax), dasiglucagon demonstrates a decline in concentration over a span of approximately 0.4-0.7 hours, as compared to glucagon's t1/2 of 0.25 hours. [14] Consequently, dasiglucagon exhibits significantly greater values for area under the curve (AUC) measurements, such as AUC0-inf, AUC0-30 min, AUC0-240 min, and maximum concentration (Cmax), when administered under euglycemic conditions. These values are approximately 1.4-4 times higher than those observed with glucagon.[10] Comparative analysis with the medication GlucaGen® (glucagon for injection 1mg/mL) reveals that dasiglucagon demonstrates more prolonged plasma exposure and higher total drug exposure (AUC0-inf). Therapeutic ratios for dasiglucagon doses of 0.6 mg and 0.3 mg, in relation to GlucaGen® doses of 1.0 mg and 0.5 mg, respectively, indicate superior effects on AUC0-inf, BL (1.59 and 1.46). In contrast, the effects on Cmax,BL are similar (1.03 and 0.91).[10][14] However, it is worth noting that the upper limit of the 95% confidence interval (CI) for Cmax and AUC0-30 min is slightly lower than 1, potentially due to higher early plasma exposure per milligram observed in the lower-dose group compared to the higher-dose group.[14] In clinical trials (NCT03216226), dasiglucagon showed a similar safety profile to reconstituted glucagon. No serious adverse events or deaths were reported. The most common side effects were nausea and vomiting. In terms of efficacy, dasiglucagon was as effective as reconstituted glucagon in reversing severe hypoglycemia induced by insulin, with a median recovery time of 10 minutes compared to 12 minutes for reconstituted glucagon. The recovery time was significantly shorter compared to the placebo group (median 40 minutes).[15]

Interactions

Dasiglucagon may cause temporary increases in blood pressure and pulse when taken concurrently with beta-blockers. When taken with indomethacin, dasiglucagon may lose its effectiveness in increasing blood sugar levels and potentially lead to hypoglycemia. Additionally, dasiglucagon has the potential to enhance the anticoagulant effect of warfarin.[8]

Mechanism of Action

Dasiglucagon operates through the same mechanism as endogenous glucagon, acting as an agonist at glucagon receptors expressed throughout the body, which are G-coupled receptors. Binding to liver glucagon receptors, dasiglucagon activates Gsα and Gq, resulting in the activation of adenylate cyclase. This, in turn, increases intracellular cyclic AMP levels, stimulating glycogenolysis and gluconeogenesis in the liver.[16] As glucose is primarily released from liver glycogen stores, the presence of glycogen stores in the liver is essential for dasiglucagon to exert its antihypoglycemic effects[8]

History

A phase III trial for dasiglucagon was started in July 2017.[13] In December 2017, Zealand (Copenhagen, Denmark) announced the initiation of a phase III trial for dasiglucagon, with the intention of submitting positive outcomes to the US Food and Drug Administration (FDA) in 2019.[17]

The FDA approved dasiglucagon based on evidence from two clinical trials conducted in adults with type 1 diabetes (169 participants) and one clinical trial conducted in pediatric participants older than six years with type 1 diabetes (31 participants).[3] The trials were conducted in the following five countries: United States, Germany, Austria, Canada, and Slovenia.[3] The same trials were used to assess the safety and efficacy of dasiglucagon: adult Trials A and B and pediatric Trial C.[3] In all trials, participants were randomized into one of three groups: one group received dasiglucagon, one group received placebo, and one group received glucagon for injection (a similar drug that is FDA approved for the same purpose as dasiglucagon).[3] In all groups, participants were given insulin to decrease their blood sugar to a low level (hypoglycemia).[3] Subjects received a single injection of either dasiglucagon, placebo, or glucagon for injection, and the ability of the treatment to increase the participants' blood sugar was evaluated.[3]

Society and culture

Legal status

Dasiglucagon was designated an orphan drug by the FDA in August 2017.[18]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Zegalogue- dasiglucagon injection, solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6c32b47-c47c-4a7f-8d4d-23578f663217. 
  2. ↑ "Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes". Expert Opinion on Pharmacotherapy 21 (11): 1311–1318. August 2020. doi:10.1080/14656566.2020.1747432. PMID 32267182. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 "Drug Trials Snapshots: Zegalogue". 22 March 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-zegalogue.  This article incorporates text from this source, which is in the public domain.
  4. ↑ 4.0 4.1 "Dasiglucagon: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=214231. 
  5. ↑ "Zealand Pharma Announces FDA Approval of Zegalogue (dasiglucagon) injection, for the Treatment of Severe Hypoglycemia in People with Diabetes" (Press release). Zealand Pharma. 22 March 2021. Retrieved 22 March 2021 – via GlobeNewswire.
  6. ↑ "Dasiglucagon: First Approval". Drugs 81 (9): 1115–1120. June 2021. doi:10.1007/s40265-021-01531-z. PMID 34047955. 
  7. ↑ "Dasiglucagon: an effective medicine for severe hypoglycemia". European Journal of Clinical Pharmacology 77 (12): 1783–1790. December 2021. doi:10.1007/s00228-021-03183-0. PMID 34223944. 
  8. ↑ 8.0 8.1 8.2 "FDA approves Zegalogue (dasiglucagon) injection for the treatment of severe hypoglycemia in people with diabetes". 2021. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/214231Orig1s000ltr.pdf. 
  9. ↑ "Dasiglucagon: lösungsstabiles, effektives und sicheres Glucagonanalogon" (in de). Diabetologie und Stoffwechsel 13 (3): 214. August 2018. doi:10.1055/a-0609-9671. ISSN 1861-9002. http://www.thieme-connect.de/DOI/DOI?10.1055/a-0609-9671. Retrieved 11 June 2023. 
  10. ↑ 10.0 10.1 10.2 10.3 "Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus". Diabetes, Obesity & Metabolism 21 (3): 601–610. March 2019. doi:10.1111/dom.13562. PMID 30350477. 
  11. ↑ "Zegalogue (dasiglucagon hydrochloride)". Drugs@FDA: FDA-Approved Drugs.. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=214231. 
  12. ↑ "Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analogue". Diabetes Technology & Therapeutics 21 (2): 94–96. February 2019. doi:10.1089/dia.2018.0363. PMID 30707621. 
  13. ↑ 13.0 13.1 "Practical Ways to Achieve Targets in Diabetes Care". Journal of Diabetes 10 (12): 911–915. December 2018. doi:10.1111/1753-0407.12842. PMID 30120823. 
  14. ↑ 14.0 14.1 14.2 "Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog". Diabetes Care 41 (3): 531–537. March 2018. doi:10.2337/dc17-1402. PMID 29273578. 
  15. ↑ "Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes". Diabetes, Obesity & Metabolism 25 (5): 1351–1360. May 2023. doi:10.1111/dom.14987. PMID 36692230. https://eprints.whiterose.ac.uk/196588/1/Diabetes%20Obesity%20Metabolism%20-%202023%20-%20Heller%20-%20Integrated%20safety%20and%20efficacy%20analysis%20of%20dasiglucagon%20for%20the%20treatment%20of.pdf. Retrieved 11 June 2023. 
  16. ↑ "Glucagon and regulation of glucose metabolism". American Journal of Physiology. Endocrinology and Metabolism 284 (4): E671–E678. April 2003. doi:10.1152/ajpendo.00492.2002. PMID 12626323. 
  17. ↑ "International Diabetes Federation 2017". Journal of Diabetes 10 (5): 353–356. May 2018. doi:10.1111/1753-0407.12644. PMID 29345068. 
  18. ↑ "Dasiglucagon Orphan Drug Designations and Approvals". 10 August 2017. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=569416. 

External links

  • Clinical trial number NCT03378635 for "A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects" at ClinicalTrials.gov
  • Clinical trial number NCT03688711 for "Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM" at ClinicalTrials.gov
  • Clinical trial number NCT03667053 for "Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children" at ClinicalTrials.gov



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