Dasiglucagon 4mg/1ml solution for infusion vials

BackgroundPost-bariatric hypoglycemia (PBH) is a challenging and increasingly recognized complication following bariatric surgery, particularly Roux-en-Y gastric bypass (RYGB). Multiple pharmacologic interventions have been explored for managing PBH, but evidence is scattered. This study aimed to systematically synthesize the evidence from comparative studies, single-intervention trials, case reports, and registered clinical trials to evaluate the efficacy of drug therapies for PBH.MethodsThis systematic review and mixed treatment comparison meta-analysis was conducted in accordance with PRISMA guidelines and registered on Open Science Framework. Databases searched included MEDLINE, Cochrane CENTRAL, and Google Scholar, with no language or year restrictions. Eligible studies included randomized clinical trials (RCTs), observational studies, single-drug evaluations, and case reports addressing pharmacologic treatments for PBH. Risk of bias was assessed using Cochrane and Joanna Briggs Institute tools. Mixed treatment comparisons were conducted with relative risk (RR) as effect estimates, and evidence quality was assessed with the GRADE approach.ResultsOut of 2134 records screened, 13 comparative studies, five single-intervention studies, and 15 case reports were included. Among comparative studies, 12 were RCTs and one was a retrospective study. Meta-analysis revealed that anakinra and empagliflozin significantly reduced the risk of hypoglycemia compared to placebo (RR: 0.29; 95% CI: 0.09-0.91 for both). Dasiglucagon showed efficacy as a rescue agent. In single-intervention studies, pasireotide and acarbose prevented hypoglycemia in all patients. Case reports suggested variable success with agents such as liraglutide, verapamil, and semaglutide. However, the certainty of evidence was rated very low, with small sample sizes, heterogeneous definitions of PBH, and imprecise effect estimates limiting the robustness of conclusions.ConclusionPharmacologic management of PBH shows promise with agents such as anakinra, empagliflozin, pasireotide, and acarbose. However, given the considerable heterogeneity, small sample sizes, and wide confidence intervals, very low quality of effect estimates, and varied definitions of PBH, these pooled estimates should be considered hypothesis-generating only, and not confirmatory. There is an urgent need for standardized PBH definitions, patient-centered outcome measures, longer follow-up, and adequately powered RCTs to establish evidence-based therapeutic guidelines.

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Abstract Context Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. Objective To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). Methods In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. Results Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. Conclusion Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

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AIMS/HYPOTHESIS: Consumption of excess carbohydrates to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. The objective of this trial was to evaluate the efficacy, safety and feasibility of pen-administered low-dose dasiglucagon for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions. METHODS: ≤70 mmol/mol [8.5%]) completed a randomised, open-label, two-period crossover study with 2 week periods. During the usual care and dasiglucagon intervention (DASI) periods, participants managed impending and manifested episodes of hypoglycaemia with regular carbohydrate consumption or pen-administered low-dose (80 μg) s.c. dasiglucagon, respectively. Glycaemic control was evaluated using continuous glucose monitoring (Dexcom G6) and event registration of prevention and treatment episodes. RESULTS: Compared with usual care, the mean difference (95% CI) in the DASI period for time in (3.9-10.0 mmol/l) and below (<3.9 mmol/l) range was 2.4 %-points (-0.7, 5.5) and -0.5 %-points (-1.2, 0.2), respectively. In the DASI period, recovery rate (time from hypoglycaemia treatment to euglycaemia) was 44% (11, 87) faster while total daily carbohydrate intake was reduced by 11% (-18, -3). Dasiglucagon use was safe and well tolerated with mild nausea being the most frequent adverse effect. Among the participants, 96% (p<0.0001) were likely to include dasiglucagon in their future routine management of hypoglycaemia. CONCLUSIONS/INTERPRETATION: Use of low-dose dasiglucagon to prevent and treat non-severe hypoglycaemia during free-living conditions was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction. TRIAL REGISTRATION: ClinicalTrials.gov NCT04764968 FUNDING: The study was an investigator-initiated trial. Zealand Pharma supplied the investigational drug and device and provided financial support for the conduct of the trial.

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CONTEXT: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia in childhood with a considerable risk of lifelong neurological sequelae. Available pharmacological therapies are limited. Dasiglucagon is a glucagon analog for the treatment of hypoglycemia. OBJECTIVE: To assess the efficacy and safety of dasiglucagon in children with CHI up to 1 year of age. METHODS: This study included a randomized, crossover, double-blind, placebo-controlled part 1 and an open-label, single-arm part 2 at 4 centers in Germany, the United Kingdom, and the United States. Participants comprised children with CHI aged 7 days to 12 months who were dependent on IV glucose. In part 1, participants were randomized to dasiglucagon or placebo for 48 hours, then crossed over to the other treatment for 48 hours. In part 2, all participants received dasiglucagon for 21 days. The primary outcome was mean IV glucose infusion rate (GIR) in the last 12 hours of part 1. RESULTS: Between June 19, 2020, and February 9, 2022, 12 eligible participants were randomized to dasiglucagon-placebo (n = 7) or placebo-dasiglucagon (n = 5). The IV GIR was significantly reduced with dasiglucagon compared with placebo (least-squares mean 4.3 mg/kg/min [95% confidence interval [CI], 1.04 to 7.60 mg/kg/min] and 9.5 mg/kg/min [95% CI, 6.24 to 12.81 mg/kg/min], respectively; P = .004). The most frequent adverse events in both treatment groups were gastrointestinal, dermatological, and metabolism and nutritional disorders. CONCLUSION: In infants with CHI, dasiglucagon significantly reduced the amount of IV glucose needed to maintain euglycemia compared with placebo. Dasiglucagon represents a promising treatment for the management of CHI.

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<p dir="ltr">Objective: Post-bariatric hypoglycemia affects more than 50% of Roux-en-Y gastric bypass-operated individuals. Despite the often debilitating nature of this complication, existing treatment options are limited and often inefficient. Dasiglucagon is a stable glucagon analog available in a ready-to-use formulation and recently shown to mitigate post-bariatric hypoglycemia in experimental settings. Here we aimed to evaluate the hypoglycemic hindering potential of dasiglucagon in an outpatient trial.</p><p dir="ltr">Research Design and Methods: We conducted a randomized, double-blind, placebo-controlled, crossover, proof-of-concept study at the Center for Clinical Metabolic Research at Gentofte Hospital Denmark. The study included 24 Roux-en-Y gastric bypass-operated individuals (23 females) with continuous glucose monitor-verified post-bariatric hypoglycemia (≥15 minutes, <3.9 mmol/L, ≥3 times/week) randomly assigned to two four-week treatment periods of self-administered subcutaneously 120 µg dasiglucagon or placebo. The primary and key secondary outcome were continuous glucose monitor-captured percentage of time in level 1 & 2 hypoglycemia (<3.9 & <3.0 mmol/L, respectively). </p><p dir="ltr">Results: Compared with placebo, treatment with dasiglucagon significantly reduced time in level 1 hypoglycemia by 33% (−1.2%-points; 95% CI −2.0 to −0.5, P=0.002) and time in level 2 hypoglycemia by 54% (−0.4%-points; 95% CI −0.6 to −0.2, P<0.0001). Furthermore, dasiglucagon corrected hypoglycemia within 15 minutes in 401 of 412 self-administrations as compared with 104 of 357 placebo self-administrations (97.3% vs 29.1% correction of hypoglycemia rate, P<0.001). Dasiglucagon was generally well tolerated, with mostly mild to moderate adverse events of nausea.</p><p dir="ltr">Conclusions: Compared with placebo, four weeks of self-administered dasiglucagon effectively reduced clinically relevant hypoglycemia in Roux-en-Y gastric bypass-operated individuals. ClinicalTrials.gov: NCT04836273.</p>

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