Home Use of Mini-Dose Glucagon As a Novel Treatment for Hypoglycemia Following Repeated, Prolonged Fasts in Type 1 Diabetes During Ramadan

Certain situations, such as physical activity and fasting, can significantly increase the risk of hypoglycemia in type 1 diabetes (T1D) (1,2). Fasting is part of several religious practices, and intermittent fasting is also commonly practiced given the potential metabolic benefits (3).

Given the known potential for glycemic derangements with intensively managed T1D in general, as well as higher risks of hypoglycemia from observational data, most international guidelines on diabetes and Ramadan consider T1D as a “high-risk” situation where fasting is not recommended (1,4). However despite recommendations and alternatives, >40% of adult Muslims with T1D continue fasting in Ramadan as they feel it is essential to their spiritual practice, which presents a challenge for health care professionals (5). Advances in therapies and technologies have provided avenues to consider safer fasting practices in T1D; nevertheless, the risks from hypoglycemia still need to be addressed (6).

Having been studied in children and exercise as a subcutaneous treatment to manage hypoglycemia, mini-dose glucagon (MDG) is now an accepted treatment for hypoglycemia in certain limited situations (7,8). Unlike oral medications, subcutaneous injections do not invalidate Ramadan fasts (9). While MDG use could be considered in Ramadan to avoid or treat hypoglycemia without having to break the fast and avoid psychological implications of doing so, its use in the context of prolonged fasts remains untested. This is of special concern during fasting given glycogen store depletion and altered glycogen synthesis in T1D (10,11). This study aimed to understand whether self-administered MDG is safe and effective in preventing or treating mild and moderate hypoglycemia in people with T1D in home settings who performed consecutive, prolonged fasts during Ramadan.

This was a 4-week prospective, randomized, controlled crossover trial recruiting adults aged 18–65 years, with T1D diagnosed for >2 years and HbA_1c <8.5% (69 mmol/mol), who chose to fast during Ramadan (fasting time window = ∼15 h). The protocol is listed on ClinicalTrials.gov (NCT03970772) and was approved by the National Committee of Bioethics (1440-1676406). All participants received real-time continuous glucose monitoring (rt-CGM) (Dexcom G5; Dexcom, San Diego, CA) and were randomized (unblinded) to 2-week MDG or 2-week oral glucose tablets (OG, control) to treat fasting-induced hypoglycemia, with a crossover thereafter.

Recruited participants were instructed to check their blood glucose with the study meter (OneTouch Verio; LifeScan, Milpitas, CA) if they developed hypoglycemia symptoms, their rt-CGM device gave a reading <70 mg/dL or rt-CGM glucose <100 mg/dL with downward arrow, and they intended to treat to prevent hypoglycemia. Participants were trained to reconstitute glucagon (GlucaGen Hypokit, Novo Nordisk) with sterile water to a concentration of 1 mg/mL just prior to each dose and then inject subcutaneously using a standard U-100 insulin syringe according to the study protocol (Supplementary Fig. 4). When the blood glucose was 50–69 mg/dL, treatment was 150 μg of MDG or 15 g of OG (depending on study period), and when the blood glucose was 40–49 mg/dL, treatment was doubled (300 μg of MDG or 30 g of OG). MDG dosage was defined based on previous literature, and the OG dosage was defined according to American Diabetes Association clinical practice guideline (2,12). Hypoglycemia events were analyzed if they met the study testing and treatment protocol (Supplementary Fig. 3).

The primary outcome was the change from baseline to 30 min in blood glucose values (Δ^t30). Secondary end points are listed in Table 1. Statistical rt-CGM metrics comparisons were analyzed using multilevel (mixed) regression models with repeated measures that accounts for the correlation due to the crossover design and multiple measures. Subgroup analysis was carried out to evaluate the effect of prolonged fasting.

There were 17 participants and 80 hypoglycemia episodes that met the criteria for analysis in the crossover trials (Supplementary Fig. 1 and Supplementary Table 1).

The primary end point Δ^t30 and secondary end point Δ^t60 were significantly higher for MDG compared with OG (65.3 ± 26.5 vs. 44.3 ± 20.1 [P < 0.001] and 74.5 ± 50.1 vs. 46.4 ± 26.3 mg/dL [P < 0.02], respectively) (Table 1). Further subanalysis revealed significantly increased Δ^t30 for MDG compared with OG for hypoglycemic events that occurred after 8 h of fasting (60.8 ± 22.1 vs. 41.5 ± 16.7 mg/dL; P = 0.01) (Supplementary Table 2).

MDG users had significantly higher mean glucose 1 and 2 h after hypoglycemic events (80.5 ± 27.9 vs. 68.1 ± 18.7 [P = 0.04] and 106.2 ± 37.7 vs. 87.3 ± 21.7 mg/dL [P = 0.03], respectively) and maximum rt-CGM glucose (114.4 ± 44.5 vs. 93.5 ± 29.3 [P = 0.03] and 143.4 ± 55.4 vs. 120.4 ± 40.6 mg/dL [P = 0.08], respectively) compared with OG. The rt-CGM glucose concentrations for 82.9% MDG events and 50% OG events were ≥100 mg/dL or increased by ≥30 mg/dL within 1 h following treatment (P = 0.01). The rt-CGM data for the entire 2-week MDG period demonstrated significantly increased time in range between 70 and 180 mg/dL (61.0% ± 10.3% vs. 55.1% ± 13.8%; P = 0.009) and less time <70 mg/dL (9.2% ± 5.8% vs. 12.8% ± 12.8%; P = 0.04). Other rt-CGM metrics were favorable for MDG but did not reach statistical significance (Table 1).

Participants with MDG showed a significant increase in completion of fasts compared with those given OG (100% vs. 88%; P < 0.001). Four events (16%) of analyzable hypoglycemic episodes required repeated dosages during the OG period compared with no events during the MDG period (P = 0.01), and success criteria were met for all seven preventable events during the MDG period (Table 1). In all cases after MDG, an acceptable glucose response occurred with no participant requiring any repeat dose within the time period of 4 h of the previous dose (Supplementary Fig. 2). Within the first hour, mean glucose at 15, 30, 45, 60 and 120 min was higher using MDG compared with OG (Supplementary Fig. 3).

Nausea and injection site discomfort were reported in 6 of 17 participants (intolerable nausea for 1 participant), and no serious adverse events were reported.

Our data demonstrate that using glucagon provides an effective alternative to oral options for treating fasting-induced hypoglycemia in the home setting for adults with T1D during Ramadan. An earlier and higher glycemic response was observed with MDG over OG (Table 1 and Supplementary Fig. 3). This approach allowed completion of more fasts successfully. It builds on previous work and presents MDG (i.e., 150 μg of glucagon) as an effective treatment for hypoglycemia that can be applied to other prolonged, repetitive fasting situations such as nocturnal hypoglycemia, intermittent fasting, or exercising in the fasted state in T1D (2,8).

The pharmacokinetic response to the 150-μg dose showed an almost identical response to previous studies (2,13). This suggests that the rapid absorption and efficacy of MDG from subcutaneous tissue is not affected by prolonged, repetitive fasting. Data from fasting 8 h and no requirement for repeated treatments further supports this (Table 1 and Supplementary Table 2).

Most participants reported a tolerable level of nausea, although slightly higher than previous reports. Further advancements in the development of a reusable pen (such as dasiglucagon) could reduce the relative discomfort associated with injections. Inhaled glucagon may provide an alternative approach, but can cause local adverse effects (14).

Participants in this study are representative of an average clinical cohort in Middle East and international clinics given their demographics and nonavailability of structured education programs. Limitations of this study include sample size, given constraints from the cost and challenge of performing larger clinical studies during Ramadan, and potential for selection bias given the use of CGM technologies.

To conclude, glucagon administration is an effective alternative to OG as for the treatment and prevention of hypoglycemia following prolonged fasts in home settings. As newer ways of delivering and administering glucagon are developed, including dual-hormone closed-loop systems, this study provides rationale and validity for the use of glucagon in managing hypoglycemia in semifasted and fasted states in T1D (15).

Acknowledgments. The clinical trials were carried out at Qassim University Outpatient Clinics and Diabetes and Endocrinology Center at King Fahd Specialist Hospital in Buraydah. The authors thank the study participants, the research nurses, and the study coordinator for contribution in execution of this study. The authors thank Dr. Nazim Ghouri for his advice and suggestions on preparing the manuscript. The authors gratefully acknowledge Qassim University, represented by the Deanship of Scientific Research, on the financial support for this research under the number 5389-med-2019-2-2-I during the academic year 2019. The authors also thank the Research Unit at Buraydah Diabetes and Endocrinology Center, Buraydah, Saudi Arabia, for assisting and supporting the conduct of this clinical trial.

Funding. The project was supported by grants from Qassim University (Agreement No. 5389-med-2019-2-2-I).

Duality of Interest. S.H. reports personal fees from Novo Nordisk, outside the submitted work. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. M.A. and S.H. contributed to data interpretation, wrote and edited the manuscript, and revised its intellectual and technical content. T.A., M.A., and H.A. reviewed and edited the manuscript. F.M. performed statistical analyses and edited the manuscript. M.A. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. Parts of this study were presented as an oral presentation at the 14th International Conference on Advanced Technologies and Treatments for Diabetes (ATTD), Paris, France, 2–5 June 2021.