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Brief Report
Diabetes, obesity and metabolism Metabolic Consequences of Glucagon-Like Peptide-1 Receptor Agonist Shortage: Deterioration of Glycemic Control in Type 2 Diabetes
Keypoint
In the context of a global shortage of glucagon-like peptide-1 receptor agonists, or GLP-1 Ras, this study assessed the impact of discontinuing dulaglutide on metabolic control in individuals with type 2 diabetes. Discontinuation of GLP-1 RAs leads to significant increases in HbA1c and fasting glucose levels. Alternatives such as DPP4i’s and SGLT2i’s do not match the efficacy of GLP-1 RAs. Continuous GLP-1 RA therapy is crucial for maintaining metabolic stability in type 2 diabetes patients.
Hun Jee Choe1orcid, Michael A. Nauck2,3, Joon Ho Moon4orcid
Endocrinology and Metabolism 2025;40(1):156-160.
DOI: https://doi.org/10.3803/EnM.2024.2150
Published online: November 25, 2024

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea

2Institute of Clinical Chemistry and Laboratory Medicine, University Greifswald, Greifswald, Germany

3Diabetes, Endocrinology, Metabolism Section, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr-University, Bochum, Germany

4Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

Corresponding author: Joon Ho Moon. Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: +82-31-787-8133, E-mail: moonjoonho@snu.ac.kr
• Received: August 19, 2024   • Revised: September 25, 2024   • Accepted: October 7, 2024

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • In the context of a global shortage of glucagon-like peptide-1 (GLP-1) receptor agonists, we assessed the impact of discontinuing dulaglutide on metabolic control in individuals with type 2 diabetes. Our analysis included data from 69 individuals and revealed a significant deterioration in glycemic control following the discontinuation. Specifically, the average hemoglobin A1c level increased from 7.0%±0.9% to 8.1%±1.4% (P<0.001), and fasting glucose levels rose from 129±31 to 156±50 mg/dL (P<0.001) within 3 months after stopping the medication. Alternative treatments such as dipeptidyl peptidase-4 inhibitors and sodium glucose cotransporter- 2 inhibitors were insufficient substitutes, highlighting the essential role of continuous GLP-1 receptor agonist therapy in maintaining metabolic health.
  • Keywords: Diabetes mellitus, type 2; Glucagon-like peptide-1 receptor agonists; Glycemic control
The global demand for glucagon-like peptide-1 (GLP-1) receptor agonists has surged due to their effectiveness in lowering blood glucose levels, promoting weight loss, and providing cardiovascular benefits [1,2]. This increased demand has resulted in a significant worldwide shortage. This situation has raised concerns among healthcare providers and individuals managing type 2 diabetes [3,4]. Registry data suggest that prolonged use of GLP-1 receptor agonists is linked to improved clinical outcomes such as a greater decrease in hemoglobin A1c (HbA1c) [5]. However, there has been no systematic analysis of the metabolic disruptions that may occur due to discontinuation of, or switching from, GLP-1 receptor agonists to other glucose-lowering treatments.
In this study, we aimed to evaluate the metabolic consequences of discontinuation of dulaglutide or switching from dulaglutide to alternative glucose-lowering treatments in individuals with type 2 diabetes due to a global shortage.
Dulaglutide received approval from the Korean Ministry of Food and Drug Safety in 2015 and was widely used until a shortage occurred in early 2023. We conducted a prospectively designed, retrospectively analyzed cohort study at the Seoul National University Bundang Hospital’s Endocrinology and Metabolism Clinic (IRB B-2401-879-106). Informed consent was waived by the board.
The initial cohort comprised 179 individuals aged between 20 and 90 years, all diagnosed with type 2 diabetes and treated with a combination of dulaglutide and metformin. These participants had baseline HbA1c levels of 9.0% or lower (Supplemental Fig. S1). We excluded 40 individuals who were already using insulin, 44 who started insulin therapy after discontinuing GLP-1 receptor agonists, and 70 with missing baseline or follow-up HbA1c values. Following these exclusions, 69 participants were eligible for the analysis.
Twelve discontinued dulaglutide without any replacement, 27 switched to dipeptidyl peptidase-4 inhibitors (DPP4i), 26 to sodium glucose cotransporter-2 inhibitors (SGLT2i), and three to a combination of both (Table 1). HbA1c levels increased from 7.0%±0.9% to 8.1%±1.4% (P<0.001) 3 months after stopping dulaglutide (Fig. 1). Similarly, the mean fasting glucose concentration rose from 129±31 to 156±50 mg/dL (P<0.001), while C-peptide concentration decreased from 4.93±3.38 to 3.44±1.85 ng/mL (P=0.007). Discontinuation of GLP-1 receptor agonists or switching to DPP4i or SGLT2i alone resulted in worsening HbA1c levels at follow-up (by 1.5%, 1.1%, and 1.1%, respectively). Those who switched to a combination of DPP4i and SGLT2i maintained stable glucose levels, although the small sample size limits definitive conclusions. Body mass index increased in those who switched to DPP4i therapy (from 28.4± 5.9 to 28.8±5.9 kg/m2, P=0.017). An exploratory analysis of those formerly using insulin in conjunction with GLP-1 receptor agonist (who were originally excluded from the main analysis) showed an increase in HbA1c (1.2%±1.3%, P=0.006) (Supplemental Table S1), suggesting that the insulin dose adjustments made after discontinuing GLP-1 receptor agonists were insufficient to maintain glycemic control.
Our study illustrates the challenges in managing type 2 diabetes when individuals are unable to continue with GLP-1 receptor agonist treatment due to supply shortages. Our findings underscore the critical need for uninterrupted treatment to sustain the metabolic control previously achieved [6]. We noted a clinically significant decline in glycemic control just 3 months after discontinuing dulaglutide treatment. This decline was particularly pronounced when GLP-1 receptor agonist treatment was halted without a substitute, or when replaced with oral glucose-lowering medications used as monotherapy.
We identified detrimental metabolic effects following either the discontinuation of GLP-1 receptor agonist therapy or its substitution with DPP4i or SGLT2i treatments. Individuals who discontinued GLP-1 receptor agonist therapy had an average HbA1c of 6.1%±0.8%, which was significantly better than that of other subgroups prior to discontinuation. However, even this group experienced a decline in glycemic control and other metabolic parameters, falling outside the target range recommended by the American Diabetes Association [7]. Although DPP4i extends the half-life of endogenous GLP-1, its effectiveness is significantly less than the supraphysiologic effects of GLP-1 receptor agonists. Likewise, while SGLT2 inhibitors introduce a new class of drugs, they only offer moderate metabolic control, which does not compare to the efficacy of GLP-1 receptor agonist therapy.
A limitation of our research was the inability to assess the effects of switching from dulaglutide to other GLP-1 receptor agonists, as they were unavailable except in fixed-ratio combinations such as insulin degludec/liraglutide and insulin glargine/ lixisenatide. In our setting, neither liraglutide nor semaglutide were available options; the former was only accessible for obesity management, and the latter had not been introduced in Korea.
In the SUSTAIN 7 study, semaglutide demonstrated greater effectiveness than other GLP-1 receptor agonists, showing marked reductions in both HbA1c and body weight compared to dulaglutide [8]. During dulaglutide shortages, it is important to consider the pharmacokinetic and pharmacodynamic differences among GLP-1 receptor agonists. Switching from dulaglutide to semaglutide often leads to significant improvements in diabetes management and weight loss, unlike discontinuing GLP-1 receptor agonist therapy or switching to DPP4i or SGLT2i therapies. Additionally, the potential for weight gain when introducing insulin therapy to maintain blood glucose levels after discontinuing GLP-1 receptor agonist treatment should be carefully evaluated. However, when discontinuation of GLP-1 receptor agonist therapy is involuntary, no other treatment fully substitutes its role.
We want to alert healthcare professionals to these risks. Pharmaceutical companies must enhance their efforts to ensure a stable supply of GLP-1 receptor agonists globally, while governments and healthcare systems should issue guidelines to guarantee the consistent availability of GLP-1 receptor agonists for patients.

Supplemental Table S1.

Metabolic Phenotype Alterations of Discontinuing Dulaglutide in Insulin Users
enm-2024-2150-Supplemental-Table-S1.pdf

Supplemental Fig. S1.

Selection criteria and participants allocation in dulaglutide discontinuation study. HbA1c, hemoglobin A1c; GLP1- RA, glucagon-like peptide-1 receptor agonist; DPP4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium glucose cotransporter-2 inhibitor. aNot further analyzed as there was only one participant in the group.
enm-2024-2150-Supplemental-Fig-S1.pdf

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Conception or design: H.J.C., M.A.N., J.H.M. Acquisition, analysis, or interpretation of data: H.J.C., M.A.N., J.H.M. Drafting the work or revising: H.J.C., M.A.N., J.H.M. Final approval of the manuscript: H.J.C., M.A.N., J.H.M.

Fig. 1.
Metabolic changes following discontinuation or switching of glucagon-like peptide-1 receptor agonist therapy in individuals with type 2 diabetes. This figure presents comparative boxplots illustrating changes in hemoglobin A1c (HbA1c; %), fasting plasma glucose (mg/dL), and body mass index (BMI; kg/m2) from baseline to 3 months after either stopping dulaglutide without replacement or switching to other glucose-lowering medications due to a shortage of dulaglutide. Each panel focuses on a different metabolic parameter: (A) blue illustrates changes in HbA1c; (B) green shows changes in fasting plasma glucose levels (mg/dL); and (C) red depicts changes in BMI. Within each panel, the groups “total,” “stop,” “dipeptidyl peptidase-4 inhibitor (DPP4i),” and “sodium glucose cotransporter-2 inhibitor (SGLT2i)” are compared. Baseline values are annotated at the bottom of each plot. The central line in each box represents the median, while the edges of the box indicate the 25th and 75th percentiles. aP<0.05; bP<0.01; cP<0.001 levels of statistical significance compared to the baseline.
enm-2024-2150f1.jpg
enm-2024-2150f2.jpg
Table 1.
Metabolic Phenotype Alterations Following the Discontinuation of Dulaglutide
Variable Total (n=69)a
 Discontinuation (n=12)
 Changed to DPP4i (n=27)
 Changed to SGLT2i (n=26)
 Changed to DPP4i and SGLT2i (n=3)
Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value
Age, yr 59.8±13.5 49.3±17.2 58.7±13.8 65.8±8.6 60.3±6.5
Female sex 30 (43.5) 8 (66.7) 14 (51.9) 6 (23.1) 1 (33.3)
Duration of diabetes, yr 12.7±7.6 10.0±6.3 11.9±8.1 13.9±7.6 19.3±3.5
Anthropometric measurements
 Body weight, kg 72.3±14.6 72.8±14.5 0.100 69.8±10 70.9±8.7 0.171 78.0±18.5 79.0±18.3 0.033 69.0±10.1 68.6±10.1 0.418 70.3±17.3 71.0±16.4 0.348
 Body mass index, kg/m2 26.9±4.7 27.1±4.8 0.074 26.2±3.8 26.7±3.8 0.150 28.9±6.1 29.3±6.1 0.026 25.7±3.1 24.5±3.3 0.469 24.5±2.0 24.8±1.9 0.347
 SBP, mm Hg 134±17 137±17 0.114 126±11 136±13 0.011 137±17 137±20 0.941 135±19 139±17 0.313 128±12 132±14 0.612
 DBP, mm Hg 78±13 79±12 0.587 78±14 79±10 0.825 81±13 81±17 0.872 75±12 78±9 0.224 78±9 74±6 0.668
 Pulse rate, /min 89±12 83±12 <0.001 90±17 81±11 0.034 89±12 87±13 0.225 89±11 82±12 0.001 83±6 81±8 0.713
Lab parameters
 HbA1c, % 7.0±0.9 8.1±1.4 <0.001 6.1±0.8 7.6±2.1 0.008 7.3±0.8 8.4±1.2 <0.001 7.0±0.7 8.1±1.2 <0.001 8.1±0.9 8.0±0.9 0.957
 Fasting glucose, mg/dL 129±31 156±50 <0.001 107±23 159±71 0.029 133±33 164±43 0.001 131±25 152±49 0.060 171±11 127±22 0.065
 eGFR CKD-EPI 88.3±20.5 87.3±21.8 0.221 103.8±23.2 102.2±24.3 0.303 88.7±21.5 87.9±24.2 0.596 82.8±15.4 81.9±15.6 0.550 72.5±14.7 68.8±9.3 0.456
 Urine protein/creatinine ratio, mg/g 138±141 196±210 <0.001 115±102 139±112 0.212 142±169 217±251 0.003 170±111 243±232 0.447 NA NA NA
 Urine microalbumin/creatinine ratio, mg/g 61±103 92±154 0.010 35±55 48±78 0.142 64±120 108±185 0.010 103±111 111±140 0.657 NA NA NA
 Uric acid, mg/dL 5.5±1.6 5.2±1.5 0.025 4.8±1.2 4.6±1.4 0.555 5.2±1.9 5.2±1.8 0.740 5.9±1.3 5.4±1.2 0.010 6.3±1.0 5.8±0.4 0.380
 White blood cell, /mm3 7.5±1.8 7.2±1.8 0.174 7.6±1.7 6.3±1.3 0.007 7.7±2.2 7.7±2.0 0.935 7.5±1.6 7.5±1.7 0.917 6.8±1.2 6.7±0.8 0.924
 Hemoglobin, g/dL 14.0±1.9 14.4±1.9 0.005 14.2±2.2 13.9±2.5 0.193 14.3±2.2 14.5±1.9 0.390 13.7±1.5 14.6±1.6 <0.001 12.7±1.3 13.9±1.4 0.006
 Platelet, /mm3 255±65 244±60 0.009 302±75 287±75 0.087 260±58 250±54 0.137 223±54 213±47 0.225 237±40 229±43 0.551

Values are expressed as mean±standard deviation or number (%).

DPP4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium glucose cotransporter-2 inhibitor; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; NA, not applicable.

a The number includes one individual who switched from dulaglutide to thiazolidinedione.

  • 1. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet 2019;394:121–30.PubMed
  • 2. Yao H, Zhang A, Li D, Wu Y, Wang CZ, Wan JY, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ 2024;384:e076410.ArticlePubMedPMC
  • 3. Mahase E. GLP-1 agonist shortage will last until end of 2024, government warns. BMJ 2024;384:q28.ArticlePubMed
  • 4. U.S. Food and Drug Administration. FDA drug shortages [Internet]. Silver Spring: FDA; 2024 [cited 2024 Oct 23]. Available from: https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredientDetails.cfm?AI=Dulaglutide%20 Injection&st=c&tab=tabs-1.
  • 5. Jung H, Tittel SR, Schloot NC, Heitmann E, Otto T, Lebrec J, et al. Clinical characteristics, treatment patterns, and persistence in individuals with type 2 diabetes initiating a glucagon-like peptide-1 receptor agonist: a retrospective analysis of the Diabetes Prospective Follow-Up Registry. Diabetes Obes Metab 2023;25:1813–22.ArticlePubMedPDF
  • 6. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA 2021;325:1414–25.PubMed
  • 7. American Diabetes Association Professional Practice Committee. 6. Glycemic goals and hypoglycemia: standards of care in diabetes-2024. Diabetes Care 2024;47(Suppl 1):S111–25.ArticlePubMedPMCPDF
  • 8. Pratley RE, Aroda VR, Lingvay I, Ludemann J, Andreassen C, Navarria A, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018;6:275–86.ArticlePubMed

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    Metabolic Consequences of Glucagon-Like Peptide-1 Receptor Agonist Shortage: Deterioration of Glycemic Control in Type 2 Diabetes
    Image Image
    Fig. 1. Metabolic changes following discontinuation or switching of glucagon-like peptide-1 receptor agonist therapy in individuals with type 2 diabetes. This figure presents comparative boxplots illustrating changes in hemoglobin A1c (HbA1c; %), fasting plasma glucose (mg/dL), and body mass index (BMI; kg/m2) from baseline to 3 months after either stopping dulaglutide without replacement or switching to other glucose-lowering medications due to a shortage of dulaglutide. Each panel focuses on a different metabolic parameter: (A) blue illustrates changes in HbA1c; (B) green shows changes in fasting plasma glucose levels (mg/dL); and (C) red depicts changes in BMI. Within each panel, the groups “total,” “stop,” “dipeptidyl peptidase-4 inhibitor (DPP4i),” and “sodium glucose cotransporter-2 inhibitor (SGLT2i)” are compared. Baseline values are annotated at the bottom of each plot. The central line in each box represents the median, while the edges of the box indicate the 25th and 75th percentiles. aP<0.05; bP<0.01; cP<0.001 levels of statistical significance compared to the baseline.
    Graphical abstract

    Fig. 1.

    Graphical abstract

    Metabolic Consequences of Glucagon-Like Peptide-1 Receptor Agonist Shortage: Deterioration of Glycemic Control in Type 2 Diabetes
    Variable Total (n=69)a
    		 Discontinuation (n=12)
    		 Changed to DPP4i (n=27)
    		 Changed to SGLT2i (n=26)
    		 Changed to DPP4i and SGLT2i (n=3)
    Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value Baseline 3 months P value
    Age, yr 59.8±13.5 49.3±17.2 58.7±13.8 65.8±8.6 60.3±6.5
    Female sex 30 (43.5) 8 (66.7) 14 (51.9) 6 (23.1) 1 (33.3)
    Duration of diabetes, yr 12.7±7.6 10.0±6.3 11.9±8.1 13.9±7.6 19.3±3.5
    Anthropometric measurements
     Body weight, kg 72.3±14.6 72.8±14.5 0.100 69.8±10 70.9±8.7 0.171 78.0±18.5 79.0±18.3 0.033 69.0±10.1 68.6±10.1 0.418 70.3±17.3 71.0±16.4 0.348
     Body mass index, kg/m2 26.9±4.7 27.1±4.8 0.074 26.2±3.8 26.7±3.8 0.150 28.9±6.1 29.3±6.1 0.026 25.7±3.1 24.5±3.3 0.469 24.5±2.0 24.8±1.9 0.347
     SBP, mm Hg 134±17 137±17 0.114 126±11 136±13 0.011 137±17 137±20 0.941 135±19 139±17 0.313 128±12 132±14 0.612
     DBP, mm Hg 78±13 79±12 0.587 78±14 79±10 0.825 81±13 81±17 0.872 75±12 78±9 0.224 78±9 74±6 0.668
     Pulse rate, /min 89±12 83±12 <0.001 90±17 81±11 0.034 89±12 87±13 0.225 89±11 82±12 0.001 83±6 81±8 0.713
    Lab parameters
     HbA1c, % 7.0±0.9 8.1±1.4 <0.001 6.1±0.8 7.6±2.1 0.008 7.3±0.8 8.4±1.2 <0.001 7.0±0.7 8.1±1.2 <0.001 8.1±0.9 8.0±0.9 0.957
     Fasting glucose, mg/dL 129±31 156±50 <0.001 107±23 159±71 0.029 133±33 164±43 0.001 131±25 152±49 0.060 171±11 127±22 0.065
     eGFR CKD-EPI 88.3±20.5 87.3±21.8 0.221 103.8±23.2 102.2±24.3 0.303 88.7±21.5 87.9±24.2 0.596 82.8±15.4 81.9±15.6 0.550 72.5±14.7 68.8±9.3 0.456
     Urine protein/creatinine ratio, mg/g 138±141 196±210 <0.001 115±102 139±112 0.212 142±169 217±251 0.003 170±111 243±232 0.447 NA NA NA
     Urine microalbumin/creatinine ratio, mg/g 61±103 92±154 0.010 35±55 48±78 0.142 64±120 108±185 0.010 103±111 111±140 0.657 NA NA NA
     Uric acid, mg/dL 5.5±1.6 5.2±1.5 0.025 4.8±1.2 4.6±1.4 0.555 5.2±1.9 5.2±1.8 0.740 5.9±1.3 5.4±1.2 0.010 6.3±1.0 5.8±0.4 0.380
     White blood cell, /mm3 7.5±1.8 7.2±1.8 0.174 7.6±1.7 6.3±1.3 0.007 7.7±2.2 7.7±2.0 0.935 7.5±1.6 7.5±1.7 0.917 6.8±1.2 6.7±0.8 0.924
     Hemoglobin, g/dL 14.0±1.9 14.4±1.9 0.005 14.2±2.2 13.9±2.5 0.193 14.3±2.2 14.5±1.9 0.390 13.7±1.5 14.6±1.6 <0.001 12.7±1.3 13.9±1.4 0.006
     Platelet, /mm3 255±65 244±60 0.009 302±75 287±75 0.087 260±58 250±54 0.137 223±54 213±47 0.225 237±40 229±43 0.551
    Table 1. Metabolic Phenotype Alterations Following the Discontinuation of Dulaglutide

    Values are expressed as mean±standard deviation or number (%).

    DPP4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium glucose cotransporter-2 inhibitor; SBP, systolic blood pressure; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; eGFR, estimated glomerular filtration rate; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; NA, not applicable.

    The number includes one individual who switched from dulaglutide to thiazolidinedione.

    Table 1.

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