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Systematic Review

Addressing the Shortage of GLP-1 RA and Dual GIP/GLP-1 RA-Based Therapies—A Systematic Review

by
Velimir Altabas
1,2,*,
Zrinka Orlović
3 and
Maja Baretić
2,4
1
Department of Endocrinology, Diabetes and Metabolic Diseases, Internal Clinic, Sestre Milosrdnice University Hospital Centre, 10000 Zagreb, Croatia
2
School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
3
Department of Managerial Economics, Faculty of Economics and Business, University of Zagreb, 10000 Zagreb, Croatia
4
Department of Endocrinology and Diabetes, Internal Clinic, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Diabetology 2025, 6(6), 52; https://doi.org/10.3390/diabetology6060052
Submission received: 30 January 2025 / Revised: 30 April 2025 / Accepted: 21 May 2025 / Published: 5 June 2025
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Abstract

:
Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonists (GIP/GLP-1 RAs) have transformed disease management, particularly in diabetes and obesity. However, recent shortages have disrupted patient care. This review explores the current evidence regarding their direct impact on patient populations and reviews the mitigation strategies recommended by relevant health organizations. Materials and Methods: We systematically searched PubMed, Scopus, and Web of Science for studies published from the earliest available data to 10 January 2025, using these terms: “GLP-1 AND shortage”, “liraglutide AND shortage”, “dulaglutide AND shortage”, “semaglutide AND shortage”, “exenatide AND shortage”, and “tirzepatide AND shortage”. Eligible studies needed to report measurable outcomes like prescription counts, specific laboratory findings, or the proportion of a study population achieving a defined outcome related to the shortage. Only English-language clinical research was considered, while other manuscripts were not included. The risk of bias was assessed using the Critical Appraisal Skills Programme checklist. Study characteristics and findings were summarized in tables. Results: Out of 295 identified manuscripts, 85 works were retained for further screening. Consequently, 8 studies met the inclusion criteria, covering 1036 participants with type 2 diabetes and 573 treated for obesity. In addition, two studies reported prescription prevalence, and one examined prescription counts. Key findings included reduced prescription rates and shifts in treatment practices. No studies assessed impacts on cardiovascular, renal outcomes, or mortality. Discussion and Conclusions: Evidence on the health effects of these shortages is limited. Existing studies highlight disruptions in diabetes and obesity care, but broader impacts remain unclear. Preventing future shortages requires coordinated efforts among all stakeholders. Therefore, we advocate for ethical planning, sustainable production, and fair distribution strategies to mitigate long-term consequences.

1. Introduction

Drug shortages are not uncommon in medicine. The first recorded instance of drug scarcity in modern medicine can be traced back to the insulin shortage of the early 1920s, shortly after insulin was discovered and introduced as a life-saving drug for type 1 diabetes [1]. Since then, drug shortages have occurred repeatedly across the globe, impacting nearly all countries regardless of their level of development or income [2,3,4,5,6,7].
Drug shortages may happen for various reasons, such as raw material unavailability, manufacturing and distribution disruptions, business decisions, and regulatory issues on the production side, and increased drug demand on the medical side. Sometimes, multiple factors coincide and result in drug shortages [8,9,10,11]. Economically, drug shortages usually generate additional costs and/or financial losses [12]. It is important to note that drug shortages can potentially create significant health crises, as they can have wide-ranging impacts on various stakeholders, including manufacturers, suppliers, legislators, hospitals, physicians, and patients [2,13]. Patients are the most vulnerable group, often suffering the most negative effects [14,15]. During drug shortages, patients may face increased monitoring and outpatient clinic visits, suboptimal treatments with alternative drugs, delays in care, transfers to other institutions, more frequent or prolonged hospital stays, and disease relapses or treatment failures. Drug shortages can also lead to care cancellations (e.g., surgeries or transplants) and, in severe cases, even premature death, raising ethical questions about equity and drug accessibility for certain patient groups [2,16,17]. Therefore, drug shortages should be managed with particular care due to their multifaceted nature.
Globally, there is no standardized definition of drug shortages, with more than 25 different definitions currently in use. Definitions vary across regulatory authorities, with some focusing on the production and supply side and others on the demand side [2,16]. These events typically refer to either a temporary or an ongoing situation. Some legislation explicitly defines the minimum period of drug unavailability required to declare a drug shortage, such as three days in France and four days in Belgium. In extreme cases, drug discontinuation as a permanent form of drug shortage occurs when a manufacturer permanently stops producing a drug or when its marketing authorization is withdrawn [16].
Various countries have implemented different strategies to tackle drug shortages. These approaches may differ based on financial circumstances, the strength of health systems, and research findings. Examples of these strategies include enhancing reporting systems, revising policies, creating drug shortage platforms, and expediting drug approvals [2,10,18].
For instance, the U.S. Food and Drug Administration (FDA) maintains a website titled Drug Shortages: Current and Resolved Drug Shortages and Discontinuations Reported to FDA. This official database categorizes both drug shortages and discontinuations [19]. The mentioned website allows anyone to search for specific compounds and review their availability and status. The database is primarily filled with manufacturers’ data; however, reports from other sources are also accepted. The FDA mandates manufacturers to notify the agency of any permanent discontinuation of certain drugs at least six months in advance. If this timeline is not feasible, manufacturers are expected to report as soon as practicable. To address shortages, the FDA assigns a “Resolved” status to a drug once it estimates that market demand can be met by supply from at least one manufacturer. According to the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 (21 USC 356e), the reasons for a drug shortage should be documented [19].
Recently, a shortage of several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) emerged, primarily due to a significant increase in demand [20,21]. This relatively new drug class is based on the discovery of the gut hormone glucagon-like peptide-1 (GLP-1) in 1986, which was found to lower blood glucose levels effectively, and initial treatments with GLP-1 RAs were designed for type 2 diabetes [22,23]. In 2005, exenatide became the first GLP-1 RA approved for the management of type 2 diabetes [24]. Since then, several GLP-1 RAs have been introduced to the market, featuring enhanced pharmacological properties. Furthermore, over time, research revealed additional benefits of these therapies. Beyond improving blood glucose control, GLP-1 RAs demonstrated significant cardioprotective and renoprotective effects, including decreased cardiovascular mortality in some trials [25,26,27,28,29,30,31]. Clinical trials and post-market surveillance reported substantial weight loss in patients using these medications [26]. All this research has resulted in updates to modern guidelines for diabetes, kidney, and heart conditions, positioning several drugs like liraglutide, dulaglutide, and semaglutide prominently in the pharmacotherapy of medical conditions such as type 2 diabetes, coronary artery disease, and chronic kidney disease [32,33,34,35]. Additionally, liraglutide was approved in 2014 for weight management after its earlier approval for diabetes at lower doses, due to its documented beneficial effects on weight loss [36]. Similarly, semaglutide, initially introduced for diabetes, received FDA approval for weight loss in 2021 at a higher dose [37]. Overall, between 2018 and 2023, prescriptions for various GLP-1-based medications surged by approximately 300% [38]. These figures are not surprising given the obesity pandemic and the subsequent rise in the number of patients with diabetes, which may result in an even greater increase in demand.
Finally, in 2022, the FDA approved tirzepatide as the first drug in the class of dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonists (GIP/GLP-1 RA). This novel therapy, indicated for both diabetes and weight management, also in different doses, was shown to be even more potent than GLP-1 RAs [39,40].
The exceptional demand for these medications, coupled with increased public familiarity due to substantial direct-to-consumer advertising, discussions on talk shows, social media, and celebrity endorsements, has resulted in a dramatic rise in prescriptions, leading to medication shortages. Combined with inadequate supply, this situation has raised concerns about sustainable access and the long-term health outcomes associated with these shortages [41,42].
Starting in 2022, there has been a growing global crisis due to medication shortages involving liraglutide, dulaglutide, semaglutide, and tirzepatide, primarily driven by a surge in demand for weight loss prescriptions [19].
The exact impact of these shortages on the health of various patient groups, including those with type 2 diabetes mellitus (T2DM), coronary heart disease, heart failure, and chronic kidney disease, remains unknown, as evidence is scarce. This review aims to explore the current evidence regarding the direct effects of GLP-1 RA and dual GIP/GLP-1 RA shortages on patient populations and to review the mitigation strategies recommended by relevant health organizations.

2. Materials and Methods

This literature review followed the guidelines outlined in the PRISMA2020 statement: An updated guideline for reporting systematic reviews [43].

2.1. Eligibility Criteria

Studies were included in this review if they reported on the effects of the GLP-1 RA and dual GIP/GLP-1 RA shortage or its associated mitigation strategies on the study population. Eligible studies had to report measurable outcomes like prescription counts, specific laboratory findings, or the proportion of a study population achieving a defined outcome related to the GLP-1 RA or dual GIP/GLP-1 RA shortage.
Only articles written in English were included in this review. Manuscripts were excluded if they lacked data or information on specific study outcomes. Studies reporting outcomes in patients but not covering the period of the drug shortage (2022 to 2024) were also excluded. Additionally, preclinical studies, reviews, editorials, commentaries, letters, notes, errata, and case reports were not included. Articles written in languages other than English were excluded as well.

2.2. Search Strategies

We conducted a comprehensive search for studies reporting the possible health impacts of the current GLP-1 RA shortage and proposed mitigation strategies in clinical settings. The search used the following terms: “GLP-1 AND shortage”, “liraglutide AND shortage”, “dulaglutide AND shortage”, “semaglutide AND shortage”, “exenatide AND shortage”, and “tirzepatide AND shortage”. The search was conducted across PubMed, Scopus, and Web of Science, encompassing studies published from the earliest available data through 10 January 2025. No filters or limits were used.

2.3. Study Selection and Data Extraction

The suitability of these articles was independently assessed by two reviewers based on predefined inclusion criteria, specifically the reporting on any measurable outcome related to GLP-1 RA and dual GIP/GLP-1 RA shortages. In addition to outcome relevance, data on study design, participant characteristics (including median age or age range, BMI, and diagnosis) were extracted. Any discrepancies were resolved through discussion.
Ultimately, all titles and abstracts that met the inclusion criteria were retrieved for a full-text review. No automation tools were used during the selection process.

2.4. Risk of Bias Assessment

The risk of bias was assessed by two independent reviewers using the Critical Appraisal Skills Programme (CASP) checklist, which includes 12 questions per manuscript. The details of these questions are described elsewhere [44].

2.5. Data Synthesis

To determine eligibility for data synthesis, the intervention characteristics of each study were first tabulated, including details such as drug type (GLP-1 RA or dual GIP/GLP-1 RA), study duration and design, and population characteristics. In cases where summary statistics were missing or incomplete, relevant pieces of information were extracted from tables, figures, or supplementary materials. Studies lacking sufficient data for inclusion in quantitative synthesis were described narratively.
Results from individual studies and syntheses were then tabulated to facilitate comparison across studies. Key variables such as intervention type, outcome measures, and main findings were organized into summary tables.
All data synthesis steps were conducted independently by two reviewers, with discrepancies resolved through discussion.

3. Results

3.1. Study Selection

A total of 295 manuscripts with the search terms in their titles or abstracts were identified across PubMed (94), Scopus (134), and Web of Science (67). After removing duplicates, 85 works were retained for further screening. Manuscripts published in languages other than English, along with articles categorized as news, reviews, preclinical studies, editorials, commentaries, guidelines, letters, notes, and corrections, were excluded, leaving 38 studies for full-text review.
The flow diagram in Figure 1 illustrates the sequence of steps involved in collecting and selecting eligible studies. In the end, 8 articles were included in this review.

3.2. Study Characteristics

The primary characteristic of the search results is the limited availability of relevant studies providing evidence. Possible reasons include a relatively recent occurrence of the GLP-1 RA and dual GIP/GLP-1 RA crisis, as well as different problems societies face worldwide, like economic disparities and competing public health priorities. In addition, drug producers may be very cautious about disclosing more detailed information related to shortages due to commercial interests or regulatory constraints.
We identified eight studies addressing various aspects of the GLP-1 RA and dual GIP/GLP-1 RA shortage. Among them, three studies analyzed trends in GLP-1 RA prescriptions in specific countries, using insurance providers’ data. They highlighted variations in prescribing patterns, influenced by factors such as geographic location, changes in guidelines, and specific timeframes of shortages of the particular drugs. Two further studies focused on the direct health effects of the shortage on patients with type 2 diabetes. Findings showed that patients experienced worsened blood glucose control due to disrupted access to GLP-1 RAs and dual GIP/GLP-1 RAs. Another study examined the difficulties in managing obesity during the shortage. It revealed significant barriers for patients relying on GLP-1 RAs, including setbacks in weight management progress. Furthermore, two studies investigated the outcomes for patients forced to switch GLP-1 RAs due to shortages. They found that medication changes may have affected their efficacy and tolerability.
Summaries of the included studies are provided in Table 1.

3.3. Risk of Bias in Studies

A critical appraisal of the quality of the selected articles was conducted using the Critical Appraisal Skills Programme (CASP) checklists, which include 12 questions per manuscript. Important shortcomings of these studies include the lack of a control group, a small sample size, as well as the predominant use of cross-sectional or retrospective study designs. Additionally, the studies focused exclusively on patients with type 2 diabetes and obesity, leaving other patient cohorts, such as those with cardiovascular or renal disease, unrepresented. The assessment outcomes of each included study are presented in Table 2.

3.4. Results of Individual Studies

The studies based on health registry data mainly reported on the timeline and trends of these drug shortages. The study using data from the British registry observed a significant increase in GLP-1 RA prescriptions following the release of the 2022 ADA guidelines [49]. In contrast, the Australian registry study reported a marked decrease in semaglutide prescriptions during spring 2022, followed by a corresponding increase in dulaglutide prescriptions [50]. Similarly, the Danish study unveiled a reduction in new semaglutide users during the same period [48]. Two studies focusing on HbA1c outcomes documented a deterioration in glycemic control over time attributed to the shortages of semaglutide and dulaglutide [45,46]. Another study reported the withholding of semaglutide in obesity treatment due to limited supply [47]. In cases where patients were switched to alternative medications, dose adjustments were made if drugs were frequently required [42]. In addition, patients were possibly less satisfied with the replacement drug (e.g., oral semaglutide instead of the subcutaneous semaglutide formulation) [51]. The major findings of each study are presented in Table 1.

4. Discussion

The onset of the global GLP-1 RA shortage coincided with the publication of the 2022 ADA diabetes treatment guidelines [49]. In these guidelines, semaglutide was recommended for the first time as a treatment for both T2DM and weight loss [52]. At the same time, some GLP-1 RA-like liraglutide and semaglutide were registered for obesity treatment, driving off-label use for preparations registered for treating T2DM and increasing the demand for these drugs.
Subsequently, GLP-1 RA and dual GIP/GLP-1 RA shortages affecting various drugs in this class occurred globally [48,50,53]. The most profound post-ADA guideline impact was on semaglutide prescriptions, which saw a significant increase in prescribing. Dulaglutide also experienced a notable rise in use, while other drugs, such as exenatide, showed minimal or negative changes, at least in the UK [49]. Unfortunately, the market supply could not meet the growing demand for these drugs, leading to shortages. Similar trends in semaglutide prescriptions were reported in Denmark, with a documented decline in prescriptions for new injectable semaglutide users during 2023. In contrast, prescriptions for oral semaglutide surged and remained unaffected [48]. A drug shortage due to the unavailability of both injectable semaglutide and dulaglutide, along with declining prescriptions, was also reported in Australia in 2022 [50].
The market has remained unstable ever since then. As of January 2025, the FDA reports regarding the GLP-1 shortage that exenatide, the first GLP-1 receptor agonist, is currently being discontinued [19]. Furthermore, there is an ongoing shortage of liraglutide, semaglutide injections, and dulaglutide. Tirzepatide experienced shortage status from 15 December 2022 until 2 October 2024. Although this shortage status has now been resolved, patients have been notified that “Even when a medication is available, patients may not always be able to fill their prescriptions immediately at a specific pharmacy”.
Table 3 summarizes the shortage information for GLP-1 RAs and dual GIP/GLP-1 RAs [19]. (FDA Drug Shortages Current and Resolved Drug Shortages and Discontinuations Reported to FDA.)
The shortage of GLP-1 RAs and dual GIP/GLP-1 RAs led to a myriad of problems that required swift resolution to prevent adverse health outcomes in patients treated for type 2 diabetes and obesity.
Table 4 summarizes the various dimensions of the GLP-1 RA and GIP/GLP-1 RA shortage.
In response to the escalating problem of medication shortages, acknowledged by the European Parliament in January 2022, the European Medicines Agency (EMA) established the “Medicine Shortages Steering Group” in March 2022 and released a report addressing the GLP-1 RA shortage [54,55]. In their report, the steering group asserts that media coverage of the use of GLP-1 receptor agonists for cosmetic weight loss in individuals without obesity or related health issues has contributed to the worsening shortages. They acknowledge that the high demand has also led to criminal activities, increasing the risk of counterfeit products. The group urges manufacturers to enhance production, collaborate with regulatory authorities, and ensure that promotional messages align with public health objectives. Furthermore, marketing authorization holders are encouraged to launch awareness campaigns focused on weight management and to educate healthcare professionals about the shortage and its clinical implications. Recommendations for healthcare professionals also include addressing off-label prescriptions. For the public, patients currently receiving GLP-1 RA treatment who encounter medication unavailability are advised to consult their physician, who may consider transitioning them to an alternative treatment.
Similar to the EMA, the American Diabetes Association (ADA) issued a special report recommending strategies to address shortages of GLP-1 and dual GIP/GLP-1 receptor agonists. Their statement offers practical advice for healthcare professionals, such as lowering the dosage to bridge the gap, switching from one GLP-1 RA to another, or using alternative incretin-based therapies like dipeptidyl peptidase 4 (DPP-4) inhibitors. For patients at cardiovascular risk, they also suggest considering other hypoglycemic agents like sodium-glucose cotransporter-2 (SGLT2) inhibitors [41]. However, these recommendations lacked evidence from real-world settings. Subsequent studies revealed that switching between diabetes medications is associated with a decline in glucose control. In a relatively small retrospective study, patients were switched from dulaglutide to either DPP-4 inhibitors, SGLT-2 inhibitors, or a combination of DPP-4 and SGLT-2 inhibitors, or were left without an alternative drug. All patient groups, except those receiving the combination of SGLT-2 inhibitors and DPP-4 inhibitors, experienced a significant increase in fasting blood glucose and HbA1c levels [45]. Although these results were reassuring for the group of patients receiving a combination of DPP-4 inhibitors and SGLT-2 inhibitors as an add-on to background therapy, not all patients could be switched to these drugs (e.g., those already receiving SGLT-2 inhibitors or those with contraindications to SGLT-2 inhibitors and/or DPP-4 inhibitors). A decline in glucose control was observed in another retrospective study involving 811 Australian patients. Among them, a significant increase in HbA1c levels was reported due to the GLP-1 RA shortage, despite prompt switching to alternative antidiabetic medications. Interestingly, despite discontinuing GLP-1 RA treatment, patients continued to lose weight during the follow-up period. However, the sustainability of this effect requires further verification [46]. Switching between GLP-1 RAs and dual GIP/GLP-1 RAs is also associated with changes in glucose regulation, as demonstrated in a study where a large proportion of patients switched from dulaglutide and semaglutide to tirzepatide. More than 50% of patients required a higher drug dose than initially anticipated, and some were unable to tolerate the alternative medication [42]. Still, for patients using semaglutide, the oral preparation of this drug was always available. Notably, a small prospective study reported a decrease in treatment satisfaction with oral semaglutide [51]. Furthermore, its requirement for daily administration on an empty stomach at least 30 min before eating or drinking creates compliance challenges, especially for patients taking other fasting-dependent medications, such as levothyroxine, bisphosphonates, or proton pump inhibitors [56,57].
Additionally, the ADA emphasizes that physicians should maintain open communication with pharmacies to facilitate access to alternative drugs and to avoid prescribing medications that are in short supply for drug-naive patients [41]. The statement concludes with the recommendation that once the drug shortage is resolved, patients, in collaboration with their healthcare providers, may choose to reinitiate their preferred GLP-1 receptor agonist therapy to optimize their diabetes management, but caution is warranted [58].
The National Health Service (NHS) in Britain provided a complex algorithm that takes into account the current HbA1c levels [59].
Moreover, drug shortages, including those affecting GLP-1 RAs and dual GIP/GLP-1 RAs, create opportunities for counterfeit medications. Patients who obtain drugs from the black market face significant risks, including the potential for fake or substandard treatments, delayed access to optimal medications, unexpected side effects, contamination, misuse, and possible legal repercussions. In a study investigating the quality of semaglutide obtained from 317 legal and illegal online pharmacies, all purchased vials were classified as probable substandard and falsified products, as visual inspection revealed noncompliance with more than half (59–63%) of the evaluated criteria [60].
The World Health Organization (WHO) has expressed concern about falsified versions of GLP-1 RA [61], and the EMA has addressed patients directly, warning them about the dangers of unsupervised treatment with both approved and unapproved substances [55]. Additionally, compounded medications, prepared by licensed pharmacists and typically used in specific cases where approved drugs cannot be administered, have also been marketed. The ADA and FDA have raised alarms about compounded GLP-1 RA medications following reports of adverse events, some of which required hospitalization [62,63]. These issues may be associated with dosing errors in compounded injectable products, including doses that exceed recommended levels or inappropriate titration [64].
Although receiving less media coverage, other patient groups, such as obese patients, are also affected by this drug shortage. A prevalent treatment strategy for obese patients was treatment interruption among current GLP-1 RA users or delaying treatment initiation for new users. In a retrospective study, nearly 10% of semaglutide users for obesity discontinued their treatment due to drug shortages [47]. Unlike T2DM treatment guidelines, there is no clear consensus on alternatives for obesity management. Orlistat has limited efficacy and significant side effects, while central appetite suppressants vary in mechanisms of action, contraindications, market availability, and lack of cardiovascular benefits. Dulaglutide is not indicated for obesity treatment, and higher doses of oral semaglutide have not been approved by the FDA or EMA for obesity alone, despite studies showing significant weight reduction in adults with overweight or obesity without type 2 diabetes compared to placebos.
The shortage of GLP-1 receptor agonists has emerged as a significant medical challenge, acknowledged by all major medical agencies, professional societies, and organizations. However, many proposed solutions impose additional burdens on physicians. These include recommendations to avoid prescribing the medication even when it may be in the patient’s best interest, reducing dosages to less effective levels, switching to less suitable alternatives, withholding prescriptions for obese patients who could benefit from the drug, consulting with pharmacists to confirm the availability of non-existent medications, and not approving compounded drugs [65]. As a result, physicians are left watching their patients have few viable treatment options [45,66]. Namely, interruptions in GLP-1 RA and dual GIP/GLP-1 RA therapy could lead to long-term glycemic variability, measured by HbA1c fluctuations. A 2015 meta-analysis revealed that greater HbA1c standard deviation (HbA1c-SD) and coefficient of variation (HbA1c-CV) were positively associated with macrovascular and microvascular complications, as well as increased mortality in diabetes patients. Additionally, glycemic variability contributes significantly to morbidity and mortality in T2DM [46,67,68].
These interruptions also raise logistical and ethical concerns about care accessibility [17]. Adjusting treatment plans often requires collaboration between diabetologists and primary care providers. While diabetologists are better equipped to manage complex cases and tailor treatments to individual needs, their availability is limited. Primary care physicians often lack the resources or guidelines to address such situations independently, particularly for broader patient populations. Lastly, there is the question of whether health insurance should cover additional patient visits necessitated by drug shortages [12,69].
In addition, focusing solely on diabetes treatment in the context of GLP-1 RA and dual GIP/GLP-1 RA therapies often results in medical obesity management being framed in a negative light. Statements such as “off-label use risks the availability of these medications for their approved indications” or “driven by high demand from individuals using them for cosmetic and weight loss purposes” are raising ethical dilemmas in treating obesity [70]. Stigmatizing obese patients and denying them treatment can lead to serious health consequences, as obesity is a chronic, relapsing condition that is not solely defined by body mass index (BMI) [71]. Furthermore, some of these drugs have been proven to reduce long-term cardiovascular morbidity and mortality in patients with obesity, even in the absence of diabetes, highlighting their right to equitable access and positive health outcomes [30,72]. For patients receiving treatment solely for obesity, discontinuation of GLP-1 RAs or GIP/GLP-1 RAs exacerbates weight cycling, or the “yo-yo effect”, marked by repeated episodes of weight loss and regain. This not only undermines metabolic health but also increases psychological distress, leading to poorer overall outcomes [73,74]. Therefore, the decision to withhold treatment from patients with obesity but without diabetes due to drug shortages lacks evidence and should not rest solely on the shoulders of healthcare providers [75]. Drug shortages should not force physicians to choose between addressing risks such as sleep apnea in obesity and macrovascular complications in diabetes [76].
Furthermore, the potential risks for patients with atherosclerotic vascular disease, heart failure, and renal disease have largely gone unnoticed, with no research addressing the implications of drug shortages in these patient populations.

5. Future Directions

While the overall health impact of this drug shortage is still under investigation, the most viable option for the future seems to be preventing such shortages. Developing a comprehensive planning strategy is essential before any medication is released to the market. This strategy should involve accurately estimating the potential demand for the drug, considering both global and regional market needs and preferences, and forecasting its long-term usage. Key factors to account for include population health, demographic trends, and the prevalence of the disease the medication is intended to treat [8]. By addressing these factors, resources can be used optimally, reducing the risk of both underproduction and overproduction. Proper production planning should ensure that sufficient supply is available across all markets, preventing scenarios where certain regions are deprived of access due to supply prioritization for higher-paying markets.
For medications with anticipated high demand, pharmaceutical companies should invest in flexible technologies and infrastructure capable of adapting to increased production needs. Manufacturers can mitigate risks and maintain a steady supply chain by prioritizing scalable and adaptable systems, even during unexpected demand surges or disruptions [77]. The pharmaceutical industry must recognize the importance of balancing medication prices, such as those for GLP-1 RA and dual GIP/GLP-1 RA therapies, and sometimes government intervention is necessary to prevent events like these. Health economists should also have a role in assessing the cost-effectiveness of these interventions and recommending sustainable policy options to support governments in their decision-making.
Figure 2 illustrates the key factors that influence effective planning for an adequate drug supply and the prevention of shortages.
Manufacturers should also be aware of the additional costs incurred by governments when drug shortages occur, such as increased hospitalizations and the development of chronic complications. Ethical planning should ensure that every patient receives proper care and access to medication. For manufacturers, adopting sustainable planning is key. This includes improving production reliability, diversifying supply chains, and ensuring transparency with healthcare providers [78]. Such practices would not only address short-term challenges but also build long-term trust, stabilizing sales and fostering patient loyalty, ultimately benefiting both businesses and patients.

6. Strengths and Limitations

This review has several notable strengths and limitations. A key strength is the involvement of a non-medical investigator with expertise in economics, offering a unique and valuable perspective. Furthermore, to the best of our knowledge, this is the first systematic review to examine the health impact of GLP-1 RA and dual GIP/GLP-1 RA shortages on patients’ health. However, the review is limited by the small number of available real-world studies with a limited sample size, their short duration, the lack of control groups, the scarcity of prospective studies, and the complete lack of research focusing on obesity treatment outcomes, as well as heart and renal condition outcomes. These limitations may partly be due to the recent occurrence of the drug shortage.

7. Conclusions

By the time this work is published, shortages of GLP-1 RAs and dual GIP/GLP-1 RAs will likely have been resolved; however, the long-term health consequences for various patient populations, including those with type 2 diabetes, obesity, cardiovascular diseases, and renal disease, will persist. The exact impact of this drug shortage remains unclear, as only limited research currently provides evidence.
However, the ultimate goal should be to prevent similar shortages in the future by implementing sustainable planning before products enter the market. Drug shortages must be addressed by the broader pharmaceutical ecosystem. Ethical planning should take into account global demand and prioritize patient health.
Last, but not least, physicians are trained to be problem solvers in clinical contexts, not marketers. They should not be put in the position of rationing medications or withholding them from patients in need due to supply issues. The health and well-being of those reliant on such therapies demand a commitment to responsible action, ensuring that no patient is left behind in their care journey.

Author Contributions

Conceptualization, V.A. and M.B.; formal analysis, V.A. and Z.O.; writing—original draft, M.B.; writing—review and editing, V.A., M.B. and Z.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Diabetology 06 00052 g001
Figure 1. Flow chart of the sequence of steps involved in the collection and selection of qualified studies.
Figure 1. Flow chart of the sequence of steps involved in the collection and selection of qualified studies.
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Figure 2. Critical factors of drug shortage prevention.
Figure 2. Critical factors of drug shortage prevention.
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Table 1. Brief summaries of research included in this report.
Table 1. Brief summaries of research included in this report.
Author/YearStudy Population/Data Source/Study DesignMajor Findings
Choe HJ et al., 2024 [45]69 patients with T2DM aged 20–90 years treated with metformin + dulaglutide, who stopped dulaglutide due to drug shortage
Follow-up period: 3 months
Retrospective design		Increase in HbA1c values (+1.1%)
Increase in FBG (+1.44 mmol/L)
Nanayakkara N et al., 2024 [46]811 patients with T2DM, aged 66.9 ± 11.3 years treated with semaglutide or dulaglutide, who stopped receiving these drugs due to shortage
Participants were promptly transitioned to alternative non GLP-1 RA medications
Follow-up from 2019 to 2023
Retrospective design		Increase in HbA1c values (+0.3%)
Decrease in body weight (−1.6 kg)
Walczuk S et al., 2024 [47]573 obese veterans treated with semaglutide for obesity
Median age 51 (42–61)
Median BMI 39 (35–44)
Retrospective design
Cross-sectional study		56 (roughly 10%) of semaglutide users needed prescription change due to drug shortage
Semaglutide was frequently not initiated for new starters, current semaglutide users were either transitioned to an alternative drug, or treatment was withheld until drug shortage resolved
Mailhac A et al., 2023 [48]Danish nationwide health registries
Cross-sectional study		The proportion of semaglutide new users who had a record of T2DM declined from 99% in 2018 to only 67% in 2022, increasing again to 87% in 2023
Ibrahim A et al., 2024 [49]British national prescription databases
Repeated cross-sectional design		Significant increase in GLP-1 RA prescribing rates after the release of the 2022 ADA guidelines
Phakey et al., 2024 [50]Australian Pharmaceutical Benefits Scheme (PBS) and Repatriation PBS databases
Retrospective analysis		Semaglutide prescriptions decreased in March–September 2022, whereas dulaglutide prescriptions increased in April–July 2022 before decreasing in August–September 2022
There were fewer semaglutide and more dulaglutide prescriptions supplied than predicted in April–July and June–July 2022, respectively
Hvisdas et al., 2025 [42]156 patients with T2DM who interchanged GLP-1 RA due to shortage
Median age 55 (45–63)
Median BMI 37.6 (32–43)		30% of GLP-1 RA interchange occurred due to drug shortage
Dose escalation occurred in 58% of patients, 41% were transitioned to an equipotent dose, and a dose decrease was considered in 1 patient
Martínez-Montoro et al., 2024 [51]48 patients with T2DM switched from subcutaneous to oral formulation of semaglutide due to drug shortage
Mean age: 58.8 ± 9.7 years
Prospective design
Follow-up period: 3 months		Switching did not result in significant changes in weight (−0.2 kg) or HbA1c (+0.13%) in the short term
A decrease in treatment satisfaction with oral semaglutide was observed
HbA1c—Glycated hemoglobin, BMI—Body Mass Index, GLP-1 RA—Glucagon-Like Peptide-1 Receptor Agonist, FBG—Fasting Blood Glucose, ADA—American Diabetes Association, T2DM Type 2 Diabetes Mellitus.
Table 2. Manuscript Quality Assessment Results.
Table 2. Manuscript Quality Assessment Results.
CASP QuestionMain Limitations
Author/Year123456789101112
Choe HJ et al., 2024 [45]+++++++++++/-+small sample size
Nanayakkara N et al., 2024 [46]+++/-+++/-++++++no control group
Walczuk S et al., 2024 [47]+++/-+/-+/--++++++no follow-up
no control group
Mailhac A et al., 2023 [48]+++/-+++/-++++++no control group
Ibrahim A et al., 2024 [49]+++/-++/-+/-++++++no control group
limited analysis of confounding factors
Phakey et al., 2024 [50]+++/-++/-+/-++++++no control group
limited analysis of confounding factors
Hvisdas et al., 2025 [42]+++/-+++/-++++++no control group
Martínez-Montoro et al., 2024 [51]+++/-+++/-+++++/-+small sample size
no control group
Table 3. The status of GLP-1 RA and dual GIP/GLP-1 RA shortage in January 2025 in the US.
Table 3. The status of GLP-1 RA and dual GIP/GLP-1 RA shortage in January 2025 in the US.
Medication/ManufacturerIndication/Brand NameShortage Start DateShortage End Date/StatusNotes
Exenatide/AstraZenecaDiabetes/Byetta daily Bydureon weeklyN/ADiscontinued in the USFirst injectable GLP-1 RA in daily and weekly forms; no longer available
Liraglutide/Novo NordiskDiabetes/Victoza, Obesity/Saxenda18.07.2023OngoingDaily injections; still under shortage.
Semaglutide/Novo NordiskDiabetes/Ozempic, Obesity/Wegovy31.03.2022OngoingWeekly injections: supply issues persist
Oral semaglutide/Novo NordiskDiabetes/RybelsusNANo shortageDaily oral therapy; no shortage
Dulaglutide/Eli LillyDiabetes/Trulicity15.12.2022OngoingWeekly injections: indication restricted to diabetes
Tirzepatide/Eli LillyDiabetes/Mounjaro, Obesity/Zepbound15.12.202202.10.2024 (resolved)Shortage status resolved, but patients may face delays filling prescriptions at pharmacies
Table 4. Observed drug shortage consequences, clinical challenges, regulatory responses, and future directions regarding the GLP-1 RA and GIP/GLP-1 RA shortage.
Table 4. Observed drug shortage consequences, clinical challenges, regulatory responses, and future directions regarding the GLP-1 RA and GIP/GLP-1 RA shortage.
GLP-1 RA and Dual GIP/GLP-1 RA Drugs Affected by Market ShortageObserved ConsequencesClinical Challenges During Drug ShortageRegulatory ResponseFuture Directions
GLP-1 RA
semaglutide
dulaglutide
liraglutide
Dual GIP/GLP-1 RA
tirzepatide		Patient dissatisfaction
Therapy failure
Physicians forced to make drug-switch decisions without satisfactory evidence
Dosing issues
Occurrence of counterfeit drugs
Deprioritization and ethical stigmatization of obesity treatment
Uneven and unstable drug availability		Worsened glycemic control
Worsened obesity treatment
Potential increased risk of chronic diabetic complications and disability
Potential progression of cardiovascular and renal disease
Potential increase in hospitalization rates and mortality		Political bodies
EMA
FDA
WHO
Medical associations
ADA
Care providers
NHS		Development of production and supply strategy
Flexible drug production
Ethical drug demand management
Timely and evidence-based regulatory responses
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Altabas, V.; Orlović, Z.; Baretić, M. Addressing the Shortage of GLP-1 RA and Dual GIP/GLP-1 RA-Based Therapies—A Systematic Review. Diabetology 2025, 6, 52. https://doi.org/10.3390/diabetology6060052

AMA Style

Altabas V, Orlović Z, Baretić M. Addressing the Shortage of GLP-1 RA and Dual GIP/GLP-1 RA-Based Therapies—A Systematic Review. Diabetology. 2025; 6(6):52. https://doi.org/10.3390/diabetology6060052

Chicago/Turabian Style

Altabas, Velimir, Zrinka Orlović, and Maja Baretić. 2025. "Addressing the Shortage of GLP-1 RA and Dual GIP/GLP-1 RA-Based Therapies—A Systematic Review" Diabetology 6, no. 6: 52. https://doi.org/10.3390/diabetology6060052

APA Style

Altabas, V., Orlović, Z., & Baretić, M. (2025). Addressing the Shortage of GLP-1 RA and Dual GIP/GLP-1 RA-Based Therapies—A Systematic Review. Diabetology, 6(6), 52. https://doi.org/10.3390/diabetology6060052

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