Article

GLP-1 Receptor Agonists and the Risk of Thyroid Cancer

November 2022
Diabetes Care 46(2)

DOI:10.2337/dc22-1148

Authors:

Julien Bezin

University of Bordeaux

Amandine Gouverneur

Centre Hospitalier Universitaire de Bordeaux

Clément Mathieu

Centre Hospitalier Universitaire de Bordeaux

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OBJECTIVE To determine whether use of glucagon-like peptide 1 (GLP-1) receptor agonists (RA) is associated with increased risk of thyroid cancer. RESEARCH DESIGN AND METHODS A nested case-control analysis was performed with use of the French national health care insurance system (SNDS) database. Individuals with type 2 diabetes treated with second-line antidiabetes drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Case subjects were matched with up to 20 control subjects on age, sex, and length of diabetes with the risk-set sampling procedure. Risk of thyroid cancer related to use of GLP-1 RA was estimated with a conditional logistic regression with adjustment for goiter, hypothyroidism, hyperthyroidism, other antidiabetes drugs, and social deprivation index. RESULTS A total of 2,562 case subjects with thyroid cancers were included in the study and matched with 45,184 control subjects. Use of GLP-1 RA for 1–3 years was associated with increased risk of all thyroid cancer (adjusted hazard ratio [HR] 1.58, 95% CI 1.27–1.95) and medullary thyroid cancer (adjusted HR 1.78, 95% CI 1.04–3.05). CONCLUSIONS In the current study we found increased risk of all thyroid cancer and medullary thyroid cancer with use of GLP-1 RA, in particular after 1–3 years of treatment.

Dual Glucagon-Like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Agonist-Associated Thyroiditis: A Case Report of Thyroid Dysfunction Following Tirzepatide Use

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Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence

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Mar 2025

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a primary first-line treatment for type 2 diabetes. This has raised concerns about their impact on cancer risk, spurring extensive research. This review systematically examines the varied effects of GLP-1RAs on the risk of different types of tumors, including overall cancer risk and specific cancers such as thyroid, pancreatic, reproductive system, liver, and colorectal cancers. The potential biological mechanisms underlying their influence on cancer risk are complex, involving metabolic regulation, direct antitumor effects, immune modulation, and epigenetic changes. A systematic comparison with other antidiabetic agents reveals notable differences in their influence on cancer risk across drug classes. Additionally, critical factors that shape the relationship between GLP-1RAs and cancer risk are thoroughly analyzed, including patient demographics, comorbidities, treatment regimens, and lifestyle factors, offering essential insights for developing individualized treatment protocols. Despite significant research progress, critical gaps remain. Future research should prioritize elucidating the molecular mechanisms behind the antitumor effects, refining individualized treatment strategies, investigating early tumor prevention applications, assessing potential benefits for non-diabetic populations, advancing the development of novel therapies, establishing robust safety monitoring frameworks, and building precision medicine decision-making platforms. These efforts aim to establish novel roles for GLP-1RAs in cancer prevention. and treatment, thereby advancing the progress of precision medicine.

Antidiabetic agents as potential cytotoxic candidates for cancer therapy

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Jun 2025

Purpose Hyperglycemia is an overlooked triggering factor for cancer, despite being critical to the survival and growth of cancer cells through a unique process known as the “Warburg effect.” Therefore, blocking glycolysis by using antidiabetic agents is an attractive approach for impeding cancer growth and enhancing their responsiveness to cancer treatments, while leaving healthy cells unaffected. This review aims to explore the potential of antidiabetics as cytotoxic agents for cancer treatment through their role as glucose deprivation candidates and the clinical considerations of using antidiabetics with their risk as carcinogenic in cancer therapy. Methods PubMed, Cochrane Library, and Google Scholar were explored by applying the main topic-relevant keywords to consider articles that had been published up to February 2024 and which met our selection criteria. Results The potential of antidiabetic agents to modify the risk of cancer is an exciting area of research in cancer therapy. Some classes of antidiabetics, such as biguanide, sulfonylureas, dipeptidyl peptidase 4 (DPP4) inhibitors, and sodium–glucose co-transporter 2 (SGLT2) inhibitors, have a direct cytotoxic effect on cancer cells, while others, such as glucagon-like peptide 1 (GLP-1) agonists and thiazolidinediones, have an indirect cytotoxic effect on cancer cells. Conclusion Antidiabetic agents differ in their cytotoxic effectiveness toward cancer cells through several mechanisms. Apart from their potential effects on carcinogenicity, these medications hold promise for future cancer treatment. However, not all antidiabetic agents were good candidates for repurposing because of the well-documented carcinogenicity risk.

Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Myth or Reality?

Article

Full-text available

May 2025

Ronald Goldenberg

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are being used increasingly for the management of type 2 diabetes mellitus (T2DM) or obesity because of their association with robust glucose lowering, weight loss, and cardiorenal benefits. The association between GLP-1RA treatments and thyroid cancer has been a topic of discussion since their early development with the understanding that GLP-1 receptors are present on rodent thyroid parafollicular cells (C-cells), and that GLP-1RAs can cause an increase in calcitonin, and both C-cell hyperplasia and medullary thyroid carcinoma (MTC). This data from rodent studies has led to GLP-1RAs being contraindicated in patients with a personal or family history of MTC or with multiple endocrine neoplasia syndrome type 2. Despite this contraindication, the human relevance of GLP-1RA induced MTC in rodents has not been proven. Normal or hyperplastic C-cells in humans may not express the GLP-1 receptor, and studies of human MTCs have shown variable expression of the GLP-1 receptor. Studies have shown conflicting evidence regarding the expression of the GLP-1 receptor in human papillary thyroid cancer (PTC) cell lines: however, GLP-1RAs did not have significant effects on the proliferation of PTC cells. Because of the data that potentially links GLP-1RAs to an increased risk of thyroid cancer, clinical studies in humans are important in addressing this issue. I will review the relevant data from human studies that have analyzed the potential link between GLP-1RA treatment and thyroid cancer, including pharmacovigilance and observational studies as well as randomized controlled trials (RCTs).

Semaglutide (Ozempic ® ): a comprehensive review of its pharmacology, efficacy, and safety profile in type 2 diabetes mellitus and weight management

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Dec 2024

The Relationship Between Obesity and Cancer: Epidemiology, Pathophysiology, and the Effect of Obesity Treatment on Cancer

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Jun 2025
Curr Oncol

There is growing evidence relating to the risk of cancer in people with obesity. Obesity is already established as one of the strongest predisposing factors to cancer, and 'obesity-related' cancers have been defined in previous studies. In this review article, we examine the epidemiological relationship and describe the potential pathophysiological mechanisms that underpin the association between obesity and cancer. These include hormonal and growth factors that are in abundance in persons living with obesity and thereby increase cancer risk. Additionally, the increased disposition towards chronic inflammation in obesity also confers cancer risk. We also examine the impact of obesity on cancer treatment outcomes, focusing on surgery, chemotherapy, and immunotherapy. Conversely, we underline the impact of weight loss on cancer risk by examining different weight loss strategies.

Navigating the clinical benefits, risks, and emerging controversies with glucagon-like peptide-1 receptor agonists

Article

May 2025
Curr Opin Anaesthesiol

Purpose of review The purpose of this review is to provide an overview of the current clinical implications, benefits, and controversies surrounding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). This review discusses the potential risks associated with GLP-1 RA therapy, such as pulmonary aspirations, tachyphylaxis, and issues with drug efficacy over time. Furthermore, it examines the increasing ethical and medical concerns related to their off-label use, safety, and accessibility. Recent findings Recent studies highlight significant discrepancies in the recommendations provided by different medical societies on the perioperative management of GLP-1 RAs. In addition, insurance barriers exacerbate access issues, with substantial disparities in coverage for weight loss versus diabetes management. The rise of counterfeit GLP-1 RAs, unintentional overdoses, and the growing concern about long-term health impacts are also prominent challenges in the current landscape. Summary Despite increasing usage and the potential benefits of GLP-1 RAs, a lack of consensus on optimal perioperative management and long-term use, coupled with financial and regulatory barriers, creates significant challenges. Medical societies differ on key aspects such as fasting requirements and the risk of aspiration, and concerns about the safety of compounded and counterfeit products remain.

Risk of thyroid cancer related to glucagon‐like peptide‐1 receptor agonists: A systematic review with meta‐analysis of harms of randomized controlled trials

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Jun 2025
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Practical application of semaglutide: From evidence-based research to expert decisions

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May 2025

The rapid progress in the development of highly effective weekly incretin-based medications offers increasingly broad opportunities for comprehensive correction of cardiometabolic disorders in patients with type 2 diabetes and/or obesity. This article aims to summarize existing research that confirms the efficacy and safety of one of the most prescribed medications from the class of glucagon-like peptide-1 receptor agonists – weekly semaglutide. In addition to presenting the main results of randomized clinical trials involving semaglutide, special emphasis is placed on experimental and clinical studies related to the drug’s effectiveness in real-world conditions and during specific life periods for patients with type 2 diabetes and/or obesity, such as surgical and endoscopic interventions, bariatric surgery, intermittent fasting, and religious dietary restrictions. Based on this evidence base and their own clinical experience, the interdisciplinary author team proposes practical approaches to adjusting hypoglycemic therapy in patients with type 2 diabetes when combined with semaglutide and switching to other therapies. Practical recommendations for the use of the drug in patients with obesity during the active weight loss phase and the weight maintenance phase are also formulated. Key considerations supporting long-term obesity treatment are presented; however, trial de-escalation therapy schemes are also provided for patients who have successfully modified their lifestyle while achieving target weight outcomes. The reasons and mechanisms behind the most common adverse events associated with semaglutide use, which represent a potential barrier to its utilization, are separately discussed. The most effective measures for their prevention and correction are outlined, which will enable the realization of the therapeutic potential of weekly semaglutide and thus improve patient outcomes in the long-term management of obesity and type 2 diabetes.

Survival Benefits of GLP-1 Receptor Agonists in Patients with Neuroendocrine Neoplasms: A Large-Scale Propensity-Matched Cohort Study

Article

Full-text available

May 2025

Background: Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies that consist of two major subtypes: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). Glucagon-like peptide-1 receptor agonists (GLP-1Ra) have demonstrated favorable results in preclinical studies, but their impact on NEN outcomes remains unexplored. Methods: Using the TriNetX US Research Network, we identified adult patients with NEN and either diabetes or obesity. After 1:1 propensity score matching based on demographics, comorbidities, procedures, and medication use, we compared survival outcomes between patients who received GLP-1Ra after NEN diagnosis and those who did not. Results: Among 32,464 eligible patients, 3139 received GLP-1Ra and 29,325 did not. After propensity matching, each cohort included 3043 patients with well-balanced baseline characteristics. During follow-up periods extending up to 15 years, all-cause mortality occurred in 356 (11.7%) GLP-1Ra users versus 753 (24.7%) non-users, representing a 13.0% absolute risk reduction (p < 0.001). GLP-1Ra use was associated with significantly improved survival (HR = 0.56, 95%CI = 0.49–0.63, p < 0.001). Both well-differentiated (HR = 0.52) and poorly differentiated tumors (HR = 0.56) showed significant improvement. Among primary sites, lung NENs demonstrated the most pronounced benefit (HR = 0.42). Tirzepatide showed the strongest association with reduced mortality (HR = 0.16), followed by semaglutide (HR = 0.27) and dulaglutide (HR = 0.52). Results: In this large propensity-matched study, GLP-1Ra use was associated with a 44.3% reduction in mortality risk among NEN patients with diabetes or obesity. The magnitude of the observed benefit suggests a potential role for GLP-1Ra as adjunctive therapy in this patient population. Prospective clinical trials are warranted to confirm these findings and explore underlying mechanisms.

Long‐term delirium and survival outcomes in patients treated with GLP‐1 receptor agonists versus metformin in type 2 diabetes: A population‐based cohort study

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May 2025
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Aim Type 2 diabetes mellitus (T2DM) is associated with an increased risk of delirium and mortality. While glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) provide metabolic and neuroprotective benefits, their long‐term impact on delirium risk remains uncertain. This study compares GLP‐1 RAs and metformin in relation to delirium and mortality in T2DM patients using real‐world data. Methods A retrospective cohort study was conducted using the TriNetX global federated research network, which primarily comprises U.S.‐based healthcare organisations (approximately 85%), with additional sites in Europe, Asia‐Pacific and the Middle East. Adults (≥18 years) with T2DM who initiated GLP‐1 RAs or metformin were included. Propensity score matching (PSM) balances baseline characteristics. The primary outcome was incident delirium; the secondary outcome was all‐cause mortality. Kaplan–Meier survival curves and time‐dependent Cox models assessed associations. Results After 1:1 PSM (N = 63 096 per group), GLP‐1 RAs showed no overall reduction in delirium risk (AHR: 0.98, 95% CI: 0.94–1.02, p = 0.3628). However, they were protective in the first 5 years (AHR: 0.89, 95% CI: 0.86–0.92, p < 0.0001) but increased delirium risk between 5 and 10 years (AHR: 1.15, 95% CI: 1.04–1.26, p = 0.0046). Subgroup analysis revealed lower delirium risk with GLP‐1 RAs in middle‐aged patients (40–79 years) and those with HbA1c <7.5%. Higher risk was observed in Asian and Native Hawaiian/Pacific Islander populations. However, these findings should be interpreted with caution due to the relatively small subgroup sizes and the limited representativeness of these groups within the predominantly U.S.‐based database, in which Asian and Native Hawaiian/Pacific Islander patients together accounted for less than 5% of the overall cohort. Mortality risk was lower in absolute terms for GLP‐1 RAs (6.28% vs. 9.95%) but higher in long‐term hazard (AHR: 1.16, 95% CI: 1.12–1.21, p < 0.001). Conclusions GLP‐1 RA use was initially associated with a lower risk of delirium, but this association reversed over time. Subgroup variations suggest individualised treatment considerations. Metformin remains a preferred option given its stable cognitive and survival benefits.

Glucagon-like Peptide-1 Receptor Agonists in the Context of Eating Disorders: A Promising Therapeutic Option or a Double-Edged Sword?

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Apr 2025

Glucagon-like peptide-1 Receptor Agonists (GLP-1 RAs) have been one of the most discussed issues in medicine for the past few years. Initially dedicated to patients with type 2 diabetes mellitus (T2DM), the medicine turned out to be an effective weight-loss treatment for people beyond this population. Whereas their beneficial somatic and metabolic effect are beyond doubt, their possible psychiatric adverse reactions have raised concerns. Eating disorders (EDs) are among the mental illnesses whose number is increasing worldwide. Thus, this review aims to summarize the status of knowledge on the correlation between the popularity of GLP-1 RAs and EDs. The conclusions are not unequivocal, pointing out that GLP-1 ARs have the potential to be an effective therapeutic option in some cases of Eds, but if used inappropriately, may increase morbidity of eating disorders.

Semaglutide treatment for type 2 diabetes in a patient with chronic myeloid leukemia: A case report and review of the literature

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Apr 2025

Background Comorbid type 2 diabetes mellitus (T2DM), severe obesity, and chronic myeloid leukemia (CML) present therapeutic challenges, especially given the limited data on glucagon-like peptide-1 (GLP-1) receptor agonists in this setting. Methods We describe a 33-year-old female with poorly controlled T2DM (HbA1c 10.7%), severe obesity (BMI 47.05 kg/m²), and stable CML on tyrosine kinase inhibitor therapy. She received once-weekly semaglutide (0.5–1.5 mg) for 6 months, alongside insulin glargine and dapagliflozin/metformin. Clinical, biochemical, and molecular parameters were monitored. Results After 6 months, her HbA1c declined from 10.7 to 5.5%, fasting plasma glucose from 16.2 to 5.3 mmol/L, and body weight decreased by 18 kg. Lipid parameters improved, and molecular analysis confirmed continued CML remission (undetectable BCR-ABL1). The patient experienced only mild, transient gastrointestinal side effects. Conclusion In this complex case, semaglutide proved safe and effective for achieving glycemic control and weight reduction without compromising CML stability. These findings suggest that GLP-1 receptor agonists may be a viable therapeutic option for patients with coexisting T2DM, severe obesity, and stable CML, warranting further investigation in broader populations.

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Investigating Risk of Cancer with Sodium-Glucose Cotransporter 2 Inhibitors: A Disproportionality Analysis in the WHO Global Pharmacovigilance Database Vigibase®

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Use of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) has significantly increased due to their cardiovascular benefits. Whether SGLT-2is increase risk of cancer has been of concern since first clinical trials, but this question remains unclear because of methodological limitations in previous studies. We conducted a disproportionality analysis using Vigibase® between 2014 and 2023 to estimate the association between SGLT-2i use and the risk of reporting of different subtypes of cancers, compared with glucagon like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors. Among 644 reported cases of cancer associated with SGLT-2i use, 427 (66.3%) were male, with a mean age of 66.5 ± 9.7 years. Sodium-glucose cotransporter 2 inhibitors showed increased reporting odds ratio for bladder cancer (ROR 4.46, 95% CI 3.23–6.17) and kidney cancer (ROR 1.84, 95% CI 1.25–2.69), but not for all other cancer subtypes. In this disproportionality analysis with a hypothesis-generating approach, SGLT-2is are associated with an increased risk of reporting bladder and kidney cancer. There is a need of an urgent clarification of this signal with further long-term observational studies. Graphical abstract of the study design and results. CI confidence interval, DPP-4i dipeptidyl peptidase 4 inhibitors, GLP-1a glucagon-like peptide 1 agonists, ROR reporting odds ratio, SGLT-2is sodium-glucose cotransporter 2 inhibitors

Incretin-Based Therapies and Cancer: What’s New?

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MED LITH

Growing interest in incretin-based therapies for diabetes mellitus has led to an increased evaluation of their potential effects on cancer development. This review aims to synthesize recent evidence regarding the relationship between incretin-based therapies and cancer risk. We conducted a comprehensive literature review focusing on studies investigating dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists in relation to various malignancies. Current findings suggest that while these therapies demonstrate potential benefits, including weight reduction and metabolic regulation, concerns remain regarding their long-term safety profile. Notably, some studies indicate an increased risk of thyroid and pancreatic cancers, while others report protective effects against prostate, colorectal, and breast cancers. Given the complexity of their effects, further long-term studies and post-marketing surveillance are warranted. This review highlights the need for careful clinical assessment when prescribing incretin-based therapies to patients who may be at increased risk of cancer.

Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions

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Apr 2025
REV ENDOCR METAB DIS

Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.

Cardiovascular effects of anti-obesity medications: the perils and promise

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Full-text available

Mar 2025

Haoyi Zheng

Anti-obesity medications have gone through a tumultuous course of approvals and withdrawals, often triggered by serious cardiovascular complications. Early agents, including amphetamines and fenfluramine–phentermine, were once widely used but ultimately banned or voluntarily withdrawn due to cardiovascular complications. Sibutramine followed a similar trajectory when clinical trials revealed increased cardiovascular event rates, prompting its market withdrawal. Lorcaserin, initially promising for weight management without significant cardiovascular risks, was withdrawn after postmarketing surveillance revealed a potential link to increased cancer incidence. Although more recent medications, including orlistat, phentermine–topiramate, and naltrexone–bupropion, remain available, their cardiometabolic benefits are modest, and long-term cardiovascular outcome data remain inconclusive or still lacking. The emergence of glucagon-like peptide 1 (GLP-1) receptor agonists or co-agonists has transformed obesity management. Liraglutide, semaglutide, and tirzepatide, originally developed for type 2 diabetes, have demonstrated substantial and sustained weight loss along with notable improvements in cardiometabolic markers. In high-risk populations, randomized trials with liraglutide and semaglutide have also shown reductions in major adverse cardiovascular events. Moreover, semaglutide and tirzepatide have exhibited benefits in patients with heart failure with preserved ejection fraction and obesity. Overall, GLP-1 receptor agonists or co-agonists hold substantial promise, however, questions remain regarding their long-term safety and effects in broader populations. The history of approval and withdrawal of anti-obesity medications underscores the importance of postmarketing surveillance. As evidence continues to accumulate, the balance between efficacy and safety will guide the optimal use of GLP-1 receptor agonists or co-agonists in both obesity management and cardiovascular risk reduction.

Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression

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Full-text available

Mar 2025

Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.

Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss

Article

Full-text available

Mar 2025

The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium–glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer’s disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.

Exploring Connections Between Weight‐Loss Medications and Thyroid Cancer: A Look at the FDA Adverse Event Reporting System Database

Article

Full-text available

Mar 2025

Aims GLP‐1 receptor agonists, such as semaglutide (Ozempic) and tirzepatide (Monjaro), have gained significant popularity for obesity management, but concerns have arisen about their potential link to thyroid cancer. This study investigates the association between thyroid cancer and weight‐loss medications. Materials and Methods A disproportionality analysis was conducted using data from the FDA Adverse Event Reporting System (FAERS) from 2004 to Q1 2024. Reporting odds ratios (RORs) were used to identify associations between thyroid cancer and weight‐loss drugs, including anti‐diabetic medications. Results Significant positive associations with thyroid cancer were found for GLP‐1 receptor agonists: semaglutide (ROR = 7.61, 95% CI: 6.37–9.08), dulaglutide (ROR = 3.59, 95% CI: 3.03–4.27), liraglutide (ROR = 15.59, 95% CI: 13.94–17.44) and tirzepatide (ROR = 2.09, 95% CI: 1.51–2.89). A weak inverse association was observed for metformin (ROR = 0.58, 95% CI: 0.36–0.93). No significant associations were found for other drugs, such as topiramate, dapagliflozin and insulin glargine. Conclusion The study, based on data from the FAERS database, suggests a potential association between GLP‐1 receptor agonists and an increased thyroid cancer risk. These findings underscore the importance of further research and continuous safety monitoring when prescribing these medications for obesity management.

TOWARD, a metabolic health intervention, demonstrates robust 1-year weight loss and cost-savings through deprescription

Article

Full-text available

Feb 2025

Background Cost, scalability, and durability represent major challenges to the implementation of intensive lifestyle treatments for obesity and diabetes. We previously reported pilot data from a 6-month intervention in which a self-insured manufacturing company partnered with a metabolic health clinic that utilizes therapeutic carbohydrate reduction (TCR), asynchronous monitoring, and a community-based approach to treat employees with metabolic disease. This manuscript presents weight loss and cost-savings from deprescription at the 12-month time point. Methods 50 employees, mean BMI 43.2 ± 8.7 kg/m², 64% with prediabetes or type 2 diabetes, were enrolled in the multimodal TOWARD telemedicine intervention, which includes: Text-based communications, Online interactions, Wellness coaching, Asynchronous education, Real-time biofeedback and remote monitoring, and Dietary modifications that emphasizes TCR. Results 41 completed the one-year intervention. Mean weight loss for the 50 subjects in the intention-to-treat analysis was 19.5 ± 11.4 kg, corresponding to 15.5% total body weight loss with concomitant deprescription of 96 medications, while starting only 8 medications. In patients who discontinued GLP-1 receptor agonists, weight loss continued or was maintained. Annualized cost savings from the TOWARD approach were approximately -

1700 per patient, as compared to an annualized cost burden of roughly +

13000 per patient for a GLP-1 receptor agonist. Conclusion The TOWARD approach represents a scalable metabolic health intervention that demonstrates robust improvements in weight while simultaneously allowing for deprescription leading to substantial cost savings. TOWARD could serve as a scalable tool to facilitate intensive lifestyle intervention with efficacy on par with GLP-1 receptor agonists.

A System-Based Review on Effects of Glucagon-Like Peptide-1 Receptor Agonists: Benefits vs Risks

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Full-text available

Feb 2025

Glucagon-like peptide 1 (GLP-1), an incretin hormone primarily secreted by L-cells in the gut, prompts insulin release, thus reducing blood sugar levels and causing weight loss by inducing feelings of fullness while curbing appetite. GLP-1 receptor agonists (GLP-1 RAs) mimic its effects, proving highly effective in managing type 2 diabetes mellitus (T2DM) and facilitating weight loss. While predominantly approved for T2DM and obesity, GLP-1 RAs also hold promise for treating other conditions like heart and kidney disease, with ongoing research exploring additional therapeutic applications. These agonists exhibit diverse effects within different organ systems, influencing conditions such as psoriasis, polycystic ovarian syndrome (PCOS), thyroid disorders, neurodegenerative diseases, and cardiopulmonary dysfunction. This study aims to comprehensively review the impact of GLP-1 RAs on various body systems, emphasizing both positive and negative effects while addressing existing knowledge gaps in the literature. By enhancing understanding of the diverse effects of GLP-1 RAs, this study aims to contribute to a broader awareness of their therapeutic potential. This systemic review uses Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a robust and transparent search process, aiming to minimize bias and maximize the retrieval of pertinent studies for review, where past research on GLP-1 RAs’ interactions with various bodily systems were analyzed. The hypothesis posits that a systems-based review of GLP-1 RA mechanisms will reveal positive and negative effects across multiple organ systems, providing comprehensive insights into the hormone's physiological impact. This systematic review will assess the appropriateness of GLP-1 RAs in various aforementioned patient health states, shedding light on their potential impacts on comorbidities. With the surge in popularity of GLP-1 RAs for weight loss and diabetes management, this study aims to enhance patient understanding and informed decision-making regarding these medications, countering trends driven by celebrity endorsements and promoting better healthcare outcomes.

Exploring the causal relationship between GLP-1R agonists and diseases related to the thyroid and parathyroid: a mendelian randomization study

Article

Full-text available

Feb 2025

Unlabelled: Glucagon-like peptide-1 receptor (GLP-1R) agonists are well-known for their benefits in managing obesity and diabetes. However, some studies indicate that they may elevate the risk of thyroid cancer. This study employed summary data-based Mendelian randomization (SMR) analysis, incorporating genetic data from GTEx V.8 and the UK Biobank, to assess how increased GLP-1R gene expression in thyroid and parathyroid tissues affects their functions. We found that increased expression of GLP-1R is a risk factor for hyperparathyroidism, but no causal relationship was found with thyroid dysfunction. Furthermore, we advise routine assessments of parathyroid function and hormone levels for patients on GLP-1R agonists. Supplementary information: The online version contains supplementary material available at 10.1007/s40200-025-01567-y.

Pancreatitis Risk Associated with GLP-1 Receptor Agonists, Considered as a Single Class, in a Comorbidity-Free Subgroup of Type 2 Diabetes Patients in the United States: A Propensity Score-Matched Analysis

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Full-text available

Feb 2025

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly prescribed for the management of type 2 diabetes mellitus (T2DM). However, the potential connection between GLP-1 RAs and the risk of pancreatitis presents a complex and nuanced issue. Although these drugs are effective in improving blood sugar control and cardiovascular health, their association with pancreatitis remains an area of concern. Our study aims to evaluate the association between the use of GLP-1 RAs, considered as a single class, and the risk of pancreatitis in a comorbidity-free subgroup of patients with type 2 diabetes mellitus (T2DM) in the United States. Methods: Data were retrieved from the TriNetX research database using the US Collaborative Network, which included information from 61 healthcare organizations within the U.S. Patients diagnosed with T2DM were categorized into two cohorts: one consisting of the patients prescribed with GLP-1 RAs and the other comprising patients who did not receive GLP-1 RAs. Of this class of medications, the agents analyzed were dulaglutide, lixisenatide, exenatide, liraglutide, and semaglutide. Using a 1:1 propensity score matching (PSM) model, we matched patients of both cohorts based on baseline demographics, comorbidities (hypertensive disorders, ischemic heart disease, gallstones, annular pancreas, alcohol use disorders, hypertriglyceridemia, hypercalcemia, cystic fibrosis, and cannabis use), medications known to cause drug-related pancreatitis, and laboratory values. Results: Of 969,240 patients with T2DM, 9.7% (93,608) were on GLP-1 RA, and 90.3% (875,632) were not. After PSM, the sample included 81,872 patients in each cohort. The risk of pancreatitis between the two groups was not statistically different between the two cohorts at 6 months at (0.1% vs. 0.1%, p = 0.04), and remained without significant increase with time; at 1 year (0.1% vs. 0.2%, p = 0.02), 3 years (0.2% vs. 0.3%, p = 0.001), and 5 years (0.3% vs. 0.4%, p < 0.001). The lifetime risk of developing pancreatitis in patients on GLP-1 RA was lower (0.3% vs. 0.4%, p < 0.001). Conclusions: In our comorbidity-free U.S.-based population with T2DM, the use of GLP-1 RAs did not increase their risk of pancreatitis. Their use was associated with a lower lifetime risk of pancreatitis.

The Cardiovascular Benefits of Glucagon-like Peptide-1 (GLP-1) Receptor Agonists

Article

Jun 2025

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were initially approved by the Food and Drug Administration to improve glycemic control in patients with type 2 diabetes (T2DM). However, their use was associated with a significant weight loss benefit, subsequently leading to their Food and Drug Administration approval for use in obesity and select overweight patients with or without T2DM. Additionally, as part of regulatory clinical trials required for approval of all antidiabetic medications, GLP-1 RAs were discovered to have significant cardiovascular benefits beyond their glycemic control and weight loss properties. Multiple cardiovascular outcome trials demonstrated that GLP-1 RAs cause a significant reduction in major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, in patients with T2DM. The proposed mechanisms of action responsible for GLP-1 RAs cardiovascular benefits include their improvement in glycemic control, substantial weight loss effect, modest reduction in blood pressure, antiatherosclerotic effect, and anti-inflammatory effect. Additionally, with the increase in the heart failure (HF) epidemic worldwide, researchers have begun investigating whether GLP-1 RAs may have a role in the treatment of HF with reduced or preserved ejection fraction in patients with or without T2DM. However, early, small, underpowered clinical trials on this topic have yielded varying results and were unable to clearly identify the role of GLP-1 RAs in the treatment of HF. There is a growing need for a large clinical trial to investigate and establish the safety and efficacy of GLP-1 RAs in HF patients with and without T2DM.

Gewichtsreduktion mit Inkretinmimetika – Chancen und RisikenWeight reduction with incretin mimetics—Opportunities and risks

Article

Jun 2025

Obesity affects a growing number of people worldwide and is associated with severe metabolic, cardiovascular and oncological complications. Obesity not only represents an individual health burden but is also a socioeconomic challenge. With the incretin mimetics liraglutide, semaglutide and tirzepatide, a new class of drugs is now available that for the first time enables substantial and clinically relevant weight reduction. The article sheds light on the efficacy, safety and prospects of obesity treatment based on glucagon-like peptide 1 (GLP-1). In addition to the results of key clinical trials, potential risks, limitations of use, typical side effects and drug interactions are discussed. Economic aspects are also explained. Clinical trials show an average weight reduction of 15–20%, with tirzepatide in particular being highly effective. Positive side effects of the treatment mainly concern metabolism (prediabetes and type 2 diabetes regression) and cardiovascular diseases. The main side effects are the frequently occurring gastrointestinal disorders, such as nausea and vomiting. The long-term safety of the substances has not yet been conclusively proven. High costs, limited access and the potential for abuse pose additional challenges. Combination preparations and orally available drugs are currently under development. Incretin mimetics represent a major advance in the treatment of obesity but require careful selection, close monitoring and long-term integration into lifestyle measures.

Mechanistic study of quercetin in the treatment of thyroid cancer with diabetes based on network pharmacology and in vitro experiments

Article

Full-text available

Jun 2025

Introduction Thyroid cancer (TC) stands as a prevalent malignancy within the global endocrine system, with its incidence notably exacerbated by the presence of diabetes. However, the specific relationship between TC and diabetes and promising treatment strategies that address both conditions simultaneously are still under exploration. Quercetin, herb medicine from traditional Chinese medicine (TCM), is widely used as an adjunctive therapy with Western medicine in the treatment of many diseases based on a wide range of biological effects. The objective of this study was to explore the efficacy of quercetin in treating TC with diabetes combining bioinformatics and network pharmacology. Methods After multistep Cox proportional hazards regressions, we built a prognostic risk model for TC-diabetes and identified targets for quercetin in treating TC with diabetes. Molecular docking was employed to evaluate the binding affinities of quercetin with core targets, and in vitro experiments verified quercetin’s targets and functions. Results 11 prognostic genes were included in the prediction model with a great performance in predicting the prognosis of TC-diabetic patients. 45 genes served as the targets of quercetin in treating TC with diabetes, among which, 5 core genes were screened as the most contributors. Through molecular docking, matrix metalloproteinase-3 (MMP3) was identified as the potential therapeutic target of quercetin. In vitro experiments have found that quercetin can inhibit the proliferation of thyroid cancer cells and the expression of MMP3 under high glucose conditions. Discussion In summary, quercetin may suppress the progression of TC-diabetes by inhibiting the proliferation of thyroid cancer cells and the expression of MMP3.

GLP‐1 receptor agonists and the risk for cancer: A meta‐analysis of randomized controlled trials

Article

Full-text available

May 2025
DIABETES OBES METAB

Aims To assess if there is a difference in the oncogenic risk between GLP‐1 RA and comparators in randomized controlled trials. Materials and Methods A meta‐analysis of randomized controlled trials comparing GLP‐1RA to any comparators for diabetes and/or obesity, lasting at least 52 weeks. The endpoints included the incidence of overall cancers and single malignancies. Results Fifty trials were included. GLP‐1RA treatment was not associated with a significant difference in risk for overall cancer (MH‐OR 1.05, 95% confidence interval [CI] [0.98, 1.13]). Uterine cancer was significantly reduced in the GLP‐1RA arm in trials performed in subjects with obesity (MH‐OR 0.24, 95% CI [0.06, 0.94]), but not in those aimed at diabetes treatment (MH‐OR 0.92, [0.58, 1.47]). We detected an increase in the risk for thyroid cancer (MH‐OR 1.55, [1.05, 2.27]), more evident in longer‐term trials, and in the risk for colorectal cancer (MH‐OR 1.27 [1.03, 1.57]), which, conversely, was significant only in shorter‐term trials. No significant difference in the risk was detected for any other cancer. Conclusions GLP‐1 RA do not appear to produce an effect on most malignancies in clinical trials. A reduction of very close obesity‐associated cancers seems possible, whereas a risk signal for thyroid cancer was observed, prompting the need for further specific studies. On the other hand, the small increase observed in colorectal cancer in shorter‐term trials may be the effect of a disproportionate increase in diagnostic procedures in the GLP‐1 RA arm, because of the suspicion raised by common side effects of GLP‐1 RA.

Pharmacovigilance analysis of neurological adverse events associated with GLP-1 receptor agonists based on the FDA Adverse Event Reporting System

Article

Full-text available

May 2025

We conducted a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database (2005 Q2–2024 Q3) to evaluate neurological adverse events (NAEs) associated with six glucagon-like peptide-1 receptor agonists (GLP-1 RAs): exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, and tirzepatide. Among 28,953 NAE reports associated with GLP-1 RAs, 19 distinct NAE signals were identified using reporting odds ratios (RORs), including dizziness, tremor, dysgeusia, lethargy, taste disorder, presyncope, parosmia, allodynia, and hypoglycemic unconsciousness, etc. Time-to-onset analysis revealed a median latency of 32 days (IQR 7–122) for GLP-1 RA-related NAEs, with 45.28% occurring within 30 days of treatment initiation. Sensitivity analyses using proportional reporting ratios (PRRs), information components (ICs), and empirical Bayes geometric means (EBGMs) confirmed robustness of these signals. While these pharmacovigilance findings underscore the need for heightened clinical vigilance, they represent associations rather than causal relationships, constrained by inherent limitations of FAERS such as reporting bias and confounding. Future prospective studies are needed to confirm these associations and clarify underlying mechanisms.

Response to Comment on Wong et al. Efficacy of GLP-1 Receptor Agonists on Weight Loss, BMI, and Waist Circumference for Patients With Obesity or Overweight: A Systematic Review, Meta-analysis, and Meta-regression of 47 Randomized Controlled Trials. Diabetes Care 2025;48:292–300

Article

May 2025

Repurposing glucose-lowering drugs for cancer therapy

Article

May 2025

Diabetes mellitus secondary to endocrine diseases: a position statement of the working group of the club of the Italian society of endocrinology (SIE)-Nutrition hormones and metabolism

Article

Apr 2025
J ENDOCRINOL INVEST

This position statement addressed the limited scientific literature on the management of diabetes mellitus secondary to endocrinopathies, despite its frequent occurrence in hormonal diseases such as acromegaly, Cushing’s syndrome, primary hyperaldosteronism, pheochromocytoma, hyperthyroidism, and neuroendocrine tumors. The aim was to review the pathophysiological mechanisms, clinical features, and management strategies, focusing on nutritional and pharmacological approaches. A comprehensive review of existing literature was conducted regarding studies on diabetes secondary to endocrinopathies and the effects of treatments for these conditions, such as somatostatin analogues and pancreatic surgery. Particular emphasis was placed on understanding glucose metabolism derangements and the interplay between endocrine excess and therapeutic interventions. Secondary diabetes arises not only from hormone excess but also as a consequence of treatments for endocrine disorders. For instance, somatostatin analogues, while effective in resolving hormone hypersecretion, impair glucose metabolism by inhibiting pancreatic insulin secretion. Similarly, pancreatic surgery for neuroendocrine tumors often exacerbates glycemic disturbances. The management of secondary diabetes requires a multidisciplinary approach that includes treating the underlying endocrine disorder, tailoring antidiabetic therapy, and optimizing nutritional strategies to mitigate metabolic disruptions. Diabetes secondary to endocrinopathies presents unique challenges due to its complex etiology and the metabolic effects of treatments. This position statement underscores the importance of an integrated management approach, offering guidance for clinicians in addressing this multifaceted condition. Further research is needed to develop evidence-based guidelines for optimal care.

GLP-1 Receptor Agonists in the Context of Cancer - The Road Ahead

Article

Apr 2025
AM J PHYSIOL-CELL PH

Isabelle R Miousse

A rapidly increasing proportion of the population in the United State is taking Glucagon-Like Peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes (T2D) or weight loss. Consequently, an increasing number of patients presenting with new cases of cancer also have a current prescription for GLP-1RAs. The impact of GLP-1RAs on metabolism is quite profound, and it is entirely reasonable to assume these agents are also very impactful on the metabolism of cancer cells, in addition to the general metabolism of the patient. Although these drugs are relatively recent on the market, the study of metabolism in cancer is a well-established field and we can make predictions about how GLP-1RAs will interface with cancer treatments. In fact, some evidence points to a possible neoadjuvant effect of these drugs for cancer patients that would justify the initiation of GLP-1RAs to support therapy in a subset of patients. At the same time, there is a very present concern that drugs that induce weight loss may also precipitate the loss of muscle mass –cachexia– in patients. Here, we will provide an overview the existing literature around diabetes and metabolism in the context of cancer and cachexia.

Impact of Incretin Mimetics on Thyroid Cancer Among Patients with Type 2 Diabetes: A Retrospective Cohort Time-to-Event Analysis

Article

Apr 2025

Background: Incretin mimetics, including glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonist) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have been increasingly utilized for glycemic control in patients with type 2 diabetes (T2D). Studies have demonstrated additional improvements in weight loss, cardiovascular health, and renal outcomes. Animal studies have shown an association between GLP-1 receptor agonists and C-cell proliferation and elevated calcitonin, resulting in an FDA black box. Insulin resistance in patients with T2D, along with the use of other glucose control medications, confounds the relationship between incretin mimetics and thyroid cancers. The true effect of incretin mimetics on thyroid cancer remains uncertain and speculative due to this confounding. Methods: This retrospective cohort study compared patients with T2D, who were new users of incretin mimetics, to new users of metformin. Study patients used no other anti-diabetes medications beyond the study medications. The risks of incident thyroid cancer and subsequent thyroidectomy were quantified using Cox proportional hazards regression models fitted with adjustments for demographic and medical covariates over a three-year study period. Medullary thyroid cancer (MTC) and multiple endocrine neoplasia type II (MEN2) cases were quantified. Results: Of the 91,394 patients, 28 incretin mimetic users had a diagnosis of thyroid cancer, and nine of these patients underwent a subsequent thyroidectomy procedure. No incretin mimetic user was diagnosed with MTC or MEN2. There was no statistically significant effect on the overall incretin mimetic category (1.28 aHR, 0.83–1.96), the incretin mimetic subcategories of GLP-1 receptor agonists (1.35 aHR, 0.80–2.29), or DPP-4 inhibitor (0.62 aHR, 0.33–1.17) users in developing thyroid cancer within three years of drug initiation. Similarly, no association was found between the overall incretin mimetic category (1.02 aHR, 0.49–2.10), the subcategories of GLP-1 receptor agonists (1.26 aHR, 0.54–2.96), or DPP-4 inhibitors (0.32 aHR, 0.08–1.37) and a subsequent thyroidectomy. Conclusions: In this real-world cohort study, exposure to incretin mimetics overall or through the incretin mimetic subcategories of GLP-1 receptor agonists and DPP-4 inhibitors was not associated with risks of thyroid cancer or thyroidectomy compared to metformin users.

Treat metabolic diseases with effective and approved therapies while new treatments are under investigation

Article

Apr 2025
Drugs Ther Perspect

Aisling McGuigan

Management of metabolic diseases, such as obesity and type 2 diabetes, typically requires pharmacotherapeutics in addition to lifestyle changes. Several glucagon-like peptide-1 receptor (GLP-1R) agonists have acquired US FDA approval for treatment of these diseases, based on efficacy in glycaemic control and weight management in randomised controlled trials (RCTs). Recently, poly-agonist drugs that target GLP-1R and other metabolic signalling pathways, such as glucose-dependent insulinotropic receptors and glucagon receptors, have shown superior glycaemic control and weight loss effects compared with mono-agonist drugs in RCTs. This highlights the potential benefit of activating multiple gut hormone signalling pathways to achieve improved outcomes in the pharmacological treatment of metabolic diseases.

On the Frontlines of Cardiovascular-Kidney-Metabolic Syndrome: A Review of GLP-1 and Dual GLP-1/GIP Receptor Agonists in Cardiovascular and Kidney Health

Article

Apr 2025
AM J HEALTH-SYST PH

Purpose The purpose of this review is to highlight the role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GLP-1/GIP RAs) in managing cardiovascular-kidney-metabolic (CKM) syndrome, focusing on their cardiovascular (CV) and kidney-protective effects beyond glycemic control. Summary In multiple randomized controlled trials, GLP-1 RAs were demonstrated to confer significant benefits in reducing CV events and preserving kidney function in patients with preexisting atherosclerotic cardiovascular disease (ASCVD) and those at high CV risk. Current guidelines, including those from the Kidney Disease: Improving Global Outcomes (KDIGO) initiative and the American Diabetes Association (ADA), underscore the therapeutic potential of these agents for managing chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and metabolic syndrome. Additionally, emerging data suggests their utility beyond T2DM. This review summarizes the evidence supporting these guidelines, along with newer findings not yet fully integrated into clinical practice. It also examines the role of pharmacists and multidisciplinary teams, safety considerations, and practical strategies for managing common adverse effects. Conclusion The integration of GLP-1 RAs and dual GLP-1/GIP RAs into clinical practice offers substantial benefits for patients, both with and without diabetes. Pharmacists play a pivotal role in recommending evidence-based treatments for those at high CV and kidney risk, educating patients, addressing social determinants of health, and bridging gaps across multidisciplinary care teams.

Late Allograft Loss and Contemporary Cardio-Renal Metabolic Therapies

Article

Apr 2025
J AM SOC NEPHROL

Late kidney allograft loss occurs through one of two mechanisms: a) deterioration of kidney function leading to re-transplantation or dialysis (death-censored graft loss) and b) premature death with a normally functioning transplant (death with graft function) –each accounting for approximately 50% of late kidney graft losses. Late death-censored graft loss typically results from a combination of immune and nonimmune events leading to common nonspecific endpoints (e.g., tubular atrophy, interstitial fibrosis and glomerulosclerosis). Conversely, leading causes of death with graft function typically include cardiovascular events, malignancy, and infection. With an improved understanding of the multiple mechanism by which late graft dysfunction develops, there is an opportunity to identify patients at greatest risk and institute novel strategies to quell the process. Newer cardiometabolic agents with proven benefit in the general population have not been well-studied in kidney transplant recipients. However, in addition to their potential benefits in terms of reducing cardiovascular, infectious and malignancy endpoints (thus minimizing death with graft function risk), many novel agents may have additional anti-inflammatory and/or anti-fibrotic benefit (minimizing death-censored graft loss risk) in the kidney transplant population. In this review, we summarize existing literature regarding major causes of death-censored graft loss and death with graft function, and discuss the potential roles of new cardio-renal metabolic agents including sodium-glucose cotransport 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (MRA), glucagon-like peptide 1 receptor agonists (GLP1-RA), and dual endothelin and angiotensin receptor antagonists in the kidney transplant population, including potential mechanisms to improve death with graft function and death-censored graft loss outcomes.

Endocrinology: What You May Have Missed in 2024

Article

Apr 2025
ANN INTERN MED

During 2024, there were many practice-changing innovations in the field of endocrinology, particularly related to the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs). From the substantial new evidence published in 2024, 10 studies are highlighted that offer critical information for clinicians who manage or comanage patients with endocrine disorders including prediabetes, diabetes, obesity, and hyperparathyroidism. Two of the 10 articles are focused on use of GLP-1RAs in multiple clinical settings not studied in the original GLP-1RA trials, including after bariatric surgery and before endoscopy. Two additional studies focused on GLP-1RA explore the risk for thyroid cancer in patients prescribed GLP-1RA and the effect of a GLP-1RA on chronic kidney disease in patients with type 2 diabetes. Three articles investigate opportunities for deintensification of insulin frequency or an alternate method of insulin delivery in patients with type 2 diabetes. One article explores the cardiometabolic effects of intermittent fasting in persons with prediabetes and type 2 diabetes. The last 2 articles explore the incidence of diabetes after SARS-CoV-2 infection and the skeletal effects of parathyroidectomy as a treatment of hyper-parathyroidism. The results of each study have a direct effect on the delivery of care for patients with prediabetes, type 2 diabetes, and hyperparathyroidism.

The promise of incretin-based pharmacotherapies for metabolic dysfunction-associated fatty liver disease

Article

Full-text available

Mar 2025
HEPATOL INT

Background The presence of excess liver fat secondary to metabolic dysregulation represents the end-organ manifestation of a systemic disease that can progress to steatohepatitis, cirrhosis and its feared complications of clinical decompensation and hepatocellular cancer. Since metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent globally, there is a pressing need to augment lifestyle interventions with pharmacotherapies to ameliorate disease burden and reduce adverse liver-related events. Purpose This review summarises current evidence for the utility of incretin mimetics in the MAFLD/MASH arena. Methods A literature review that encompassed multiple database searches to inform the evidence base for incretin drugs in MAFLD/MASH. Results Incretin mimetics demonstrate multifarious benefits across the metabolic diseases spectrum with mounting evidence for their role in remitting steatohepatitis and liver fibrosis. Weight loss and insulin sensitisation contribute, but additional mechanisms may also be engaged. Gastrointestinal adverse effects are common but for most, can be managed while preserving the hepatic and cardiometabolic benefits. Conclusion The literature reveals benefits from incretin-based therapies for MASH, but data on whether they improve long-term hepatic outcomes are awaited to support their future incorporation into routine clinical care.

The Evolving Role of Weight Loss Pharmacotherapy

Article

Mar 2025

The Ins and Outs of Glp-1 Agonists

Preprint

Full-text available

Dec 2024

Human Relevance of Pharmaceutical Drug-Induced Thyroid Tumors in Rats, Labeling Implications, and Carcinogenicity Study Requirements

Article

Mar 2025
J APPL TOXICOL

In rats, thyroid tumors are common age‐related findings with reported incidence rates up to 8.1% and 11.86% for follicular and C‐cell adenomas, respectively. Increases of thyroid follicular neoplasms in rodents via the induction of hepatic UDP‐glucuronosyltransferase (UGT) enzymes, resulting in elevated thyroid hormone (TH) metabolism, excretion, and subsequent follicular cell proliferation are generally accepted to have little or no relevance to humans due to species differences in sensitivity to this pathophysiologic process. In this analysis, we reviewed approved drugs that resulted in thyroid tumors in 2‐year rat carcinogenicity studies and summarized the positioning of these findings in product labeling language and human risk assessments in the United States and Europe. Overall, although thyroid follicular cell tumors are commonly observed, the labels reviewed listed no suspected human risk or directly state the absence of human relevance for these findings. Like follicular cell tumors, thyroid C‐cell tumors are common background findings in rats but comparatively are not as commonly increased in frequency as drug‐related findings in 2‐year rodent carcinogenicity studies. These findings are most notably observed with GLP‐1 agonists and their human relevance is a topic of ongoing clinical safety surveillance analysis. Thyroid follicular cell hyperplasia, when specifically occurring through hepatic enzyme induction and/or enhanced TH clearance, should be evaluated for anticipated human translational relevance using nonclinical and clinical data. If no human relevance is anticipated, this rationale should be incorporated into a weight of evidence approach for carcinogenicity studies as outlined in the ICH S1B addendum.

Weight Reduction with GLP-1 Agonists and Paths for Discontinuation While Maintaining Weight Loss

Article

Full-text available

Mar 2025

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal.

Role of Incretin Mimetics in the Management of Obesity

Chapter

Mar 2025

Gut hormones are known to play a critical role in the regulation of appetite and energy expenditure. Some of the important hormones that have been explored in the management of obesity includes ghrelin, glucagon-like peptide 1 (GLP-1), peptide tyrosine-tyrosine, oxyntomodulin, glicentin, pancreatic polypeptide, amylin, and cholecystokinin. Imbalance in the level of these hormones likely contributes to the development of obesity. The role of these gut hormones has received a lot of attention in the last few years as important therapeutic targets in the management of obesity.

Treatments for weight gain in schizophrenia

Article

Feb 2025
CURR OPIN PSYCHIATR

Igor Elman

Purpose of review Obesity and related metabolic disorders are extremely common in psychiatric patients, particularly in those with schizophrenia. Elucidating this link's neurobiology may inform clinicians and researchers of rational therapeutic approaches necessary to optimize clinical outcomes. Recent findings Current literature highlights the pivotal role of the inflammation-oxidative stress-insulin resistance loop in the pathophysiology of both metabolic and neuropsychiatric disorders. The concept of ‘diabetophrenia’ is put forward to highlight the overlapping neurobiological mechanisms underlying metabolic dysfunction and schizophrenia symptoms. Innovative treatments, including the combination of xanomeline with trospium and incretin-based medicines, demonstrate encouraging potential in addressing such complex health challenges. Summary The nuanced dynamics of chronic inflammation and psychiatric symptomatology underscore the significance of addressing both metabolic and mental health factors in a cohesive fashion while considering unique psychosocial contexts, dietary preferences, and lifestyle choices. A multidisciplinary strategy is essential for incorporating counseling, dietary interventions, behavioral therapies, and pharmacotherapy into the management of schizophrenia. The ensuing enhanced collaboration among healthcare professionals may render obsolete the prevailing siloed conceptualizations of mental disorders, opening new vistas for generating synergistic insights into the mind-body systems and leading to improved health and quality of life for patients with schizophrenia and other psychiatric conditions.

Exploring the Link Between Thyroid Disorders and Obesity : Mechanisms, Impacts, and Clinical Implications

Article

Feb 2025

Glucose-Dependent Insulinotropic Polypeptide in Incretin Physiology: Role in Health and Disease

Article

Feb 2025
ENDOCR REV

Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone that is synthesized and released from upper intestinal enteroendocrine K-cells in response to the ingestion of glucose or fat. The structure of GIP places it in the secretin/vasoactive intestinal polypeptide family of gastrointestinal regulatory peptides. Although originally named “gastric inhibitory polypeptide” on the basis of its ability to inhibit gastric acid secretion, GIP accounts for 60%-80% of the postprandial insulin response, consistent with the notion that this regulatory peptide constitutes the principal physiological incretin. Under normal conditions, GIP plays a major role in nutrient deposition and storage, both directly through its insulin mimetic properties and indirectly by enhancing insulin release. GIP is overexpressed in obese individuals, which may exacerbate insulin resistance manifested by many patients with type 2 diabetes mellitus. Enhanced postprandial secretion of GIP also initiates a vicious cycle characterized by increased nutrient uptake and storage in adipocytes, leading to insulin resistance and hyperinsulinemia, which then further increases adipocyte nutrient uptake and storage. Despite the deleterious consequences of GIP overexpression, when combined with glucagon-like peptide-1 analogues, GIP agonism has been demonstrated to provide benefit in treating obesity by mechanisms currently not fully elucidated. In contrast, consistent with the etiologic role of GIP overexpression in the pathogenesis of obesity, both genetic abrogation and immunoneutralization of GIP signaling have been shown to reduce the development of obesity in preclinical models. Whether these beneficial effects of GIP antagonism will be extended to humans needs to be determined.

Novel pharmacotherapies for weight loss: Understanding the role of incretins to enable weight loss and improved health outcomes

Article

Feb 2025
DIABETES OBES METAB

Obesity and type 2 diabetes mellitus (T2D) are widespread diseases that significantly impact cardiovascular and renal morbidity and mortality. In the recent years, intensive research has been performed to assess the role of adipose tissue and body fat distribution in the development of metabolic and non‐metabolic complications in individuals with obesity. In addition to lifestyle modifications, glucagon‐like peptide‐1 receptor agonists (GLP‐1‐RA) have become a meaningful treatment expansion for the management of both disorders. In addition to improving metabolic control and reducing body weight, treatment with GLP‐1‐RAs reduces cardiovascular and renal events in individuals with obesity with and without diabetes. These important benefits of GLP‐1‐RAs have triggered new interest in other enteroendocrine and enteropancreatic peptides for treating obesity and its metabolic and non‐metabolic consequences. The first peptide dual‐agonist targeting glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 receptors has been approved for the treatment of T2D and obesity. GIP/GLP‐1 dual‐agonism appear to provide better metabolic control and greater weight reduction compared with GLP‐1‐R mono‐agonism. Other peptide and non‐peptide co‐agonists are in clinical development for obesity, T2D, metabolic dysfunction‐associated steatotic liver disease (MASLD) and other metabolic disorders. This narrative review aims to summarize the available data on approved and emerging enteroendocrine and enteropancreatic based treatment approaches for obesity and metabolic disorders. In addition to available clinical efficacy measures, side effects, limitations and open challenges will also be addressed.

Semaglutide reprograms macrophages via the GLP-1R/PPARG/ACSL1 pathway to suppress papillary thyroid carcinoma growth

Article

Feb 2025
J CLIN ENDOCR METAB

Context The use of glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide, a novel class of antidiabetic medications, has raised concerns about potential adverse effects, particularly a possible association with thyroid cancer (TC). Objective This study aims to evaluate whether semaglutide influences the progression of TC by modulating tumor-associated macrophages (TAMs). Methods Semaglutide was administered to human papillary thyroid carcinoma (PTC) xenograft mouse models, coculture systems consisting of human THP-1 macrophage cells and PTC cells, and primary murine peritoneal macrophages. Assessments included tumor size, M1/M2 macrophage ratio, PTC cell proliferation, and polarization marker expression. Results Semaglutide did not significantly impact the proliferation of PTC cells but reduced tumor size and inhibited the proliferation of PTC cells in coculture systems. It increased M1 and decreased M2 macrophages, reprogramming polarization by downregulating PPARG expression. Cotreatment with semaglutide and a PPARG agonist in the coculture system confirmed the upregulation of downstream genes RSAD2, ACSL1, and PLA2G7. Silencing ACSL1 inhibited lipid accumulation in THP-1 cells and promoted polarization toward the M2 macrophage phenotype. Conclusion Semaglutide modulates macrophage lipid metabolism through the GLP-1R/PPARG/ACSL1 signaling pathway. This modulation promotes the conversion of TAMs to the M1 macrophage phenotype, enhancing their anticancer activity. These findings suggest that semaglutide may improve therapeutic strategies, reduce unnecessary thyroid nodule screenings, and broaden its clinical applications.

Exenatide use and incidence of pancreatic and thyroid cancer: A retrospective cohort study

Article

Full-text available

Dec 2018
DIABETES OBES METAB

A retrospective cohort study, supplemented with a nested case‐control study, was performed using two administrative databases from commercial health plans in the United States to compare the incidence of pancreatic and thyroid cancer among users of exenatide versus other antidiabetic drugs (OADs). Patients with type 2 diabetes who initiated exenatide or OADs between 1 June 2005 and 30 June 2015 were included. Pancreatic and thyroid cancers were identified using chart‐validated algorithms in the cohort study. Cases in the nested case‐control study were chart‐confirmed pancreatic or thyroid cancers, and controls were sampled using risk‐set sampling. The time‐fixed analyses comparing 33 629 exenatide initiators with 49 317 propensity‐score‐matched OAD initiators yielded hazard ratios of 0.76 (95% confidence interval [CI] 0.47‐1.21) for pancreatic cancer and 1.46 (95% CI 0.98‐2.19) for thyroid cancer. Results in the time‐dependent analyses by cumulative duration or dose were similar. Nested case‐control analyses yielded rate ratios of 0.61 (95%CI, 0.37–1.00) for pancreatic cancer and 0.89 (95% CI, 0.64–1.24) for thyroid cancer. This observational study suggested exenatide use was not associated with an increased risk of pancreatic or thyroid cancer.

Expression of GLP-1 receptor and CD26 in human thyroid C-cells: The association of thyroid C-cell tumorigenesis with incretin-based medicine

Article

Full-text available

Feb 2017

Recent reports have demonstrated that long-term and high dosage treatments with incretin-based medicine, such as hormone glucagon-like peptide-1 (GLP-1) may induce thyroid C-cell pathological changes in rodents, rather than in humans. Doubts regarding the tumorigenic potential of GLP-1 analogues in human thyroid C-cells remain. The present study aimed to determine the expression levels of GLP-1 receptor (GLP-1R) and cluster of differentiation 26 (CD26) in the C-cells of thyroid tissues from non-neoplastic, medullary carcinoma and hyperplasia subjects, and to explore the potential clinical significance. The following cases were analyzed: Medullary thyroid carcinoma (n=62, including 59 paraffin-embedded samples and 3 fresh frozen samples), C-cell hyperplasia (n=20, paraffin-embedded samples) and non-neoplastic thyroid tissue samples (n=7, paraffin-embedded samples). GLP-1R and CD26 expression was detected using immunohistochemical staining and western blotting. There were significant differences in the expression levels of the two markers between medullary thyroid carcinoma and C-cell hyperplasia, in addition to between medullary thyroid carcinoma and non-neoplastic thyroid tissue following immunohistochemical staining. Similar significant differences in the expression of GLP-1R and CD26 were detected using western blot analysis in the medullary thyroid carcinoma compared with non-neoplastic thyroid tissue sectioned from the aforementioned fresh frozen samples. There was a significant negative correlation between GLP-1R and CD26 expression. In addition, the present data indicated that GLP-1R expression was associated with the age of the patients with medullary thyroid carcinoma. These results suggested that GLP-1R and CD26 may be closely associated with the development of thyroid C-cell hyperplasia and medullary thyroid carcinoma, and indicated the importance of being aware of the side effects of incretin medicine.

Chronic Toxicity and Carcinogenicity Studies of the Long-Acting GLP-1 Receptor Agonist Dulaglutide in Rodents

Article

Full-text available

Apr 2015
ENDOCRINOLOGY

The tumorigenic potential of dulaglutide was evaluated in rats and transgenic mice. Rats were injected subcutaneously twice weekly for 93 weeks with dulaglutide 0, 0.05, 0.5, 1.5, or 5 mg/kg corresponding to 0, 0.5, 7, 20, and 58 times, respectively, the maximum recommended human dose based on plasma AUC. Transgenic mice were dosed subcutaneously twice weekly with dulaglutide 0, 0.3, 1, or 3 mg/kg for 26 weeks. Dulaglutide effects were limited to the thyroid C-cells. In rats, diffuse C-cell hyperplasia and adenomas were statistically increased at ≥0.5 mg/kg (P ≤ 0.01 at 5 mg/kg) and C-cell carcinomas were numerically increased at 5 mg/kg. Focal C-cell hyperplasia was higher compared to controls in females given 0.5, 1.5, and 5 mg/kg. In transgenic mice, no dulaglutide-related C-cell hyperplasia or neoplasia was observed at any dose; however, minimal cytoplasmic hypertrophy of C-cells was observed in all dulaglutide groups. Systemic exposures decreased over time in mice, possibly due to an anti-drug antibody response. In a 52-week study designed to quantitate C-cell mass and plasma calcitonin responses, rats received twice weekly subcutaneous injections of dulaglutide 0 or 5 mg/kg. Dulaglutide increased focal C-cell hyperplasia; however, quantitative increases in C-cell mass did not occur. Consistent with the lack of morphometric changes in C-cell mass, dulaglutide did not affect the incidence of diffuse C-cell hyperplasia or basal- or calcium-stimulated plasma calcitonin, suggesting that diffuse increases in C-cell mass did not occur during the initial 52 weeks of the rat carcinogenicity study.

Incidence of health insurance claims for thyroid neoplasm and pancreatic malignancy in association with exenatide: Signal refinement using active safety surveillance

Article

Full-text available

Aug 2012

Objectives: As part of a regulatory postmarketing commitment, we assessed the risk of claims for thyroid and pancreatic cancer among users of exenatide using an active drug safety surveillance system. Methods: This active surveillance assessment used cohort methodology and commercial health insurance claims data to identify initiators of exenatide and propensity score-matched initiators of metformin or glyburide between June 2005 and September 2009, with up to 1 year of follow up through December 2009. The primary analysis estimated absolute and relative risk (RR) of inpatient or outpatient claims with diagnosis codes for thyroid neoplasm (benign or malignant) or pancreatic malignancies after exclusion of patients with a history of the same diagnosis at baseline. Results: Among the matched comparison cohorts (N ≈ 32,800 each), there were 37 claims-suggested thyroid malignancies among exenatide initiators and 26 among metformin or glyburide initiators [RR 1.4; 95% confidence interval (CI) 0.8-2.4]. This association was attenuated when limited to inpatient thyroid cancer claims (RR 0.9; CI 0.3-2.6). Exenatide use was not associated with an increased risk of benign thyroid neoplasm (RR 0.7; CI 0.3-1.7), or pancreatic cancer (RR 0.8; CI 0.5-1.6). Conclusions: Use of exenatide was associated with a modestly higher incidence of inpatient and outpatient claims, but not inpatient claims for thyroid malignancies. Exenatide was not associated with higher risk of benign thyroid neoplasm or pancreatic cancer. Misclassification of outcomes and exposure, and residual confounding remain limitations of this analysis to be considered when interpreting the results. We have initiated a formal epidemiologic investigation to explore these relationships.

Glucagon-Like Peptide-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell Proliferation

Article

Full-text available

Mar 2010
ENDOCRINOLOGY

Liraglutide is a glucagon-like peptide-1 (GLP-1) analog developed for type 2 diabetes. Long-term liraglutide exposure in rodents was associated with thyroid C-cell hyperplasia and tumors. Here, we report data supporting a GLP-1 receptor-mediated mechanism for these changes in rodents. The GLP-1 receptor was localized to rodent C-cells. GLP-1 receptor agonists stimulated calcitonin release, up-regulation of calcitonin gene expression, and subsequently C-cell hyperplasia in rats and, to a lesser extent, in mice. In contrast, humans and/or cynomolgus monkeys had low GLP-1 receptor expression in thyroid C-cells, and GLP-1 receptor agonists did not activate adenylate cyclase or generate calcitonin release in primates. Moreover, 20 months of liraglutide treatment (at >60 times human exposure levels) did not lead to C-cell hyperplasia in monkeys. Mean calcitonin levels in patients exposed to liraglutide for 2 yr remained at the lower end of the normal range, and there was no difference in the proportion of patients with calcitonin levels increasing above the clinically relevant cutoff level of 20 pg/ml. Our findings delineate important species-specific differences in GLP-1 receptor expression and action in the thyroid. Nevertheless, the long-term consequences of sustained GLP-1 receptor activation in the human thyroid remain unknown and merit further investigation.

Comparison of nested case-control and survival analysis methodologies for analysis of time-dependent exposure

Article

Full-text available

Feb 2005
BMC MED RES METHODOL

Epidemiological studies of exposures that vary with time require an additional level of methodological complexity to account for the time-dependence of exposure. This study compares a nested case-control approach for the study of time-dependent exposure with cohort analysis using Cox regression including time-dependent covariates. A cohort of 1340 subjects with four fixed and seven time-dependent covariates was used for this study. Nested case-control analyses were repeated 100 times for each of 4, 8, 16, 32, and 64 controls per case, and point estimates were compared to those obtained using Cox regression on the full cohort. Computational efficiencies were evaluated by comparing central processing unit times required for analysis of the cohort at sizes 1, 2, 4, 8, 16, and 32 times its initial size. Nested case-control analyses yielded results that were similar to results of Cox regression on the full cohort. Cox regression was found to be 125 times slower than the nested case-control approach (using four controls per case). The nested case-control approach is a useful alternative for cohort analysis when studying time-dependent exposures. Its superior computational efficiency may be particularly useful when studying rare outcomes in databases, where the ability to analyze larger sample sizes can improve the power of the study.

Changes in Serum Calcitonin Concentrations, Incidence of Medullary Thyroid Carcinoma, and Impact of Routine Calcitonin Concentration Monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL)

Article

Apr 2019
DIABETES CARE

Objective: Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. Research design and methods: EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively. Results: At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L). Conclusions: During a median 3.2 years' follow-up, no change in serum calcitonin was seen with exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during exenatide treatment.

Neoplasms Reported With Liraglutide or Placebo in People With Type 2 Diabetes: Results From the LEADER Randomized Trial

Article

Jun 2018
DIABETES CARE

Objective: This study explored neoplasm risk with liraglutide versus placebo in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) cohort. Research design and methods: LEADER (NCT01179048) was an international, phase 3b, randomized, double-blind, controlled trial. Participants aged ≥50 years with type 2 diabetes and high cardiovascular risk were assigned 1:1 to receive liraglutide (≤1.8 mg daily; n = 4,668) or placebo (n = 4,672) in addition to standard care and monitored for 3.5-5 years (median follow-up 3.8 years). The occurrence of neoplasms was a prespecified, exploratory secondary end point. Post hoc analyses of the time to the first confirmed neoplasms were conducted using a Cox regression model. Results: Neoplasm was confirmed in 10.1% of patients with liraglutide versus 9.0% with placebo (hazard ratio [HR] 1.12 [95% CI 0.99; 1.28]). The HR (95% CI) for liraglutide versus placebo was 1.06 (0.90; 1.25) for malignant neoplasms and 1.16 (0.93; 1.44) for benign neoplasms. Sensitivity analyses excluding neoplasms occurring <1 year or <2 years after randomization and analyses by sex provided similar results. In our main analyses, the 95% CI for the HR included one for all malignant neoplasms evaluated (including pancreatic and thyroid neoplasms), except for prostate neoplasms, which occurred in fewer liraglutide-treated patients. Conclusions: LEADER was not primarily designed to assess neoplasm risk. Firm conclusions cannot be made regarding numeric imbalances observed for individual neoplasm types (e.g., pancreatic cancer) that occurred infrequently. LEADER data do, however, exclude a major increase in the risk of total malignant neoplasms with liraglutide versus placebo. Additional studies are needed to assess longer-term exposure.

No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial

Article

Dec 2017
DIABETES CARE

Objective: To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial over a 3.5-5-year period. Research design and methods: Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels throughout the trial, and thyroid and C-cell adverse events and neoplasms. Results: At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. Conclusions: There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group.

The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology

Article

May 2017
PHARMACOEPIDEM DR S

The French health care system is based on universal coverage by one of several health care insurance plans. The SNIIRAM database merges anonymous information of reimbursed claims from all these plans, linked to the national hospital‐discharge summaries database system (PMSI) and the national death registry. It now covers 98.8% of the French population, over 66 million persons, from birth (or immigration) to death (or emigration), making it possibly the world's largest continuous homogeneous claims database. The database includes demographic data; health care encounters such as physician or paramedical visits, medicines, medical devices, and lab tests (without results); chronic medical conditions (ICD10 codes); hospitalisations with ICD10 codes for primary, linked and associated diagnoses, date and duration, procedures, diagnostic‐related groups, and cost coding; date but currently not cause of death. The power of the database is correlatively great, and its representativeness is near perfect, since it essentially includes the whole country's population. The main difficulty in using the database, beyond its sheer size and complexity, is the administrative process necessary to access it. Recent legislative advances are making this easier. EGB (Echantillon Généraliste de Bénéficiaires) is the 1/97th random permanent representative sample of SNIIRAM, with planned 20‐year longitudinal data (10 years at this time). Access time is 1 to 3 months, but its power is less (780 000 subjects). This is enough to study common issues with older drugs but may be limited for new products or rare events.

A meta-analysis of serious adverse events reported with exenatide and liraglutide: Acute pancreatitis and cancer

Article

Sep 2012

Aims: The association between GLP-1 agonists, acute pancreatitis (AP), any cancer and thyroid cancer is discussed. This meta-analysis was aimed at evaluating the risk of those serious adverse events associated with GLP-1 agonists in patients with type 2 diabetes. Methods: Medline, EMBASE, Cochrane Library and clinicaltrials.gov were searched in order to identify longitudinal studies evaluating exenatide or liraglutide use and reporting data on AP or cancer. Odds ratios (ORs) were pooled using a random-effects model. I(2) statistics assessed heterogeneity. Results: Twenty-five studies were included. Neither exenatide (OR 0.84 [95% CI 0.58-1.22], I(2) = 30%) nor liraglutide (OR 0.97 [95% CI 0.21-4.39], I(2) = 0%) were associated with an increased risk of AP, independent of baseline comparator. The pooled OR for cancer associated with exenatide was 0.86 (95% CI 0.29, 2.60, I(2) = 0%) and for liraglutide was 1.35 (95% CI 0.70, 2.59, I(2) = 0%). Liraglutide was not associated with an increased risk for thyroid cancer (OR 1.54 [95% CI 0.40-6.02], I(2) = 0%). For exenatide, no thyroid malignancies were reported. Conclusions: Current available published evidence is insufficient to support an increased risk of AP or cancer associated with GLP-1 agonists. These rare and long-term adverse events deserve properly monitoring in future studies evaluating GLP-1 agonists.

Effect of exendin (exenatide)—GLP 1 receptor agonist on the thyroid and parathyroid gland in a rat model

Article

Jul 2012

Exenatide or Exendin-4 is a 39-amino acid agonist of the glucagon like peptide (GLP-1) receptor approved for the adjunctive treatment for type 2 diabetes. Recent reports suggest that GLP-1 agonists may also have distant effects including C-cell thyroid hyperplasia. The aim of this study was to evaluate the effect of exendin-4 on the thyroid and parathyroid cells in a rat model. Rat thyroids were stained for calcitonin, H&E and for carcinoembryonic antigen (CEA). Thyroid C-cell hyperplasia was graded on H&E stained slides using cell size and secretory granule numbers, morphological features of the parathyroid glands and the serum calcium concentrations of the rats were also evaluated. Counts of stained cells/high power field and intensity of staining were recorded by two pathologists. Data were analyzed by ANOVA/post-tests. C cell hypertrophy was elevated in exenatide-treated vs. untreated animals (22.5 ± 8.7 vs. 10.5 ± 2.7 cells/HPF). CEA staining failed to show effects by exendin. Calcitonin staining was significantly elevated in exenatide treated controls (P<0.001). Parathyroid glands were histologically normal in both groups, and serum calcium levels were within normal range in all animals. In summary, exenatide was associated with C cell hyperplasia and increased calcitonin staining of thyroids, but was unrelated to CEA levels. These data raise important concerns about the effects of exenatide which, given its wide clinical use, should be clarified with urgency.

Incretin Receptors in Non-Neoplastic and Neoplastic Thyroid C Cells in Rodents and Humans: Relevance for Incretin-Based Diabetes Therapy

Article

Sep 2011
NEUROENDOCRINOLOGY

While incretins are of great interest for the therapy of diabetes 2, the focus has recently been brought to the thyroid, since rodents treated with glucagon-like peptide-1 (GLP-1) analogs were found to occasionally develop medullary thyroid carcinomas. Incretin receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) were therefore measured in various rodent and human thyroid conditions. In vitro GLP-1 and GIP receptor autoradiography were performed in normal thyroids, C-cell hyperplasia and medullary thyroid carcinomas in rodents. Receptor incidence and density were assessed and compared with the receptor expression in human thyroids, medullary thyroid carcinomas, and TT cells. GLP-1 receptors are expressed in C cells of normal rat and mice thyroids. Their density is markedly increased in rat C-cell hyperplasia and medullary thyroid carcinomas, where their incidence amounts to 100%. GIP receptors are neither detected in normal rodent thyroids nor in C-cell hyperplasia, but are present in all rat medullary thyroid carcinomas. No GLP-1 or GIP receptors are detected in normal human thyroids. Whereas only 27% of all human medullary thyroid carcinomas express GLP-1 receptors, up to 89% express GIP receptors in a high density. TT cells lack GLP-1 receptors but express GIP receptors. GLP-1 receptors are frequently expressed in non-neoplastic and neoplastic C cells in rodents while they are rarely detected in human C-cell neoplasia, suggesting species differences. Conversely, GIP receptors appear to be massively overexpressed in neoplastic C cells in both species. The presence of incretin receptors in thyroid C cell lesions suggests that this organ should be monitored before and during incretin-based therapy of diabetes.

Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1-Based Therapies

Article

Feb 2011

Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function. We examined the US Food and Drug Administration's database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls. The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies. Use of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20). These data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Asymptotic Theory for Nested Case-Control Sampling in the Cox Regression Model

Article

Dec 1992
ANN STAT

By providing a probabilistic model for nested case-control sampling in epidemiologic cohort studies, consistency and asymptotic normality of the maximum partial likelihood estimator of regression parameters in a Cox proportional hazards model can be derived using process and martingale theory as in Andersen and Gill. A general expression for the asymptotic variance is given and used to calculate asymptotic relative efficiencies relative to the full cohort variance in some important special cases.

Biological actions and therapeutic potential of the glucagon-like peptides

Article

Mar 2002
GASTROENTEROLOGY

Daniel J Drucker

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

A comparison of methods of disporportionality for signal detection in spontaneous reporting systems for adverse drug reactions

Article

Feb 2002

A continuous systematic review of all combinations of drugs and suspected adverse reactions (ADRs) reported to a spontaneous reporting system, is necessary to optimize signal detection. To focus attention of human reviewers, quantitative procedures can be used to sift data in different ways. In various centres, different measures are used to quantify the extent to which an ADR is reported disproportionally to a certain drug compared to the generality of the database. The objective of this study is to examine the level of concordance of the various estimates to the measure used by the WHO Collaborating Centre for International ADR monitoring, the information component (IC), when applied to the dataset of the Netherlands Pharmacovigilance Foundation Lareb. The Reporting Odds Ratio--1.96 standard errors (SE), proportional reporting ratio--1.96 SE, Yule's Q--1.96 SE, the Poisson probability and Chi-square test of all 17,330 combinations were compared with the IC minus 2 standard deviations. Additionally, the concordance of the various tests, in respect to the number of reports per combination, was examined. In general, sensitivity was high in respect to the reference measure when a combination of point- and precision estimate was used. The concordance increased dramatically when the number of reports per combination increased. This study shows that the different measures used are broadly comparable when four or more cases per combination have been collected.

Jan 2018
1663-1671

M A Nauck
T J Jensen
C Rosenkilde
S Calanna

Nauck MA, Jensen TJ, Rosenkilde C, Calanna S; Care 2018;41:1663-1671

GLP-1 Receptor Agonists and the Risk of Thyroid Cancer

Abstract

No full-text available

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