Glucagon-like peptide 1 receptor agonist: A potential game changer for cholangiocarcinoma.

Glucagon-like peptide-1 receptor (GLP-1R) agonist, a subgroup of incretin-based anti-diabetic therapies, is an emerging medication with benefits in reducing blood glucose and weight and increasing cardiovascular protection. Contrarily, concerns have been raised about GLP-1R agonists increasing the risk of particular cancers. Recently, several epidemiological studies reported contradictory findings of incretin-based therapy on the risk modification for cholangiocarcinoma (CCA). The first cohort study demonstrated that incretin-based therapy was associated with an increased risk of CCA. Later studies, however, showed a null effect of incretin-based therapy on CCA risk for dipeptidyl peptidase-4 inhibitor nor GLP-1R agonist. Mechanistically, glucagon-like peptide 1 receptor is multifunctional, including promoting cell growth. High GLP-1R expressions were associated with progressive phenotypes of CCA cells in vitro. Unexpectedly, the GLP-1R agonist showed anti-tumor effects on CCA cells in vitro and in vivo with unclear mechanisms. Our recent report also showed that GLP-1R agonists suppressed the expression of GLP-1R in CCA cells in vitro and in vivo, leading to the inhibition of CCA tumor growth. This editorial reviews recent evidence, discusses the potential effects of GLP-1R agonists in CCA patients, and proposes underlying mechanisms that would benefit from further basic and clinical investigation.

Glucagon-like peptide-1 receptor agonists: Exploring the mechanisms from glycemic control to treatment of multisystemic diseases.

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani, which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) for metabolic dysfunction-associated fatty liver disease. We provide supplementary insights to their research, highlighting the broader systemic implications of GLP-1RAs, synthesizing the current understanding of their mechanisms and the trajectory of research in this field. GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond. Beyond glycemic control, GLP-1RAs demonstrate cardiovascular and renal protective effects, offering potential in managing diabetic kidney disease al-ongside renin-angiotensin-aldosterone system inhibitors. Their role in bone metabolism hints at benefits for diabetic osteoporosis, while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling. Additionally, they improve hormonal and metabolic profiles in polycystic ovary syndrome. This editorial highlights the multifaceted mechanisms of GLP-1RAs, emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

GLP-1 programs the neurovascular landscape.

Readily available nutrient-rich foods exploit our inherent drive to overconsume, creating an environment of overnutrition. This transformative setting has led to persistent health issues, such as obesity and metabolic syndrome. The development of glucagon-like peptide-1 receptor (GLP-1R) agonists reveals our ability to pharmacologically manage weight and address metabolic conditions. Obesity is directly linked to chronic low-grade inflammation, connecting our metabolic environment to neurodegenerative diseases. GLP-1R agonism in curbing obesity, achieved by impacting appetite and addressing associated metabolic defects, is revealing additional benefits extending beyond weight loss. Whether GLP-1R agonism directly impacts brain health or does so indirectly through improved metabolic health remains to be elucidated. In exploring the intricate connection between obesity and neurological conditions, recent literature suggests that GLP-1R agonism may have the capacity to shape the neurovascular landscape. Thus, GLP-1R agonism emerges as a promising strategy for addressing the complex interplay between metabolic health and cognitive well-being.

Geriatric Pharmacotherapy Case Series: Medications for Diabetes-A Focus on Secondary Stroke Prevention.

This report addresses evidence for efficacy of diabetes medications with a focus on stroke risk reduction. The cardiovascular benefits of SGLT-2 inhibitors and GLP-1 receptor agonists have been well-established; however, clinical trials to date have examined composite cardiovascular endpoints that include, but do not specifically focus on, stroke. The purpose of this case review is to examine the evidence for the various diabetes medications in reducing the risk for stroke. This literature review was inspired by a patient seen in a geriatric day hospital program with diabetes and a history of multiple strokes. Our goal was to select a diabetes management regimen that would provide both glycemic control and stroke risk reduction. As diabetes and cerebrovascular disease commonly coexist and are important contributors to morbidity and mortality in older individuals, appropriate management must incorporate both current evidence as well as consideration for patient-specific factors that may influence the treatment plan. This patient case illustrates the importance of both.

Glucagon-like peptide-1 receptor agonists and kidney outcomes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes mellitus (T2DM) with chronic kidney disease (CKD). Most supportive evidence of a kidney-protective effect of the GLP-1RA class of medications has been derived from kidney-related outcomes reported from cardiovascular outcome trials (CVOTs). GLP-1RAs have been shown to reduce albuminuria, mitigate cardiovascular risk, and possibly attenuate estimated glomerular filtration rate (eGFR) decline. The kidney-protective effects of GLP-1RAs are thought to be attributed to their anti-inflammatory, antioxidant, and vasodilatory properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure in people with T2DM. The Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) is the first major trial assessing the potential of a GLP-1RA to slow progression of kidney disease in people with established CKD to clinically important kidney end points. On March 5, 2024, the top line result from FLOW was announced with semaglutide 1.0 mg being reported to reduce the primary end point of the trial by a significant 24% compared with placebo. Here, we summarize the kidney outcomes reported from CVOTs for the GLP-1RA class of medication and briefly describe kidney outcomes from other major GLP-1RAs trials. We also discuss a potential role of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, as a kidney-protective agent.

Comparing Glucagon-like peptide-1 receptor agonists versus metformin in drug-naive patients: A nationwide cohort study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly being prescribed in drug-naive patients. We aimed to contrast add-on therapy, adherence, and changes in biomarkers, 1 year after treatment initiation with GLP-1 RA or metformin. METHODS: Using Danish nationwide registers, we included incident GLP-1 RA or metformin users from 2018 to 2021 with glycated hemoglobin (HbA1c) ≥ 42 mmol/mol. GLP-1 RA initiators were matched to metformin initiators in a ratio of 1:1 to assess outcomes in prediabetes and diabetes. Main outcomes analyzed were 1-year risk of add-on glucose-lowering medication and 1-year risk of nonadherence. One-year risks were estimated with multiple logistic regression and standardized. Multiple linear regression was used to estimate the average differences in biomarker changes. RESULTS: In total, 1778 individuals initiating GLP-1 RA and metformin were included. After standardizing for various factors, GLP-1 RA compared with metformin was associated with reduced 1-year risk of add-on glucose-lowering treatment in patients with prediabetes (1-year risk ratio [RR]: 0.27, 95% confidence interval [CI]: 0.10-0.44) and diabetes (RR: 0.67, 95% CI: 0.37-0.98). GLP-1 RA was associated with higher 1-year risk of nonadherence among patients with prediabetes (RR: 1.60, 95% CI: 1.45-1.75), but no difference in patients with diabetes (RR: 0.88, 95% CI: 0.70-1.06). Compared to metformin, GLP-1 RA was associated with greater HbA1c reduction (prediabetes: -2.59 mmol/mol 95% CI: -3.10 to -2.09, diabetes: -3.79 mmol/mol, 95% CI: -5.28 to -2.30). CONCLUSIONS: GLP-1 RA was associated with a reduced risk of additional glucose-lowering medication, achieving better glycated hemoglobin control overall. However, among patients with prediabetes, metformin was associated with better adherence.

Glucagon-like peptide-1 receptor agonists in neoplastic diseases.

Glucagon-like peptide-1 receptor agonist (GLP-1RA), a novel hypoglycemic agent for the treatment of type 2 diabetes, has well-known effects such as lowering blood sugar, ameliorating inflammation, reducing weight, and lowering blood lipids. It has also been shown that it can influence the proliferation and survival of cells and has a certain effect on the prognosis of some neoplastic diseases. In this study, the potential effects of GLP-1RAs on the occurrence and development of tumors were reviewed to provide new ideas for the prevention and treatment of tumors in patients.

Inflammatory proteins associated with Alzheimer's disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial.

BACKGROUND: Glucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer's disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters. METHODS: The Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models. RESULTS: EQW affected FCN2 (Cohen's d -0.019), PAI-1 (Cohen's d -0.033), sVCAM-1 (Cohen's d 0.035) and a cytokine-cytokine cluster (Cohen's d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65. CONCLUSIONS: EQW treatment was associated with significant change in inflammatory proteins associated with AD. TRIAL REGISTRATION: EXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Recent trends in GLP-1 RA and SGLT2i use among people with type 2 diabetes and atherosclerotic cardiovascular disease in the USA.

INTRODUCTION: This study aimed to assess recent trends in the US use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) in people with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD), including incident use following newly diagnosed ASCVD. RESEARCH DESIGN AND METHODS: This real-world, retrospective observational study used de-identified data from the TriNetX Dataworks-USA network. A longitudinal analysis of cross-sectional data (interval: January 01, 2018 to December 31, 2022) assessed the yearly prevalent use of GLP-1 RA and SGLT2i. A nested cohort study (January 01, 2017 to January 31, 2023) assessed the proportions of patients with T2D newly prescribed GLP-1 RAs and SGLT2is after incident ASCVD diagnosis. RESULTS: Prevalent use of GLP-1 RA and/or SGLT2i increased from 9.2% of patients in 2018 to 27.1% in 2022, with eligible annual patient numbers ranging from 279,474 to 348,997. GLP-1 RA-alone use rose from 5.2% to 9.9% and SGLT2i-alone use rose from 2.8% to 12.2% over this interval. Incident use of GLP-1 RA and/or SGLT2i within the year following ASCVD diagnosis increased from 5.9% to 17.0% (2018-2022). For GLP-1 RA alone, this increase was from 3.6% to 7.8%, while for SGLT2i alone, it was from 1.8% to 7.0%. CONCLUSIONS: Use of GLP-1 RAs/SGLT2is in patients with T2D and ASCVD has increased in recent years in the USA, but remains suboptimal given the prevalence of ASCVD and its high morbidity and mortality.

Food Retention at Endoscopy Among Adults Using Glucagon-Like Peptide-1 Receptor Agonists.

This cross-sectional study investigates the association between glucagon-like peptide-1 receptor agonists and food retention during esophagogastroduodenoscopy.

Impaired brain glucose metabolism in glucagon-like peptide-1 receptor knockout mice.

BACKGROUND: Quantitative mapping of the brain's metabolism is a critical tool in studying and diagnosing many conditions, from obesity to neurodegenerative diseases. In particular, noninvasive approaches are urgently required. Recently, there have been promising drug development approaches for the treatment of disorders related to glucose metabolism in the brain and, therefore, against obesity-associated diseases. One of the most important drug targets to emerge has been the Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R). GLP and GLP-1R play an important role in regulating blood sugar and maintaining energy homeostasis. However, the macroscopic effects on brain metabolism and function due to the presence of GLP-1R are unclear. METHODS: To explore the physiological role of GLP-1R in mouse brain glucose metabolism, and its relationship to brain function, we used three methods. We used deuterium magnetic resonance spectroscopy (DMRS) to provide quantitative information about metabolic flux, fluorodeoxyglucose positron emission tomography (FDG-PET) to measure brain glucose metabolism, and resting state-functional MRI (rs-fMRI) to measure brain functional connectivity. We used these methods in both mice with complete GLP-1R knockout (GLP-1R KO) and wild-type C57BL/6N (WT) mice. RESULTS: The metabolic rate of GLP-1R KO mice was significantly slower than that of WT mice (p = 0.0345, WT mice 0.02335 ± 0.057 mM/min, GLP-1R KO mice 0.01998 ± 0.07 mM/min). Quantification of the mean [18F]FDG signal in the whole brain also showed significantly reduced glucose uptake in GLP-1R KO mice versus control mice (p = 0.0314). Observing rs-fMRI, the functional brain connectivity in GLP-1R KO mice was significantly lower than that in the WT group (p = 0.0032 for gFCD, p = 0.0002 for whole-brain correlation, p < 0.0001 for ALFF). CONCLUSIONS: GLP-1R KO mice exhibit impaired brain glucose metabolism to high doses of exogenous glucose, and they also have reduced functional connectivity. This suggests that the GLP-1R KO mouse model may serve as a model for correlated metabolic and functional connectivity loss.

Editorial: Potentials and Pitfalls in Targeting Glucagon-Like Peptide-1 (GLP-1) in the Management of Increasing Levels of Obesity.

Rising levels of obesity in all age groups are associated with profound effects on health and economies in developed and developing countries. This year, the scientific research behind the development of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 analogs or incretin mimetics) has been recognized. On 19 September 2024, three scientists were presented with a Lasker Award for their basic clinical research on identifying and studying the roles of GLP-1. The research by Joel Habener, Svetlana Mojsov, and Lotte Bjerre Knudsen began three decades ago and has led to new anti-obesity drugs, which mimic GLP-1 to lower blood glucose levels and control appetite. The efficacy of GLP-1 receptor agonists in the management of obesity in adults, as well as in children and adolescents, has now been supported by several clinical trials. This editorial aims to describe the research behind developing GLP-1 receptor agonists and their potential and pitfalls in managing obesity in all age groups.

The Influence of Non-Pharmacological and Pharmacological Interventions on the Course of Autosomal Dominant Polycystic Kidney Disease.

Polycystic kidney disease (PKD) includes autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms, both of which are primary genetic causes of kidney disease in adults and children. ADPKD is the most common hereditary kidney disease, with a prevalence of 329 cases per million in Europe. This condition accounts for 5-15% of end-stage chronic kidney disease (ESKD) cases, and in developed countries such as Poland, 8-10% of all dialysis patients have ESKD due to ADPKD. The disease is caused by mutations in the PKD1 and PKD2 genes, with PKD1 mutations responsible for 85% of cases, leading to a more aggressive disease course. Recent research suggests that ADPKD involves a metabolic defect contributing to cystic epithelial proliferation and cyst growth. Aim: This review explores the interplay between metabolism, obesity, and ADPKD, discussing dietary and pharmacological strategies that target these metabolic abnormalities to slow disease progression. Conclusion: Metabolic reprogramming therapies, including GLP-1 analogs and dual agonists of GIP/GLP-1 or glucagon/GLP-1 receptors, show promise, though further research is needed to understand their potential in ADPKD treatment fully.

New Perspectives on Obesity-Associated Nephropathy from Pathophysiology to Therapeutics: Revealing the Promise of GLP-1 RA Therapy.

Obesity represents a substantial risk factor for a multitude of metabolic disorders, which seriously threatens human life and health. As the global obesity epidemic intensifies, obesity-related nephropathy (ORN) has attracted great attention. ORN arises from both physical/mechanical and non-physical insults to the glomerular and tubular structures precipitated by obesity, culminating in structural impairments and functional aberrations within the kidneys. Physical injury factors include changes in renal hemodynamics, renal compression, and mechanical stretching of podocytes. Non-physical injury factors include overactivation of the RAAS system, insulin resistance, lipotoxicity, inflammation, and dysregulation of bile acid metabolism. Exploring molecules that target modulation of physical or nonphysical injury factors is a potential approach to ORN treatment. ORN is characterized clinically by microproteinuria and pathologically by glomerulomegaly, which is atypical and makes early diagnosis difficult. Investigating early diagnostic markers for ORN thus emerges as a critical direction for future research. Additionally, there is no specific drug for ORN in clinical treatment, which mainly focuses on weight reduction, mitigating proteinuria, and preserving renal function. In our review, we delineate a progressive therapeutic approach involving enhancements in lifestyle, pharmacotherapy, and bariatric surgery. Our emphasis underscores glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as poised to emerge as pivotal therapeutic modalities for ORN in forthcoming clinical avenues.

Insights into the structure and activation mechanism of some class B1 GPCR family members.

In humans, 15 genes encode the class B1 family of GPCRs, which are polypeptide hormone receptors characterized by having a large N-terminal extracellular domain (ECD) and receive signals from outside the cell to activate cellular response. For example, the insulinotropic polypeptide (GIP) stimulates the glucose-dependent insulinotropic polypeptide receptor (GIPR), while the glucagon receptor (GCGR) responds to glucagon by increasing blood glucose levels and promoting the breakdown of liver glycogen to induce the production of insulin. The glucagon-like peptides 1 and 2 (GLP-1 and GLP-2) elicit a response from glucagon-like peptide receptor types 1 and 2 (GLP1R and GLP2R), respectively. Since these receptors are implicated in the pathogenesis of diabetes, studying their activation is crucial for the development of effective therapies for the condition. With more structural information being revealed by experimental methods such as X-ray crystallography, cryo-EM, and NMR, the activation mechanism of class B1 GPCRs becomes unraveled. The available crystal and cryo-EM structures reveal that class B1 GPCRs follow a two-step model for peptide binding and receptor activation. The regions close to the C-termini of hormones interact with the N-terminal ECD of the receptor while the regions close to the N-terminus of the peptide interact with the TM domain and transmit signals. This review highlights the structural details of class B1 GPCRs and their conformational changes following activation. The roles of MD simulation in characterizing those conformational changes are briefly discussed, providing insights into the potential structural exploration for future ligand designs.

Glucagon-like peptide-1 receptor agonists and risk of gastrointestinal cancers: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used for glucose lowering and weight-loss. However, their association with gastrointestinal cancer remains uncertain. This meta-analysis assesses the risk of gastrointestinal cancer in patients treated with GLP-1 RAs. METHODS: We searched Medline/PubMed, Embase, and Scopus databases from inception to November 15, 2023, for randomized controlled trials (RCTs) with at least 24 weeks of safety follow-up. Pooled risk ratios (RRs) were calculated using fixed- and random-effect models. Risk of bias was assessed using the revised Cochrane risk-of-bias tool, and certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: We included 90 RCTs with 124,791 participants, with an average follow-up of 3.1 years per participant. No significant association was found between GLP-1 RAs and the risk of any gastrointestinal cancer (RRrandom=0.99, 95 % CI: 0.86-1.13), or site-specific gastrointestinal cancers including biliary tract (RR=0.98, 0.54-1.78), colorectal (RR=1.13, 0.92-1.39), gallbladder (RR=1.32, 0.43-4.00), gastric (RR=0.88, 0.58-1.33), hepatic (RR=0.79, 0.51-1.21), oesophageal (RR=0.70, 0.38-1.28), pancreatic (RR=1.05, 0.77-1.43), and small intestine cancer (RR=0.78, 0.20-3.04). The corresponding absolute risk differences excluded important impacts on risk. Additional analyses, limited to placebo-controlled trials, high-dose studies, or those with a follow-up duration of ≥5 years, confirmed these findings. Risk of bias was generally low and the certainty of evidence was high for all outcomes. CONCLUSIONS: This meta-analysis found no significant impact of GLP-1 RAs on gastrointestinal cancer risk. Long-term safety monitoring of these agents remains important. SYSTEMATIC REVIEW REGISTRATION: CRD42023476762.

Improved Clinical Outcomes with the Combination Therapy of a Glucagon-like Peptide-1 Receptor Agonists and a Sodium-glucose Cotransporter-2 Inhibitor in Overweight/Obese People with Type 2 Diabetes: Real-world Evidence from the Indian Subcontinent.

OBJECTIVE: Type 2 diabetes (T2D) mellitus is increasing exponentially in India, with overweight/obesity being prime contributors. This study aimed at assessing the clinical impact of the combination therapy of a glucagon-like peptide-1 receptor agonist (GLP-1RA) injection (inj.) and a sodium-glucose cotransporter-2 inhibitor (SGLT-2i) in overweight/obese patients from the Indian subcontinent. METHODS: In two real-world evidence (RWE) studies (RWE1 and 2), we retrospectively observed the effect of the combination therapy of a GLP-1RA, injection dulaglutide (DU) 1.5 mg/week, and an SGLT-2i, canagliflozin (CAN) 100 mg/day at weeks 16, 32, and 52 on HbA1c, body weight (weight), systolic blood pressure (SBP), lipids, change in doses of antidiabetic agents (ADA) and antihypertensive agents (AHA) in overweight/obese Asian Indian subjects with T2D, who had suboptimal glycemic control. RESULTS: A total of 95 T2D patients [51 males (M), 44 females (F)] completed the two RWE studies. In RWE 1, 40 patients (20 M/20 F), mean [standard deviation (SD)] age 49.4 (10.7) years (Y), weight 92.6 (6.6) kg, body mass index (BMI) 30.6 (2.3) kg/m2, duration of T2D 8.1 (3.2) Y, completed the study. At week 32, the mean (SD) reduction in A1c (%) was -1.3% [8.4 (0.7) to 7.1 (0.3); p < 0.01] and mean (SD) weight (kg) loss was -5.5 [92.6 (6.6) to 87.9 (7.02); p < 0.00001]. This group was then followed up until week 52. In RWE 2, 55 patients (31 M/24 F), age 51 (5.8) Y, weight 92.6 ± 3.4 kg, BMI 31.1 ± 2.1 kg/m2, SBP 142.4 ± 3.9 mm Hg, estimated glomerular filtration rate (eGFR) 62 ± 5 mL/minute/1.73 m2, with 8.4 ± 3.3 Y duration of diabetes met the inclusion criteria. In 71% of subjects, A1c decreased by -1.4% [8.5 ± 0.4 to 7.1 ± 0.2; p < 0.0001] at week 16 and was 6.8 ± 0.3 (p = 0.0002) in 18% at week 32. CONCLUSION: A statistically significant (SS) improvement in glycemic control, weight, and improvement in cardiovascular (CV) risk factors was observed with the GLP-1RA/SGLT-2i combination, which was well tolerated.

Effect of frailty on effectiveness and safety of GLP-1 receptor agonists versus SGLT2 inhibitors in people with type 2 diabetes in Taiwan: a retrospective, nationwide, longitudinal study.

BACKGROUND: GLP-1 receptor agonists and SGLT2 inhibitors are increasingly being used in people with type 2 diabetes on the basis of findings from randomised clinical trials; however, little is known of whether clinical outcomes are affected by frailty in real-world settings. We aimed to compare the clinical effectiveness and safety of GLP-1 receptor agonists and SGLT2 inhibitors in managing type 2 diabetes, with a specific focus on stratifying people by their frailty status. METHODS: In this retrospective, nationwide, longitudinal study, we identified people (aged ≥20 years) with type 2 diabetes who newly initiated either a GLP-1 receptor agonist or an SGLT2 inhibitor during the period Jan 1, 2017 to Dec 31, 2019 from the Taiwan National Health Insurance database. Individuals were excluded if they had been diagnosed with cancer, received dialysis for kidney failure, or had prescriptions for a GLP-1 receptor agonist or an SGLT2 inhibitor, within 1 year before the index date. Mortality data were collected from the Taiwan National Death Registry. Eligible individuals were categorised into three frailty subgroups-fit, mild frailty, and moderate or severe frailty-on the basis of the multimorbidity frailty index. Propensity score matching (1:1) was used to balance covariates between recipients of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup. Clinical outcomes of interest included three-point major adverse cardiovascular events (non-fatal acute myocardial infarction, non-fatal stroke, and fatal cardiovascular disease), all-cause mortality, hospitalisation for heart failure, dialysis or renal transplant, severe diabetic foot complications, retinopathy, hospitalisation for severe hyperglycaemia, and hospitalisation for severe hypoglycaemia. The association between the use of a GLP-1 receptor agonist versus an SGLT2 inhibitor and the risk of the outcomes of interest among each frailty subgroup was examined using a subdistribution hazard model. FINDINGS: We identified 320 210 people with type 2 diabetes, of whom 280 163 met the eligibility criteria, who initiated either a GLP-1 receptor agonist (n=22 968; mean age 57·7 years [SD 13·9], 11 338 [49·4%] were female, and 11 630 [50·6%] were male) or SGLT2 inhibitor (n=257 195; mean age 58·8 years [12·3], 107 988 [42·0%] were female, and 149 207 [58·0%] were male) during 2017-19. After matching, 11 882, 7210, and 3414 pairs of GLP-1 receptor agonist and SGLT2 inhibitor users were assigned in the fit, mild frailty, and moderate or severe frailty subgroups. All clinical outcomes were comparable between users of GLP-1 receptor agonists and SGLT2 inhibitors among each frailty subgroup, except for a higher risk of hospitalisation for severe hyperglycaemia with GLP-1 receptor agonists than with SGLT2 inhibitors in the mild frailty subgroup (subdistribution hazard ratio 1·25 [95% CI 1·13-1·38]; p<0·0001) and a higher risk of dialysis or renal transplant with GLP-1 receptor agonists than with SGLT2 inhibitors in the fit (2·43 [1·82-3·23]; p<0·0001), mild frailty (3·93 [3·03 -5·09]; p<0·0001), and moderate or severe frailty (2·60 [2·03-3·31]; p<0·0001) subgroups. INTERPRETATION: Formulating clear and updated guidelines on the use of GLP-1 receptor agonists and SGLT2 inhibitors according to frailty status could improve management of type 2 diabetes. FUNDING: Ministry of Education, Taiwan.