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Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

ABSTRACT: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP-1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatric type 2 diabetes and the mechanism of action of GLP-1RAs as it pertains to physiological pathways relevant for type 2 diabetes, obesity and their related comorbidities. The outcomes of paediatric trials evaluating liraglutide, exenatide, semaglutide and dulaglutide in paediatric type 2 diabetes and obesity will be closely examined, including differences compared with adult studies. Finally, potential barriers and strategies to expanding GLP-1RA access in adolescents will be discussed. Future studies are needed to determine if the cardio-and renal-protective benefits of GLP-1RAs apply to youth-onset type 2 diabetes.

SUBMITTER: Berman C

PROVIDER: S-EPMC10258616 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

Berman Casey C Vidmar Alaina P AP Chao Lily C LC

TouchREVIEWS in endocrinology 20230523 1

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained traction for the management of type 2 diabetes and obesity. Unlike several classes of antidiabetic medications that contribute to weight gain, GLP-1RAs not only reduce haemoglobin A1c, but also promote weight loss. While there is a large body of evidence supporting its safety and efficacy in adults, paediatric clinical trial data have only emerged in recent years. This review will discuss the limited treatment options for paediatri ...[more]

PMID: 37313232

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Project description:ImportanceConcerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer.ObjectiveTo investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up.Design, setting, and participantsIn this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023.ExposuresTreatment with GLP-1RA was compared with basal insulin.Main outcome and measuresPancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized.ResultsDuring a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively.Conclusions and relevanceIn this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required.Trial registrationClinicalTrials.gov Identifier: NCT02072902.

Project description:ImportanceThirteen human malignant neoplasms have been identified as obesity-associated cancers (OACs), ie, the presence of excess body fat is associated with increased risk of developing cancer and worse prognosis in patients with these specific tumors. The glucagon-like peptide receptor agonist (GLP-1RA) class of pharmaceuticals are effective agents for the treatment of type 2 diabetes (T2D) and for achieving weight loss, but the association of GLP-1RAs with the incident risk of 13 OACs is unclear.ObjectiveTo compare the incident risk of each of the 13 OACs in patients with T2D who were prescribed GLP-1RAs vs insulins or metformin.Design, setting, and participantsThis retrospective cohort study was based on a nationwide multicenter database of electronic health records (EHRs) of 113 million US patients. The study population included 1 651 452 patients with T2D who had no prior diagnosis of OACs and were prescribed GLP-1RAs, insulins, or metformin during March 2005 to November 2018. Data analysis was conducted on April 26, 2024.ExposuresPrescription of GLP-1RAs, insulins, or metformin.Main outcomes and measuresIncident (first-time) diagnosis of each of the 13 OACs occurring during a 15-year follow-up after the exposure was examined using Cox proportional hazard and Kaplan-Meier survival analyses with censoring applied. Hazard ratios (HRs), cumulative incidences, and 95% CIs were calculated. All models were adjusted for confounders at baseline by propensity-score matching baseline covariates.ResultsIn the study population of 1 651 452 patients with T2D (mean [SD] age, 59.8 [15.1] years; 827 873 [50.1%] male and 775 687 [47.0%] female participants; 5780 [0.4%] American Indian or Alaska Native, 65 893 [4.0%] Asian, 281 242 [17.0%] Black, 13 707 [0.8%] Native Hawaiian or Other Pacific Islander, and 1 000 780 [60.6%] White participants), GLP-1RAs compared with insulin were associated with a significant risk reduction in 10 of 13 OACs, including in gallbladder cancer (HR, 0.35; 95% CI, 0.15-0.83), meningioma (HR, 0.37; 95% CI, 0.18-0.74), pancreatic cancer (HR, 0.41; 95% CI, 0.33-0.50), hepatocellular carcinoma (HR, 0.47; 95% CI, 0.36-0.61), ovarian cancer (HR, 0.52; 95% CI, 0.03-0.74), colorectal cancer (HR, 0.54; 95% CI, 0.46-0.64), multiple myeloma (HR, 0.59; 95% CI, 0.44-0.77), esophageal cancer (HR, 0.60; 95% CI, 0.42-0.86), endometrial cancer (HR, 0.74; 95% CI, 0.60-0.91), and kidney cancer (HR, 0.76; 95% CI, 0.64-0.91). Although not statistically significant, the HR for stomach cancer was less than 1 among patients who took GLP-1RAs compared with those who took insulin (HR, 0.73; 95% CI, 0.51-1.03). GLP-1RAs were not associated with a reduced risk of postmenopausal breast cancer or thyroid cancer. Of those cancers that showed a decreased risk among patients taking GLP-1RAs compared with those taking insulin, HRs for patients taking GLP-1RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant. Compared with metformin, GLP-1RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87).Conclusions and relevanceIn this study, GLP-1RAs were associated with lower risks of specific types of OACs compared with insulins or metformin in patients with T2D. These findings provide preliminary evidence of the potential benefit of GLP-1RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.

Project description:Rationale: GLP-1R (glucagon-like peptide-1 receptor) agonists are approved to treat type 2 diabetes mellitus and obesity. GLP-1R agonists reduce airway inflammation and hyperresponsiveness in preclinical models.Objectives: To compare rates of asthma exacerbations and symptoms between adults with type 2 diabetes and asthma prescribed GLP-1R agonists and those prescribed SGLT-2 (sodium-glucose cotransporter-2) inhibitors, DPP-4 (dipeptidyl peptidase-4) inhibitors, sulfonylureas, or basal insulin for diabetes treatment intensification.Methods: This study was an electronic health records-based new-user, active-comparator, retrospective cohort study of patients with type 2 diabetes and asthma newly prescribed GLP-1R agonists or comparator drugs at an academic healthcare system from January 2000 to March 2018. The primary outcome was asthma exacerbations; the secondary outcome was encounters for asthma symptoms. Propensity scores were calculated for GLP-1R agonist and non-GLP-1R agonist use. Zero-inflated Poisson regression models included adjustment for multiple covariates.Measurements and Main Results: Patients initiating GLP-1R agonists (n = 448), SGLT-2 inhibitors (n = 112), DPP-4 inhibitors (n = 435), sulfonylureas (n = 2,253), or basal insulin (n = 2,692) were identified. At 6 months, asthma exacerbation counts were lower in persons initiating GLP-1R agonists (reference) compared with SGLT-2 inhibitors (incidence rate ratio [IRR], 2.98; 95% confidence interval [CI], 1.30-6.80), DPP-4 inhibitors (IRR, 2.45; 95% CI, 1.54-3.89), sulfonylureas (IRR, 1.83; 95% CI, 1.20-2.77), and basal insulin (IRR, 2.58; 95% CI, 1.72-3.88). Healthcare encounters for asthma symptoms were also lower among GLP-1R agonist users.Conclusions: Adult patients with asthma prescribed GLP-1R agonists for type 2 diabetes had lower counts of asthma exacerbations compared with other drugs initiated for treatment intensification. GLP-1R agonists may represent a novel treatment for asthma associated with metabolic dysfunction.

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Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

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Glucagon-like Peptide-1 Receptor Agonists for the Treatment of Type 2 Diabetes in Youth.

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