Response to comment on "Exploratory real-world experience with GLP-1 receptor agonists vs. metformin in youth with new-onset type 2 diabetes: a single-center retrospective study".

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Overweight and obesity seriously damages human health. The World Health Organization estimates that 1.5 billion adults were overweight in the year of 2011. Of this overweight population, over 200 million men and nearly 300 million women were obese. At least 2.8 million adults die each year as a result of being overweight or obese. A total of 44% of the diabetes burden and 23% of the ischemic heart disease burden are attributable to overweight and obesity1. More than 70% of diabetic patients will experience macrovascular disease that is strongly associated with overweight and obesity2. Type 2 diabetes is continuing to be the leading cause of cardiovascular disorders, end-stage renal disease, blindness and amputations. Therefore, effective interventions designed to achieve weight reduction are a critical part of type 2 diabetes management to prevent the development of microvascular and macrovascular complications. However, the majority of diabetic patients gain rather than lose weight, particularly during intensifying glycemic control. Many antidiabetic agents are currently available for glycemic control, but less than 50% of type 2 diabetic patients can reach their therapeutic goal. This problem might be related to the side-effects of antidiabetic agents, including hypoglycemia (insulin, sulfonylureas and repaglinides) and bodyweight increase (insulin, thiazolidinediones, sulfonylureas and lifestyle). Action to Control Cardiovascular Risk in Diabetes (ACCORD) initially aimed to investigate the effects of intensive glycemic control on cardiovascular end-points in type 2 diabetes patients at high risk of cardiovascular events, but a 22% increase in total mortality was observed in this group, mainly driven by cardiovascular mortality. The explanation for higher cardiovascular (CV) mortality remains unclear, but hypoglycemia and weight gain were responsible for the adverse outcomes3. These results make a great impact on the concept of hyperglycemic management in type 2 diabetes, and patients should receive treatment that enables them to safely achieve an ideal glycemic control without a risk of hypoglycemia or higher gain in bodyweight. Hyperglycemia in type 2 diabetes has been well investigated and can be attributed to increased hepatic glucose production, defective insulin-stimulated glucose disposal in target tissues, abnormal islet cell function and hypersecretion of glucagon. Antihyperglycemic agents are directed to one or more of the aforementioned defects of type 2 diabetes, or to modify physiological processes relating to appetite or to nutrient absorption or excretion. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are secreted from the intestines, and can enhance the endogenous secretion of insulin induced by meal ingestion and inhibit glucagon secretion, thereby improving glucose homoeostasis. Notably, GLP-1 also suppresses food intake and appetite. Abnormalities in this incretin system were found in type 2 diabetes. GLP-1 receptor (GLP-1R) agonists were recently introduced as a new treatment for patients with type 2 diabetes. Several clinical trials have shown that GLP-1R agonists can effectively and safely lower hyperglycemic parameters by dependently stimulating insulin secretion and inhibiting glucagon secretion. They have a rather low risk of hypoglycemia because of their mode of action. GLP-1 can slow down gastric emptying after a meal. Additionally, GLP-1 binds to its receptor on hypothalamic neurons and stimulates satiety by directly acting on its receptor. All clinical trials of GLP-1R agonists have shown that agonists could lead to weight reduction in type 2 diabetes. Recently, Vilsbøll et al.4 carried out a systematic review with meta-analyses to determine whether treatment with GLP-1R agonist resulted in weight reduction in overweight or obese patients with type 2 diabetes. Adult participants with a body mass index of 25 or higher were included in these randomized controlled trials. They received exenatide twice daily, exenatide once weekly or liraglutide once daily for at least 20 weeks. Control interventions were placebo, oral antidiabetic drugs or insulin. Vilsbøll et al. carried out a random effects meta-analysis of 3,395 participants randomly assigned to GLP-1R agonists and 3,016 assigned to control groups for the change of bodyweight from 21 trials. They found that the mean change in bodyweight was larger for patients with GLP-1R agonist treatment than those in the control groups (weighted mean difference −2.9 kg; 95% confidence interval −3.6 to −2.2; Table 1). In the overall analysis, GLP-1R agonists improved glycemic control, with an increase in patients who achieved the therapeutic glycated hemoglobin (HbA1c) goals. Additionally, GLP-1R agonists had beneficial effects on systolic and diastolic blood pressure, and plasma concentrations of cholesterol. Importantly, they also found that GLP-1R agonists were not associated with hypoglycemia, despite the side-effects of nausea, diarrhea and vomiting. The present meta-analysis provides convincing evidence that GLP-1R agonists should be considered in patients with diabetes who are obese or overweight4. Several once-weekly GLP-1R agonists have been found to decrease HbA1c, and fasting and postprandial hyperglycemia. They can also greatly reduce bodyweight. More recently, the position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) for the management of hyperglycemia in type 2 diabetes was published. In this statement, metformin is the preferred first agent if it is not contraindicated or if tolerated. If metformin alone does not achieve or maintain a HbA1c target over 3 months, a second oral agent, GLP-1R agonist or basal insulin, would be added. When a two-drug combination is not yet or no longer achieving the glycemic target, this statement suggests adding a third non-insulin agent, including GLP-1R agonist5. Some studies have shown advantages from the addition of GLP-1R to a combination therapy. Over 80% of individuals with type 2 diabetes are overweight or obese. GLP-1R agonists show their beneficial effects on weight loss and safety without hypoglycemia in type 2 diabetes. The systematic review with meta-analysis carried out by Vilsbøll et al. convincingly confirms the place of GLP-1R agonists in guidelines for management of hyperglycemia in type 2 diabetes.

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications

ObjectivesIn youth with type 2 diabetes (YT2D), glucagon-like peptide 1 receptor agonists (GLP1) are recommended as adjuncts to metformin (Met) when glycemic targets are not achieved. Early GLP1 use may improve weight and glycemic control, but its efficacy as monotherapy in treatment-naïve YT2D remains unstudied. This exploratory study compares GLP1 and Met monotherapy for glycemic and weight outcomes in newly diagnosed YT2D.MethodsThis retrospective study analyzed patients<21 diagnosed with T2D between January 2022 and March 2024 at a single center. Data were collected for up to 1 year following diagnosis for patients prescribed GLP1 or Met alone. Records were excluded if additional diabetes medication or bariatric surgery was introduced. A mixed effects linear regression model adjusted for baseline BMI, HbA1c, age, and gender.ResultsThe cohort included 12 GLP1 and 113 Met patients. About 83 % GLP1 patients were female (vs. Met 51 %). All were publicly insured. Median age at diagnosis was 14.8 years. Baseline and final HbA1c were similar: GLP1 (52–36 mmol/mol) and Met (52–44 mmol/mol), with 83 % GLP1 and 67 % Met patients achieving HbA1c≤48 mmol/mol (6.5 %) (p=0.253). Baseline BMI was higher in GLP1 (46.37 vs. Met 35.06 kg/m2). Percentage BMI reduction favored GLP1 (−5.10 %) over Met (−0.59 %). Regression analysis showed GLP1 was associated with greater monthly percentage BMI reduction (β= −1.08 %, p=0.001) but not with HbA1c change (β= −1.1, p=0.308).ConclusionsGLP1 led to greater BMI reduction with comparable glycemic control relative to Met in newly diagnosed YT2D.

New Medications for the Treatment of Diabetes

ObjectiveTo evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk.DesignNetwork meta-analysis.Data sourcesMedline, Embase, and Cochrane CENTRAL...

Spinal fusion is a widely performed surgical procedure for treating various spinal disorders, with lumbar fusion showing remarkably rapid growth worldwide. Despite positive outcomes after the procedure, it carries significant complications, most notably pseudarthrosis. Compromised blood supply is a key factor disrupting normal bone fusion, making optimal vascularization crucial for successful outcomes. Glucagon-like peptide-1 (GLP-1) receptor agonists, primarily used for diabetes management, demonstrate promising effects including enhanced glycemic control, improved vascular endothelial function, and direct enhancement of osteoblastic cell activity through GLP-1 receptors on bone precursor cells. Theoretically, GLP-1 receptor agonists should be beneficial for optimizing spinal fusion outcomes. We aim to systematically review and analyze the current evidence on the efficacy and safety of GLP-1 receptor agonists in promoting bone fusion and reducing complications in patients undergoing spinal fusion surgery.We conducted a comprehensive systematic review following Cochrane guidelines. We searched PubMed, Web of Science, Scopus, Embase, and Cochrane Library for studies examining GLP-1 receptor agonists in spinal fusion procedures. We used the Newcastle-Ottawa Scale for the quality assessment of the included studies. We conducted a statistical analysis using RevMan 5.4 with risk ratios for dichotomous outcomes.In total, 11 studies with a total of 14,344 participants were analyzed. GLP-1 receptor agonists significantly reduced pseudoarthrosis at six months (risk ratio (RR) = 0.63, 95% confidence interval (CI) = 0.54-0.74) and 12 months (RR = 0.64, 95% CI = 0.57-0.72), and significantly increased acute kidney injury (RR = 1.30, 95% CI = 1.03-1.65). No significant differences were observed for pseudoarthrosis at 24 months (RR = 1.03, 95% CI = 0.53-2.03), readmission rates (RR = 0.85, 95% CI = 0.48-1.51), cerebrovascular accidents (RR = 1.01, 95% CI = 0.63-1.62), and deep vein thrombosis (RR = 1.16, 95% CI = 0.78-1.72). Additionally, no significant reoperations or adverse effects were found. We also performed a subgroup analysis considering the diabetic stage, which showed valuable insights.GLP-1 receptor agonists showed promising results in reducing pseudoarthrosis at short- to medium-term follow-up, indicating potential therapeutic benefits in bone healing applications. However, the increased risk of acute kidney injury suggests the need for careful patient monitoring and risk stratification. The lack of sustained benefit at 24 months and significant heterogeneity observed in several outcomes indicate that further investigation is warranted. Future research should focus on conducting larger, well-designed randomized controlled trials with standardized outcome definitions, longer follow-up periods, and comprehensive safety monitoring to establish optimal dosing protocols and patient selection criteria for GLP-1 receptor agonist therapy in orthopedic applications.

ObjectivesPrevious studies have shown conflicting results on the relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and diabetic retinopathy (DR). This systematic review and meta-analysis aimed to clarify the association between GLP-1 receptor agonists use and the development or progression of DR.MethodsA comprehensive search of MEDLINE (via OVID and PubMed), Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from inception to March 2025. We included randomized controlled trials (RCTs) and observational studies reporting on the association between GLP-1 receptor agonists and DR. Screening, data extraction, and quality appraisal were performed independently and in duplicate. We assessed study quality using the Cochrane risk-of-bias tool for RCTs and the Newcastle-Ottawa Scale for observational studies. Meta-analysis was conducted using Stata 17, following PRISMA and MOOSE guidelines.ResultsThe search identified 6,922 studies. Of these, 39 articles (24 RCTs and 15 observational studies) met the inclusion criteria and 23 were included in the meta-analysis. The pooled analysis showed that GLP-1 receptor agonists were not significantly associated with the risk of DR compared with comparators (pooled RR = 1.00, 95% CI 0.71–1.43). Subgroup analyses by study design yielded similar non-significant results, with a pooled RR of 0.91 (95% CI 0.73–1.14) for randomized controlled trials and 2.09 (95% CI 0.47–9.19) for observational studies. After excluding studies with a high risk of bias, the pooled estimate remained non-significant (RR = 1.06, 95% CI 0.67–1.67), supporting the robustness of the overall findings. The association remained non-significant when restricted to larger studies (>500 participants; RR = 1.13, 95% CI 0.70–1.84).ConclusionIn conclusions, this systematic review found no significant association between GLP-1 receptor agonists and DR risk, though a non-significant trend toward lower risk was observed in randomized trials. Given the limited number of long-term studies, the current evidence remains inconclusive. Future studies with longer follow-up period are warranted to clarify the long-term ocular safety of GLP-1 receptor agonists.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251007882.

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Advances in the management of diabetes mellitus have come a long way in the 21st century. One of the most important developments in diabetes management has been the discovery of...

BackgroundThe cardiovascular effects of glucagon-like peptide-1 (GLP-1) receptor agonists are still controversial in the treatment of type 2 diabetes mellitus (T2DM) patients. The purpose of this study was to evaluate the risk of cardiovascular events of GLP-1 (albiglutide, exenatide, liraglutide, semaglutide, lixisenatide and dulaglutide) receptor agonists in T2DM patients.MethodsPubMed and Embase were searched to find relevant randomized controlled trials (RCTs) from inception to June 2019 that evaluated the effect of GLP-1 receptor agonists on cardiovascular events in patients with T2DM. The T2DM patients of all the eligible trials received either GLP-1 therapy or placebo, and the cardiovascular outcomes included death from cardiovascular causes, fatal or non-fatal myocardial infarction and fatal or non-fatal stroke.ResultsWe included 6 multinational double-blind randomized placebo-control trials that included a total of 52821 T2DM patients. The results indicated that GLP-1 receptor agonists reduced the risk of death from cardiovascular causes (RR: 0.90; 95% CI: 0.83–0.97; P = 0.004) and fatal or non-fatal stroke (RR: 0.85; 95% CI: 0.77–0.94; P = 0.001) compared with the placebo controls. But GLP-1 receptor agonists did not significantly alter the fatal or non-fatal myocardial infarction compared with the placebo (RR: 0.91; 95% CI: 0.82 – 1.01; P = 0.06).ConclusionWe concluded that GLP-1 receptor agonist therapy could reduce the risk of death from cardiovascular causes and fatal or non-fatal stroke compared with the placebo in the treatment of T2DM patients in trials with cardiovascular outcomes.

ObjectivesTo evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in...

ObjectiveSeveral glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1Ra) have been made recently available in Spain for type 2 diabetes mellitus (DM2) treatment. There are no published data on the clinical and...

In patients with diabetes and monoclonal gammopathy of uncertain significance (MGUS), the impact of glucagon-like peptide-1 (GLP-1) receptor agonists on the natural history of MGUS is unknown. We aimed to assess the association of GLP-1 receptor agonist use in the progression of MGUS to multiple myeloma in patients with diabetes. This is a population-based cohort study of veterans diagnosed with MGUS from 2006 to 2021 with a prior diagnosis of diabetes. A validated natural language processing algorithm was used to confirm MGUS and progression to multiple myeloma. We performed 1:2 matching for individuals with and without GLP-1 receptor agonist exposure. The Gray test was performed to detect the difference in cumulative incidence functions for progression by GLP-1 receptor agonist use status. The association between time-varying GLP-1 receptor agonist use and progression was estimated through multivariable-adjusted hazard ratio using a stratified Fine-Gray distribution hazard model, with death as a competing event and stratum for the matched patient triad. Our matched cohort included 1097 individuals with MGUS who had ever used GLP-1 receptor agonists and the matched 2194 patients who had never used GLP-1 receptor agonists. Overall, 2.6% of individuals progressed in the GLP-1 receptor agonist ever use group compared with 5.0% in the GLP-1 receptor agonist never use group. Cumulative incidence functions were statistically significantly different between the exposed and unexposed groups (P = .02). GLP-1 receptor agonist use vs no use was associated with decreased progression to multiple myeloma (hazard ratio = 0.45, 95% confidence interval = 0.22 to 0.93, P = .03). For patients with diabetes and MGUS, GLP-1 receptor agonist use is associated with a 55% reduction in risk of progression from MGUS to multiple myeloma compared with no use.

Background:Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared.Data sources:Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles.Findings:Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size.Conclusions:Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.