Glucagon-like Peptide-1 Receptor Agonists Research Articles

Long-term safety and efficacy of glucagon-like peptide-1 receptor agonists in individuals with obesity and without type 2 diabetes: A global retrospective cohort study.

We aimed to investigate the long-term impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on thyroid function, cardiovascular health, renal outcomes and adverse events in individuals with obesity and without type 2 diabetes (T2D). In this observational cohort study, we used propensity score matching to construct comparable cohorts of individuals with obesity and without T2D who were new to GLP-1 RA treatment and those who did not receive glucose-lowering medications. In total, 3,729,925 individuals with obesity were selected from the TriNetX Global Network, with an index event between 1 January 2016 and 31 March 2024. The primary outcomes were safety, cardiovascular, thyroid and clinical biochemical profile outcomes occurring within 5 years following the index event. After propensity score matching, the study included 12,123 individuals in each group. GLP-1 RA treatment was associated with a significantly lower risk of all-cause mortality (hazard ratio 0.23; 95% confidence interval 0.15-0.34) and several cardiovascular complications, including ischaemic heart disease, heart failure, arrhythmias, hypertension, stroke and atrial fibrillation (all p < 0.05). GLP-1 RAs were also associated with a lower risk of acute kidney injury and allergic reactions. These protective effects were consistent across various subgroups and regions. In this large observational study, GLP-1 RAs showed long-term protective effects on cardiovascular health, renal outcomes and adverse events in individuals with obesity and without T2D. Our findings suggest that GLP-1 RAs may offer a comprehensive approach to managing obesity and its related comorbidities, potentially improving overall health and survival in this population.

Effect of GLP-1 receptor agonists on weight and cardiovascular outcomes: A review.

Diet and lifestyle modifications remain the foundation of obesity treatment, but they have historically proven insufficient for significant, long-term weight loss. As a result, there is a high demand for new pharmacologic treatments to promote weight loss and prevent life-threatening diseases associated with obesity. Researchers are particularly interested in 1 type of drug, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), because of its promising potential in addressing the limitations of non-pharmacologic treatments. In addition to their role in weight loss, these drugs have shown promising early evidence of cardiovascular benefits in obese patients, further enhancing their clinical relevance. Semaglutide and liraglutide, which were initially approved for the treatment of type 2 diabetes, have since been approved by the Food and Drug Administration as weight loss medications due to their effectiveness in promoting significant and sustained weight loss. In this narrative review, we will explore the mechanism of GLP-1 RAs, their effects on weight loss, cardiovascular risk factors and outcomes, common adverse effects, and strategies for managing these effects.

Effect of GLP-1 receptor agonist therapy on endometrial cancer

Effect of GLP-1 receptor agonist therapy on endometrial cancer

Impact of GLP-1 Receptor Agonists on Psoriasis and Cardiovascular Comorbidities: A Narrative Review

Impact of GLP-1 Receptor Agonists on Psoriasis and Cardiovascular Comorbidities: A Narrative Review

Evaluating the benefits of the early use of GLP-1 receptor agonists.

Evaluating the benefits of the early use of GLP-1 receptor agonists.

Transforming steatotic liver disease management: The emerging role of GLP-1 receptor agonists.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Semaglutide normalizes increased cardiomyocyte calcium transients in a rat model of high fat diet-induced obesity.

Obesity increases the risk of heart failure with preserved (HFpEF), but not reduced ejection fraction (HFrEF). The glucagon-like peptide-1 receptor agonist (GLP-1-RA) semaglutide improves outcome of patients with obesity with or without HFpEF, while GLP-1-RAs were associated with adverse outcome in patients with HFrEF. Here, we investigate the effect of in vivo treatment with semaglutide on excitation-contraction coupling in a rat model of obesity. Rats received high-fat/high-fructose diet for 8weeks and were then randomized to semaglutide (HFD/Sema) or vehicle (HFD/Veh) for another 8weeks, during which they could choose between HFD and a low-fat/high-fructose diet (LFD). Control rats received either standard chow (CON), HFD or LFD only, without treatment. After 16weeks, sarcomere shortening and cytosolic Ca2+ concentrations ([Ca2+]c) were determined in isolated cardiomyocytes. Compared with CON, HFD/Veh increased the amplitude of [Ca2+]c transients and systolic sarcomere shortening in absence or presence of β-adrenergic stimulation, which was reversed by HFD/Sema. Caffeine-induced sarcoplasmic reticulum (SR) Ca2+ release and L-type Ca2+ channel (LTCC) currents were reduced by HFD/Sema versus HFD/Veh, while SR Ca2+ ATPase activity remained unaffected. Compared with HFD, LFD increased [Ca2+]c transients and sarcomere shortening further despite similar effects on body weight. While HFD increased cardiomyocyte [Ca2+]c transients and systolic sarcomere shortening, semaglutide normalized these alterations, mediated by reduced SR Ca2+ load and LTCC currents. Because increased LTCC currents were previously traced to cardiac hypertrophy, these effects may explain why GLP-1-RAs provide benefits for patients with obesity with or without HFpEF, but rather adverse outcome in HFrEF.

Neuroprotective effects of GLP-1 receptor agonists in neurodegenerative Disorders: A Large-Scale Propensity-Matched cohort study

BackgroundGLP-1 receptor agonists, traditionally used for treating type 2 diabetes mellitus and obesity, have demonstrated anti-inflammatory properties. However, their potential neuroprotective effects in neurodegenerative disorders remain unclear. ObjectiveTo evaluate the impact of GLP-1 receptor agonists on the risk of developing various neurodegenerative conditions in obese patients. MethodsThis comprehensive retrospective cohort study analyzed data from 5,307,845 obese adult patients across 73 healthcare organizations in 17 countries. Propensity score matching was performed, resulting in 102,935 patients in each cohort. We compared the risk of developing neurodegenerative disorders between obese patients receiving GLP-1 receptor agonist therapy and those who were not. ResultsObese patients treated with GLP-1 receptor agonists showed significantly lower risks of developing Alzheimer’s disease (RR = 0.627, 95 %CI = 0.481–0.817), Lewy body dementia (RR = 0.590, 95 %CI = 0.462–0.753), and vascular dementia (RR = 0.438, 95 %CI = 0.327–0.588). The risk reduction for Parkinson’s disease was not statistically significant overall (RR = 0.784, 95 %CI = 0.580–1.058) but was significant for semaglutide users (RR = 0.574, 95 %CI = 0.369–0.893). Semaglutide consistently showed the most pronounced protective effects across all disorders. Additionally, a significant reduction in all-cause mortality was observed (HR = 0.525, 95 %CI = 0.493–0.558). ConclusionThis study provides evidence that the effects of GLP-1 receptor agonists may extend beyond their known metabolic and cardioprotective benefits to include neuroprotection, associated with a decreased risk of developing various neurodegenerative disorders. These findings suggest the potential for expanding the therapeutic applications of GLP-1 receptor agonists to improve neurocognitive outcomes. Further research is warranted to elucidate the mechanisms underlying these neuroprotective effects and to explore their clinical applications in neurodegenerative disease prevention and treatment.

Role of Dual GIP and GLP-1 Receptor Agonist, Tirzepatide in the Management of Weight Loss; A Systematic Review.

The eventuality of tirzepatide, a binary GIP and GLP- 1 receptor agonist, as a treatment for rotundity and metabolic diseases is addressed in this comprehensive review. A definition of tirzepatide is that it is an implicit intervention for rotundity, given its effectualness per the cure-dependent effect. Beyond the beneficial effects on body weight loss, tirzepatide also brings about an improvement in lipid biographies and insulin perceptivity, in harmony with binary receptor activation. Assaying data from seven phases 3 trials, it's constantly shown that tirizepatide reduces body weight in a significant and clinically meaningful way for a variety of party biographies and lengths of time. The drug's effect was supported by its favorable safety profile, which shows low prevalence rates of common adverse goods. Its efficacy in the management of type 2 diabetes is supported by relative evaluations, underscoring the inevitability of its breakthrough as a therapeutic volition. Treatment individualization is key, as evidenced by the tailor-made response proposed by group analysis based on birth BMI. The efficacy, safety, and demand for personalized treatment plans of tirzepatide are each supported in recommendations for clinical practice. Tirzepatide's eventuality as a long-term strategy for habitual rotundity is corroborated by long-term follow-up studies that show sustained weight loss. Indeed with these encouraging results, further study and clinical experience are demanded to completely comprehend the safety, optimal integration, and long-term effectiveness of tirzepatide in a multiplicity of patient populations.

Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes

The UK Prospective Diabetes Study was the first study to investigate the effectiveness of glycemic control in patients with type 2 diabetes. Since then, many studies have evaluated the impact of intensive glycemic control on diabetes-related morbidities and mortality. The results of these studies were intended to change the paradigm for controlling glycated hemoglobin and preventing diabetes-related complications, but the beneficial outcomes were limited to microvascular diseases rather than diabetes-related cardiorenal diseases and deaths. This has emphasized the need for comprehensive management of other risk factors (hypertension, dyslipidemia, renal failure, etc.) in addition to hyperglycemia to prevent atherosclerotic cardiovascular diseases and end-stage renal disease in type 2 diabetes. Since 2008, clinical trials to demonstrate cardiovascular safety have shown a beneficial effect of sodium-glucose transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists on macrovascular or renal complications in patients with type 2 diabetes. Recently, major societies around the world including the Korean Diabetes Association, have shifted the goals of diabetes management from the typical glucocentric view to cardiorenal outcome-oriented (organ protection) care, which has been widely accepted and is gradually applied to primary care.

Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis

BackgroundWeight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.MethodsWe conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).ResultsA total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was −13.7% with semaglutide and −3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was −41.7 points with semaglutide and −27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.ConclusionsAmong participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.)

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for recurrent nephrolithiasis among patients with pre-existing nephrolithiasis or gout: target trial emulation studies.

To emulate target trials comparing recurrence of nephrolithiasis among patients with pre-existing nephrolithiasis (overall and stratified by concomitant gout) initiating sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus an active comparator. Target trial emulation studies. Canadian population database, January 2014 to June 2022. 20 146 patients with nephrolithiasis and type 2 diabetes, including those with concomitant gout at baseline, a high risk group. Initiation of an SGLT-2 inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist, with a dipeptidyl peptidase-4 (DPP-4) inhibitor as alternative comparator. The primary outcome was recurrent nephrolithiasis events ascertained from diagnoses during emergency department visits, hospital admissions, or outpatient visits. Secondary outcomes included nephrolithiasis resulting in hospital admission or emergency department visits and flare-up of gout, as well as a positive control outcome (genital infection) and negative control outcomes (osteoarthritis encounter and appendicitis). Poisson and Cox proportional hazards regression models were used (primary analyses), as well as overlap weighting. After inverse probability of treatment weighting, 1924 recurrent nephrolithiasis events occurred among the 14 456 weighted patients who used an SGLT-2 inhibitor (105.3 per 1000 person years), compared with 853 events among the 5877 weighted patients who used a GLP-1 receptor agonist (156.4 per 1000 person years). The adjusted rate ratio was 0.67 (95% confidence interval (CI) 0.57 to 0.79) and rate difference was -51 (95% CI -63 to -40) per 1000 person years, with a number needed to treat (NNT) of 20. Among those with recently active nephrolithiasis, the absolute rate difference was 219 per 1000 person years (NNT of 5). Protective associations persisted for nephrolithiasis events that required emergency department visits, hospital admissions, or procedures, and when an SGLT-2 inhibitor was compared with a DPP-4 inhibitor (rate ratio 0.73 (0.68 to 0.78), rate difference -38 (-46 to -29) per 1000 person years (NNT of 26)). Protective associations also persisted among patients with nephrolithiasis and concomitant gout, with a rate ratio of 0.67 (0.57 to 0.79) and rate difference of -53 (95% CI -78 to -27) per 1000 person years versus a GLP-1 receptor agonist (NNT of 19), and 0.63 (0.55 to 0.72) and-62 (-81 to -42) per 1000 person years, respectively, versus a DPP-4 inhibitor (NNT of 16). Furthermore, SGLT-2 inhibitor use was associated with a lower rate of gout flare-ups (rate ratio 0.72, 0.54 to 0.95, rate difference -16, -31 to -1 per 1000 person years) compared with GLP-1 receptor agonists (0.65, 0.52 to 0.82, and -21, -33 to -9 per 1000 person years) compared with DPP-4 inhibitors. SGLT-2 inhibitor initiators showed higher risk of genital infection (eg, hazard ratio 2.21, 95% CI 1.68 to 2.90, and rate difference 13 per 1000 person years), but no altered risk of osteoarthritis encounter (0.87, 0.68 to 1.1, and -2 per 1000 person years) or appendicitis (1.07, 0.69 to 1.67, and 1 per 1000 person years). Results were similar when propensity score overlap weighting was applied. The benefits associated with SGLT-2 inhibitor for patients with nephrolithiasis in these target trial emulations suggest they may be a useful addition to current treatments to simultaneously manage nephrolithiasis recurrence and comorbidities, including gout.

Effectiveness and Safety of GLP-1 Receptor Agonists in Patients with Type 1 Diabetes.

Background: GLP-1 receptor agonists (GLP-1RA) are used in the management of type II diabetes mellitus or obesity, although its role in patients with type I diabetes mellitus (T1DM) has been debated. This study aimed to investigate the efficacy and safety of GLP-1RA in patients with T1DM using real-world data. Methods: This multicenter, retrospective study was conducted at three tertiary medical centers in Riyadh, Saudi Arabia. The study followed up patients (>16 years old) with T1DM treated with insulin followed by GLP-1RA add-on therapy. The efficacy outcomes included changes in HbA1c, body weight, and insulin requirements from baseline to each follow-up visit. The main safety outcomes assessed included hypoglycemic events and gastrointestinal (GI) adverse events. Results: The study included 144 patients with a mean age of 33.0 ± 10.1 years. Semaglutide was the most used GLP-1RA (63.9%) followed by liraglutide (34.0%). From baseline to 3-month follow-up, HbA1c (mean difference (MD) = -0.8%; p = 0.0053), weight (MD = -2.4 kg; p = 0.0253), and daily basal insulin dose (MD = -2.1 units; p = 0.0349) were significantly reduced. Likewise, HbA1c (MD = -0.5%; p = 0.0004), weight (MD = -3.6 kg; p < 0.0001), and daily basal insulin (MD = -2.4 units; p = 0.0282) were significantly reduced at the 4-6-month follow-up. The significant reductions in HbA1c, weight, and daily basal insulin levels were consistent for up to 18-month follow-up. Only one patient had a major hypoglycemic event, whereas 8.3% of the patients had GI adverse events. Conclusions: Overall, significant improvements in glycemic control, weight loss, and insulin requirements were observed with the use of GLP-1RA in patients with T1DM, with a limited number of GI adverse events.

Twelve-month analysis of real-world evidence from a telehealth obesity-treatment provider using antiobesity medications.

The objective of this study was to describe weight changes in members of a large-scale telehealth obesity-treatment provider who were using antiobesity medications (AOMs). This retrospective observational study analyzed real-world data from adults who initiated AOM treatment with the WW International, Inc. (formerly Weight Watchers) Clinic telehealth program between January 2022 and July 2023 (n = 53,590). The main outcomes were changes in body weight over 12 months, side effects over follow-up, and medication usage patterns. The 53,590 patients who initiated treatment were predominantly female (88.6%), with a mean BMI of 36.9 kg/m2. Mean (SD) treatment duration was 5.3 (4.3) months. Program retention rates based on the number of patients whose time from enrollment was at least 3, 6, 9, and 12 months were 78% (n = 39,907/51,247), 63% (n = 25,515/40,203), 58% (n = 15,472/26,794), and 77% (n = 6459/8394), respectively. Average weight loss was 8.9% at 3 months (n = 37,565), 14.1% at 6 months (n = 24,140), 17.7% at 9 months (n = 15,169), and 19.4% at 12 months (n = 6089). Glucagon-like peptide-1 receptor agonist (GLP-1-RA)-based treatments were predominant. Side effects were consistent with the classes of medications used, and frequency declined over time. This real-world analysis of a telehealth-delivered obesity-treatment program demonstrated outcomes consistent with recent phase 3 clinical trials of AOMs, suggesting generalizability beyond clinical trial and in-person settings.

GLP-1 receptor agonist liraglutide alleviates kidney injury by regulating nuclear translocation of NRF2 in diabetic nephropathy.

Diabetic nephropathy (DN) is a severe renal disorder that arises as a complication of diabetes. Liraglutide, an analogue of a glucagon-like peptide 1 (GLP-1) receptor agonist, has been shown to decrease diabetes-caused renal damage. Nevertheless, the complete understanding of the roles and mechanism remains unclear. In our study, diabetic rat models were created through a single intraperitoneal injection of streptozotocin (STZ). The level of fasting blood glucose, 24-h urine protein, serum creatinine (Scr) and blood urea nitrogen (BUN) were assessed. Periodic acid-Schiff (PAS) staining was applied to examine the pathological changes in renal tissues. Reactive oxygen species (ROS) formation was measured via dichloro-dihydro-fluorescein diacetate (DCFH-DA) probes. Western blot was conducted to examine the levels of oxidative stress-related and extracellular matrix (ECM)-associated proteins. The nuclear translocation of NRF2 was investigated through immunofluorescence and Western blot assays. We demonstrated that liraglutide attenuated DN-induced oxidative stress and ECM deposition in vitro and in vivo. Liraglutide exerted a reno-protective effect by promoting nuclear translocation of NRF2 in mesangial cells. ML385, an NRF2 inhibitor, counteracted the beneficial impact of liraglutide.

Engineering Supramolecular Nanofiber Depots from a Glucagon-Like Peptide-1 Therapeutic.

Diabetes and obesity have emerged as major global health concerns. Glucagon-like peptide-1 (GLP-1), a natural incretin hormone, stimulates insulin production and suppresses glucagon secretion to stabilize and reduce blood glucose levels and control appetite. The therapeutic use of GLP-1 receptor agonists (e.g., semaglutide) has transformed the standard of care in recent years for treating type 2 diabetes and reversing obesity. The native GLP-1 sequence has a very short half-life, and therapeutic advances have come from molecular engineering to alter the pharmacokinetic profile of synthetic GLP-1 receptor agonists to enable once-weekly administration, reduce the frequency of injection, and improve adherence. Efforts to further extend this profile would offer additional convenience or enable entirely different treatment modalities. Here, an injectable GLP-1 receptor agonist depot is engineered through integration of a prosthetic self-assembling peptide motif to enable supramolecular nanofiber formation and hydrogelation. This supramolecular GLP-1 receptor agonistic (PA-GLP1) offers sustained release in vitro for multiple weeks, supporting long-lasting therapy. Moreover, in a rat model of type 2 diabetes, a single injection of the supramolecular PA-GLP1 formulation achieved sustained serum concentrations for at least 40 days, with an overall reduction in blood glucose levels and reduced weight gain, comparing favorably to daily injections of semaglutide. The general and modular approach is also extensible to other next-generation peptide therapies. Accordingly, the formation of supramolecular nanofiber depots offers a more convenient and long-lasting therapeutic option to manage diabetes and treat metabolic disorders.

Current Status of Semaglutide Injection andDevelopment Prospects in China

Obesity is a global issue that closely affects public health, and China’s obesity rate is among the highest in the world. Recently, Semaglutide injection was approved for marketing in China as the first weekly formulation for long-term weight control. This review consolidates and analyzes various types of research related to Semaglutide regarding weight loss, to comprehensively describe the different aspects of the drug. As a glucagon-like peptide 1 receptor agonists (GLP-1RA), Semaglutide works by mimicking the action of innate hormone to enhance the cell signaling activity and corresponding outcome. It has been approved to effectively reduce weight and improve weight-related factors in overweight or obese patients with a guaranteed safety profile. Comparing to traditional methods of losing weight, this medication is time and effort-saving, which makes it highly competitive in this field. Although there are still unsolved issues and challenges faced by the drug, such as high price and acceptance among doctors and patients, it is highly likely to become a new and anticipated method of weight management in China

Preprocedure Care of Patients on Glucagon-like Peptide-1 Receptor Agonists: A Multisociety Clinical Practice Guidance.

Preprocedure Care of Patients on Glucagon-like Peptide-1 Receptor Agonists: A Multisociety Clinical Practice Guidance.

Perioperative Management of Patients Taking Glucagon-like Peptide-1 Receptor Agonists: Applying Evidence to Clinical Practice

This review discusses recent evidence addressing risks in patients taking glucagon-like peptide-1 receptor agonist medications and proposes a framework for perioperative management.

Preoperative Strategies for Patients on Glucagon-like Peptide-1 Receptor Agonists Navigating Current Controversies and Future Directions.

Preoperative Strategies for Patients on Glucagon-like Peptide-1 Receptor Agonists Navigating Current Controversies and Future Directions.