Peptide-1 Receptor Agonists Research Articles

The Use of SGLT-2 Inhibitors and GLP-1RA in Frail Older People with Diabetes: A Personalised Approach Is Required

Background: Frailty is an increasingly recognised complication of diabetes in older people and should be taken into consideration in management plans, including the use of the new therapies of sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon like peptide-1 receptor agonists (GLP-1RA). The frailty syndrome appears to span across a spectrum, from a sarcopenic obese phenotype at one end, characterised by obesity, insulin resistance, and prevalent cardiovascular risk factors, to an anorexic malnourished phenotype at the other end, characterised by significant weight loss, reduced insulin resistance, and less prevalent cardiovascular risk factors. Therefore, the use of the new therapies may not be suitable for every frail older individual with diabetes. Objectives: To review the characteristics and phenotype of frail older people with diabetes who should benefit from the use of SGLT-2 inhibitors or GLP-1RA. Methods: A narrative review of the studies investigating the benefits of SGLT-2 inhibitors and GLP-1RA in frail older people with diabetes. Results: The current evidence is indirect, and the literature suggests that the new therapies are effective in frail older people with diabetes and the benefit appears to be proportional with the severity of frailty. However, frail patients described in the literature who benefited from such therapy appeared to be either overweight or obese, and to have a higher prevalence of unfavourable metabolism and cardiovascular risk factors such as dyslipidaemia, gout, and hypertension compared to non-frail subjects. They also have a higher prevalence of established cardiovascular disease compared with non-frail individuals. In absolute terms, their higher cardiovascular baseline risk meant that they benefited the most from such therapy. The characteristics of this group of frail patients fulfil the criteria of the sarcopenic obese frailty phenotype, which is likely to benefit most from the new therapies due to the unfavourable metabolic profile of this phenotype. There is no current evidence to suggest the benefit of the new therapies in the anorexic malnourished phenotype, which is underrepresented or totally excluded from these studies, such as in patients living in care homes. This phenotype is likely to be intolerant to such therapy due to its associated risk of inducing further weight loss, dehydration, and hypotension. Conclusions: Clinicians should consider the early use of the new therapies in frail older people with diabetes who are either of normal weight, overweight, or obese with prevalent cardiovascular risk factors, and avoid their use in those frail subjects who ae underweight, anorexic, and malnourished.

A Narrative Review of the Interplay Between Carbohydrate Intake and Diabetes Medications: Unexplored Connections and Clinical Implications

This narrative review examines the dynamic interplay between carbohydrate intake and diabetes medications, highlighting their combined molecular and clinical effects on glycemic control. Carbohydrates, a primary energy source, significantly influence postprandial glucose regulation and necessitate careful coordination with pharmacological therapies, including insulin, metformin, glucagon-like peptide (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Low-glycemic-index (GI) foods enhance insulin sensitivity, stabilize glycemic variability, and optimize medication efficacy, while high-GI foods exacerbate glycemic excursions and insulin resistance. Continuous glucose monitoring (CGM) offers real-time insights to tailor dietary and pharmacological interventions, improving glycemic outcomes and reducing complications. Despite advancements, gaps persist in understanding nutrient–drug interactions, particularly with emerging antidiabetic agents. This review underscores the need for integrating carbohydrate-focused dietary strategies with pharmacotherapy to enhance diabetes management. Future research should prioritize clinical trials leveraging CGM technology to explore how glycemic index, glycemic load, and carbohydrate quality interact with newer diabetes medications. Such studies can refine evidence-based recommendations, support individualized care plans, and improve long-term outcomes. Addressing systemic barriers, such as limited access to dietitians and CGM technology in underserved regions, is critical for equitable care. Expanding the roles of community health workers and training healthcare providers in basic nutrition counseling can bridge gaps, promoting sustainable and inclusive diabetes management strategies. These efforts are essential for advancing personalized, effective, and equitable care for individuals with diabetes.

Elective peri-operative management of adults taking glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic peptide agonists and sodium-glucose cotransporter-2 inhibitors: a multidisciplinary consensus statement: A consensus statement from the Association of Anaesthetists, Association of BritishClinical Diabetologists, British Obesity and Metabolic Surgery Society, Centrefor Perioperative Care, Joint British Diabetes Societies for Inpatient Care, RoyalCollege of Anaesthetists, Society for Obesity and Bariatric Anaesthesia and

Glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic peptide receptor agonists and sodium-glucose cotransporter-2 inhibitors are used increasingly in patients receiving peri-operative care. These drugs may be associated with risks of peri-operative pulmonary aspiration or euglycaemic ketoacidosis. We produced a consensus statement for the peri-operative management of adults taking these drugs. This multidisciplinary consensus statement included surgeons, anaesthetists, physicians, pharmacists and people with lived experience relevant to these guidelines. Following the directed literature review, a three-round modified Delphi process was conducted to generate and ratify recommendations. Patients taking glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic peptide receptor agonists should: continue these drugs before surgery; have full risk assessment and stratification; and receive peri-operative techniques that may mitigate risk of pulmonary aspiration before, during and after sedation or general anaesthesia. Patients taking sodium-glucose cotransporter-2 inhibitors should omit them the day before and the day of a procedure. All patients should have risks and mitigation strategies discussed with a shared decision-making approach. Until more evidence becomes available, this pragmatic, multidisciplinary consensus statement aims to support shared decision-making and improve safety for patients taking glucagon-like peptide-1 receptor agonists, dual glucose-dependent insulinotropic peptide receptor agonists and sodium-glucose cotransporter-2 inhibitors during the peri-operative period.

Circulating and hepatic levels of growth differentiation factor 15 in patients with metabolic dysfunction‐associated steatotic liver disease

AbstractAimIncreased growth differentiation factor 15 (GDF15) may reflect impaired metabolic health and an inflammatory state in metabolic dysfunction‐associated steatotic liver disease (MASLD). We investigated the role of GDF15 in histologically verified MASLD in a meal test (discovery) cohort (n = 20) and a prospective (validation) cohort with 2 years of follow‐up (n = 276).MethodsParticipants were evaluated clinically and histologically in both cohorts. Fibrosis severity was classified as no/mild (F0/F1) or significant (F2–4). Plasma GDF15 was measured by enzyme‐linked immunosorbent assays and the SOMAScan platform. Hepatic GDF15 mRNA expression was analyzed by RNA in situ hybridization and bulk RNA‐sequencing. In addition, we used data from public single‐nucleus RNA‐sequencing datasets.ResultsIn both cohorts, plasma GDF15 was increased in MASLD compared with healthy controls (p < 0.0001) with the highest levels in patients with significant fibrosis (area under the curve 0.83; 95% confidence interval [CI], 0.76–0.91). The GDF15 levels were unaffected by a standardized meal and there was no difference in peripheral or hepatic venous concentrations. After 2 years, the increase in GDF15 levels was reduced in patients treated with glucagon‐like peptide receptor agonists (GLP‐1‐RA) compared to patients receiving lifestyle advice (−28%; 95% CI, −44 to −8; p = 0.01). Plasma GDF15 was associated with circulating insulin‐like growth factor 1 and related proteins. Hepatic GDF15 mRNA was mainly expressed in hepatocytes and in cholangiocytes in fibrotic areas and was increased in MASLD (p = 0.02) with the highest expression in the group with steatohepatitis (p = 0.009).ConclusionsIncreased hepatic and circulating GDF15 are found in MASLD. Treatment with GLP‐1‐RA may reduce GDF15, possibly reflecting beneficial metabolic and inflammatory effects.

Association between Semaglutide and Non-Arteritic Anterior Ischemic Optic Neuropathy: A Multinational Population-Based Real-World Study

ObjectiveTo investigate whether semaglutide increases the risk of non-arteritic anterior ischemic optic neuropathy (NAION) in the general population. DesignThis retrospective cohort study utilized a de-identified global electronic medical records database. The enrollment period was extended from January 2017 to August 2023, with observations concluding in August 2024. ParticipantsThis study included individuals with type 2 diabetes mellitus (T2DM) or obesity. They were further categorized into T2DM-only, obesity-only, and T2DM with obesity groups to assess the differences among these subgroups. The effects of semaglutide were compared with those of glucose-lowering or weight loss medications other than glucagon-like peptide receptor agonists. MethodsPatient data were obtained from 160 healthcare organizations across 21 countries. Outcomes were evaluated at one, two, and three years of follow-up. A 1:1 propensity score matching was performed to balance age, sex, body mass index, hemoglobin A1C, medications, and underlying comorbidities. Cox regression models were used to compute hazard ratios (HR) and 95% confidence intervals (CI). Main Outcome MeasuresThe occurrence of NAION. ResultsThe final analysis included 37,245 participants with T2DM-only, 33,537 participants with obesity-only, and 64,989 participants with both T2DM and obesity. The results indicated that the administration of semaglutide was not associated with the development of NAION in the T2DM-only group (1 year follow-up: HR, 2.32; 95% CI, 0.60–8.97; 2 years: HR, 2.31; 95% CI, 0.86–6.17; 3 years: HR, 1.51; 95% CI, 0.71–3.25), the obesity-only group (1 year follow-up: HR, 0.25; 95% CI, 0.03–2.28; 2 years: HR, 0.44; 95% CI, 0.09–2.21; 3 years: HR, 0.44; 95% CI, 0.09–2.21), and the T2DM with obesity group (1 year follow-up: HR, 0.81; 95% CI, 0.42–1.57; 2 years: HR, 1.2; 95% CI, 0.74–1.94; 3 years: HR, 1.19; 95% CI, 0.78–1.82). ConclusionsThe findings suggest that semaglutide may not be associated with an increased risk of NAION in the general population. Therefore, avoidance of semaglutide based solely on concerns regarding the risk of NAION may not be warranted, as its potential benefits for blood glucose control and cardiovascular health likely outweigh its potential risks.

Effects of SGLT-2i and GLP-1RA in vascular function parameters: the impact of the weight loss

Abstract Background Arterial stiffness and endothelial function markers flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness and endothelial function as well as the metabolic parameters of HbA1c and Weight in T2DM patients. Patients and Methods: We enrolled 99 consecutive patients under stable antidiabetic therapy who did not reach therapeutic targets. Subjects were assessed to receive an additional antidiabetic agent to optimize glucose control; glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Glycosylated hemoglobin (Hba1c) and weight expressed through Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) and flow-mediated dilatation (FMD), as biomarkers of arterial stiffness and endothelial function accordingly, were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups in traditional risk factors of age and sex or baseline HbA1c, BMI, PWV, and FMD levels (ps=NS for all). In both groups PWV values displayed a statistically significant improvement from 11.2±2.5 to 9.3±2.2 m/sec (p<0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group, as presented in Figure 1 through the differences in the values of PWV. FMD values were also significantly improve in both groups from baseline to follow-up; from 6.04±1.22 to 6.50±1.26% (p<0,001) for the GLP-1RA group and from 6.38±1.21 to 6.81±1.29% (p<0.001) for the SGLT-2i group. Moreover, both groups achieved better weight management goals in terms of BMI values between baseline and follow-up; from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group (p<0.001) and from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p<0.001), in addition to achieving better glycemic control in terms of HbA1c values, as seen in their paired differences: for GLP-1RA: 1.3±0.7% and for SGLT-2i: 0.8±0.5%. Interestingly, in the SGLT-2i group the magnitude of the PWV improvement was correlated with the weight loss (r=0.368, p=0.007). Conclusion These data provide evidence that the newer antidiabetic drugs, both GLP1-RA and SGLT-2i, have actions that benefit both vascular function, endothelium as well as metabolic parameters. Interestingly, in the patients receiving SGLT-2i the magnitude of the PWV improvement was correlated with the weight loss.delta PWV for SGLT-2i & GLP-1RA groupsCorrelation of deltaWeight & deltaPWV

Parallel improvement of arterial stiffness with weight loss following intensification of antidiabetic treatment

Abstract Background Arterial stiffness is a marker that can flag increased cardiovascular disease risk in patients with type 2 Diabetes Mellitus (T2DM), while weight management plays a crucial role for the management of glycemic control and prevention of complications in these patients. Purpose To investigate the effects of novel antidiabetic agents on arterial stiffness in T2DM patients as well as potential associations with their weight status before and after treatment. Patients and Methods We enrolled 118 consecutive patients under stable antidiabetic therapy. According to their physician they start treatment with an additional antidiabetic agent; either dipeptidyl peptidase-4 inhibitor (DPP-4i, n=19), or glucagon like peptide-1 receptor agonist (GLP-1RA, n=50) or sodium/glucose cotransporter-2 inhibitor (SGLT-2i, n=49). Body Mass Index (BMI) along with carotid-femoral pulse wave velocity (PWV) as a biomarker of arterial stiffness were measured at baseline and 3 months after treatment intensification. Results There were no differences between the study groups regarding their sex, age and other traditional risk factors or the values of PWV and BMI at baselined (p=NS for all). All groups achieved better glycemic control in terms of HbA1c values between baseline and follow-up; from 7.4±1.2% to 7.4±1.2% in the DPP4i group (p<0.001 for all), from 8.6±0.7% to 6.7±0.8% in the GLP-1RA group (p=0.07) and from 7.7±1.1% to 6.7±0.7% in the SGLT-2i group (p<0.001). PWV showed a decrease from 10.6±2.7 to 9.0±1.6 m/sec (p=0.001) in the DPP4-i group, from 11.2±2.5 to 9.3±2.2 m/sec (p<0.001) in the GLP-1RA group and from 10.7±2.4 to 8.9±2.0 m/sec (p=0.001) in the SGLT-2i group as presented in Figure 1. Regarding BMI, a reduction in the values between groups from baseline to follow-up was also observed; from 27.4±5.3 to 26.1±5.0 kg/m2 for the DPP-4i group, from 33.6±4.9 to 31.5±4.6 kg/m2 for the GLP-1RA group, from 31.8±5.5 to 30.5±5.6 kg/m2 for the SGLT-2i group (p<0.001 for all). Moreover, in the entire study population there was significant correlation between PWV and BMI improvement following treatment initiation (rho=0.247, p=0.007) (Figure 2). Conclusion Diabetes mellitus treatment intensification with GLP1-RA or SGLT-2i or DPP4i, ameliorated arteriosclerosis, improved PWV and BMI while there is significant association between BMI and PWV improvement.Changes in PWV values among the groupsCorrelation between deltaBMI & deltaPWV

Extent and impact of obesity in patients with diabetes and acute myocardial infarction - experience from a national cohort

Abstract Background Elevated body mass index (BMI) has an adverse effect on cardiovascular riskfactors where diabetes and coronary artery disease increases with obesity. However, less in known about the prevalence and the grades of obesity in a diabetes population with acute myocardial infarction (AMI) and the impact on prognosis. Further, for the moment there is a shortage of access to cardioprotective weight loss medications as Glucagon Like Peptide Receptor Agonists (GLP-1 RA). Purpose To explore features and grades of obesity in patients with diabetes and AMI and impact on outcome in a national perspective. Methods All patients with diabetes and AMI admitted for coronary angiography in Sweden the years 2010-2021 were included. Information on BMI was collected at the time of angiography and grouped into obesity categories: low BMI (<18.5 kg/m2), normal BMI (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obesity grade 1 (30.0-34.9 kg/m2), obesity grade 2 (35.0-39.9 kg/m2) and obesity grade 3 (≥40.0 kg/m2). Information on baseline characteristics and outcome was collected from national registries. Mortality was followed until March 2022. Restricted cubic spline analysis of association between continuous BMI and age-adjusted mortality was performed where normal BMI served as a reference with Hazard Ratio (HR) 1.0. Results Of 19 378 patients with diabetes, 67% were men and 46% suffered a STEMI. Normal BMI was present in 21%, overweight in 41%, obesity grade 1 in 25%, obesity grade 2 in 9% and obesity grade 3 in 3% (Figure 1). Age was decreasing with grade of obesity (72 years in normal BMI vs. 62 years in obesity grade 3, p<0.001). Hypertension and hyperlipidaemia were more common in patients with more severe obesity than in those with normal BMI (67% vs. 80%, p<0.001, and 44% vs. 50%, p<0.001, in normal BMI and obesity grade 3 respectively) while a higher proportion of those with normal BMI had suffered a previous MI (10% vs. 6% in obesity grade 3, p<0.001) and a previous stroke (10% vs. 5% in obesity grade 3, p<0.001). In patients with normal BMI STEMI was more common (51% vs. 39%, p<0.001) than in those with obesity grade 3. In patients with obesity grade 3 GLP-1 RA was used in 14% compared to 4% in those with normal BMI. Figure 2 depicts age-adjusted HR and 95% Confidence Interval for mortality for different BMI levels with a U-shaped pattern illustrating that associated mortality risk is higher when obesity is present especially grade 2 and 3. Conclusion Obesity is common affecting around one third of patients with diabetes and AMI and impacts survival. This strengthens that after AMI use of effective weight loss cardioprotective treatment should be prioritised in patients with diabetes and obesity especially if severe.

Semaglutide modulates adipogenic differentiation and extracellular acidification in epicardial (EAT) and subcutaneous (SAT) adipose tissue stromal cells from patients with cardiovascular disease

Abstract Backround Cardiovascular disease (CVD) is the main cause of death in the world. One of the known risk factors is the epicardial fat (EAT) accumulation, which is around the myocardium and coronaries playing a paracrine role over them. Although mature and functional adipocytes are involved in energy balance and glucose metabolism, the hypertrophic state increases the production of fatty acid binding protein 4 (FABP4), which is a pro-inflammatory adipokine, with consequences on extracellular acidification. Recent data shows that glucagon-like peptide receptor agonists 1 (GLP1ra) drug improves the insulin response and reduces EAT thickness. Although GLP1ra has a direct effect on hypothalamus for reducing food intake, this drug might play a direct role on adipogenesis process in this fat stromal cells. Purpose Our study aims to demonstrate the effect of semaglutide on adipogenesis and metabolism in epicardial and subcutaneous stromal cells from patients with cardiovascular disease. Methods The study was approved by the Galician Research Ethics Committee, and subcutaneous adipose tissue (SAT) and EAT samples from 17 patients were obtained undergoing open-heart surgery with informed consent. Stromal cells from biopsies were isolated and cultured. Adipogenesis was induced for 15 days with or without 1 nM semaglutide, given by Novo-Nordisk (Bagsværd, Denmark), using an adipogenesis cocktail. Cells were lysed and RNA was isolated for RT-qPCR. Target genes were amplified for Glucagon like peptide 1- receptor (GLP1R), differentiation, adipogenesis, glucose metabolism and cellular markers. Extracellular acidification rate was measured with glycolytic rate assay on Seahorse. Lipids accumulation was tested by AdipoRed staining. Results Stromal cells from both tissues express GLP1R but higher differentiation factor (PGC1α) was detected in SAT compared to EAT (p=0.02), as well as adipogenesis induction. After semaglutide treatment, we observed a downregulation of FABP4 and GLUT1 in EAT (p=0.01 and p=0.02, respectively). Despite FABP4 was not modulated on SAT, there was a reduction of PGC1α levels. (p=0.02). Since glitazones upregulate PGC1α, which is used for adipogenesis induction, these results might suggest the counteract mechanism of semaglutide. The metabolism assay showed that semaglutide reduces extracellular acidification rate in EAT cells (p=0.04) and oxidative glycolysis with semaglutide treatment (p=0.003) but not in SAT cells. Conclusions Semaglutide reduces adipogenesis, through modulation of PGC1α transcription factor in EAT from patients with cardiovascular disease and extracellular acidification and oxidative glycolysis. These results might help to understand one of the mechanisms associated with EAT reduction in patients with semaglutide treatment.

Associations of semaglutide with first-time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real-world data in the US.

Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking. We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses. Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups. These findings support further studies to assess semaglutide's potential in preventing AD. Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

Evaluation of TikTok social media posts on side effect information for popular weight loss medications

AbstractIntroductionThe prevalence of overweight and obesity is increasing in America, contributing to various health risks. Glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory peptide (GIP) receptor agonists have bloomed in popularity due to their efficacy and United States Food and Drug Administration (FDA) approval for weight loss, igniting popularity on social media. This study focuses on the role of TikTok™ (ByteDance, Haidian, Beijing, China), a popular social media platform, in disseminating understandable and actionable information about the side effects of weight loss medications.MethodsThe study analyzed the top 50 TikTok videos for each of the following hashtags: #ozempicsideeffects, #semaglutidesideeffects, #mounjarosideeffects, and #wegovysideeffects. Videos were evaluated based on their understandability and actionability using the Patient Education Materials Assessment Tool (PEMAT) for audio‐visual (AV) products. PEMAT‐AV scores and popularity of videos were compared between hashtags utilizing one‐way analysis of variance (ANOVA). An alpha of 0.05 was used, with Bonferroni correction.ResultsA total of 165 videos were reviewed for PEMAT‐AV understandability and actionability scores. The total visibility of the videos reached over 19.4 million views. A majority of the videos were personal experiences (89%), with only 5% being health care education videos. The average understandability and actionability scores for all videos were 43% and 20%, respectfully. The data presented a difference between searched hashtags for both evaluation scores, p‐values of <0.001 and 0.093, respectively.ConclusionTikTok videos covering weight loss medication side effects have poor understandability and actionability scores. This study highlights the opportunity for more educational videos produced by health care professionals on TikTok, and a potential need for health care organizations and/or colleges of pharmacy to provide education to health care providers on how to create quality content for medication education on social media‐based platforms. Further research is needed to evaluate the credibility of content.

12467 Ethical Challenges During Medication Scarcity

Abstract Disclosure: K. Seetharaman: None. R. Alvi: None. V. Roth: None. J. Maheswaran: None. Ethical considerations while rationing GLP-1 RA during medication scarcity crisis: The prevalence of type 2 diabetes and obesity have risen over the past decade. Type 2 diabetes affects nearly 29 million Americans, and one in 3 Americans are obese. Prompt treatment of type 2 diabetes can result in prevention and progression of several diabetes related complications. In the past 3 decades, advancements in scientific research has led to invention of newer therapeutic agents such as the glucagon like peptide-1 receptor agonist (GLP-1 RA) for management of type 2 diabetes and these medications have shown to provide cardiovascular benefit and renal protective effects. More recently, with increasing benefits of GLP-1 RA in treating obesity even in the absence of diabetes, the prescription rates of GLP-1 RA has increased sharply leading to acute medication scarcity and the resultant crisis has created a chaos in health care having multi-faceted repercussions.We present a short movie enacting 2 clinical scenarios with doctor and patients to initiate discussions on how to ration GLP-1 receptor agonists during times of medication scarcity crisis and the bioethical aspects to consider while making such decisions. We further include discussions by enacting pharmacy care coordinator, bioethicist, critique and defense discussion. Bioethics involved in medication scarcity crisis:https://hu-my.sharepoint.com/:v:/g/personal/kseetharaman_hsph_harvard_edu/EZIHpFRCgb5AsoKLk898TgUBsdp8JNjdAGQ6vOIpZIP1Qg?e=TkxRhz We hope our enacting of various scenarios has given you all valuable ethical perspectives to consider while rationing during times of medicine scarcity.

Rates of repeat EGD in nondiabetic adults with glucagon-like peptide-1 receptor agonist prescription: a retrospective matched cohort study

Background and aimsData on endoscopic outcomes in adults without diabetes who are taking glucagon like peptide receptor agonist (GLP-1 RA) is limited so we aimed to compare repeat esophagogastroduodenoscopy (EGD) in this population to those without GLP-1 using retrospective matched case-control study. MethodsUsing TriNetX (Cambridge, MA), adults with BMI of ≥27 kg/m2 without diabetes who underwent diagnostic EGD were analyzed. Study group included individuals with ≥3 GLP-1 prescriptions and EGD ≥30 days after initial GLP-1 prescription. Control group was never prescribed GLP-1 RAs but had EGD after prescription of other weight loss medications. Outcomes were compared using risk-ratio in matched cohorts. ResultNo significant difference in repeat EGD (5.4% vs 4.2%, RR 1.28, 0.95–1.71) or new diagnosis of gastroparesis (1.1% vs 0.6%, RR 2.00, 0.94–4.27) was noted between the groups. ConclusionGLP-1 RAs may not substantially increase the risk of repeat endoscopy in individuals without diabetes.

The blood pressure-lowering property of subcutaneous semaglutide: a systematic review, meta-analysis, and meta-regression.

Semaglutide is a glucagon-like peptide (GLP1) receptor agonist with unprecedented weight-lowering and anti-hyperglycemic properties. Recent clinical trials reported that subcutaneous semaglutide can modulate blood pressure; however, its effect on blood pressure widely varied in different studies and different subgroups of patients. PubMed, Web of Science, Scopus, and the Cochrane Library were systematically searched from the inception to July 18, 2024. Due to high heterogeneity, a random-effects model was adopted to pool data. Twenty clinical trials with 15,312 participants in the placebo group and 18,231 participants in the semaglutide group were included in this study. Subcutaneous semaglutide significantly decreased both systolic (WMD - 3.71 mmHg, 95% CI (-4.29, -3.13), I2: 50.2%) and diastolic (WMD - 1.10 mmHg, 95% CI (-1.58, -0.63), I2: 69.7%) blood pressure. Subgroup analyses indicated that the blood pressure-lowering property of subcutaneous semaglutide was greater among patients without diabetes, with lower baseline hemoglobin A1c (HbA1c), baseline body mass index (BMI) greater than 35kg/m2, dose of semaglutide more than 1mg/week, baseline systolic blood pressure equal or less than 130 mmHg, weight loss greater than 10kg, and BMI reduction greater than 3kg/m2. In addition, a treatment length of 50 to 100 weeks was associated with greater blood pressure-lowering effects in subgroup analysis. After adjusting for other factors, meta-regression revealed that placebo-adjusted weight change was independently correlated with the effect of semaglutide on systolic and diastolic blood pressure. Subcutaneous semaglutide can significantly decrease systolic and diastolic blood pressure, particularly in selected groups of patients.

GLP-1 and GIP analogues in the treatment of obesity

Obesity is a chronic disease and a significant public health problem. It is estimated that more than 650 million adults, 340 million adolescents, and 39 million children are obese. Obesity leads to organ complications including type 2 diabetes, hypertension and heart diseases. The management of obesity is based on nutritional therapy combined with lifestyle changes and increased physical activity. Pharmacotherapy is also crucial, and incretin analogues are a relatively new group of drugs. Glucose-independent insulinotropic peptide and glucagon-like peptide-1 are natural incretins. These short half-life hormones are degraded by the enzyme dipeptidyl peptidase-4. Glucose-independent insulinotropic peptide and glucagon-like peptide-1 receptor agonists increase blood glucose-dependent insulin secretion while inhibiting glucagon secretion and delaying gastric emptying, thus enabling the treatment of both type 2 diabetes and obesity. Glucagon-like peptide-1 also exhibits cardioprotective and neuroprotective effects. This study aimed to review the literature on the use of glucagon-like peptide-1 analogues and verify reports on the use of glucose-dependent insulinotropic polypeptide for weight reduction. An analysis of the available literature on the efficacy and safety of liraglutide, semaglutide and tirzepatide was conducted. The potential role of these drugs in weight reduction and possible adverse effects are discussed. Attention was also paid to the pharmacokinetics of the drugs and the mechanism of incretin action in the body.

Management of early onset obesity due to melanocortin 4 receptor (MC4R) defect with glucagon- like -peptide receptor agonist

Management of early onset obesity due to melanocortin 4 receptor (MC4R) defect with glucagon- like -peptide receptor agonist

Real-World Impact of GLP-1 Receptor Agonists on Endoscopic Patient Outcomes in an Ambulatory Setting: A Retrospective Study at a Large Tertiary Center.

Background: Glucagon-like peptide receptor agonists (GLP-1 RAs) are associated with delayed gastric emptying and may increase the risk of aspiration due to retained gastric contents. There are no guidelines on peri-endoscopic use of GLP-1 RAs, and real-world outcomes in an ambulatory setting remain unknown. This study reports real-world data from an ambulatory center associated with a large tertiary hospital. Methods: A retrospective review of electronic medical records was conducted for patients who underwent esophagogastroduodenoscopy (EGD) at a hospital-based outpatient center from January to June 2023. Exclusions included non-elective procedures, current opioid use, altered foregut anatomy, and known gastroparesis. All patients were on GLP-1 RAs before endoscopy and followed standard fasting protocols. Adverse event rates were recorded, and patients were divided into cohorts based on GLP-1 RA use. Univariate and multivariate regression analyses identified risk factors for food retention and complications. Results: A total of 1438 patients underwent elective EGD during the study period. Among the 1046 patients included, 73 (7%) were on GLP-1 RAs. The procedure was aborted in four patients (0.4%) due to gastric food retention, with two (50%) on GLP-1 RAs. Independent risk factors for food retention included GLP-1 RA use (OR: 9.19; 95% CI: 2.73-30.8; p = 0.0003) and diabetes (OR 5.6; 95% CI: 1.72-18.2; p = 0.004). Tirzepatide showed the strongest association (p = 0.0056). Factors that did not impact food retention included A1c, BMI, and gender. Protective factors were age (OR 0.96; 95% CI: 0.93-0.99; p = 0.02) and same-day colonoscopy (OR 0.18; 95% CI: 0.06-0.58; p = 0.003). Conclusions: GLP-1 RA use in diabetics increases the risk of retained gastric contents during elective EGD, particularly with tirzepatide, without increasing aspiration risk. Patients undergoing simultaneous colonoscopy had a lower risk of retained gastric contents. Further studies are needed to evaluate the impact of GLP-1 RAs on gastric food retention and procedural risk.

Real-world evaluation of the effects of tirzepatide in patients with type 2 diabetes mellitus.

Tirzepatide is a first-in-class combination glucose-dependent insulinotropic polypeptide (GIP) receptor agonist and glucagon-like peptide 1 receptor agonist (GLP1-RA) approved for treatment of adults with type 2 diabetes mellitus (T2DM) and chronic weight management. The aim of this analysis was to assess the real-world efficacy of tirzepatide in patients with T2DM. This retrospective observational study evaluated patients with T2DM from a large urban academic medical centre who received at least 3 months of continuous tirzepatide treatment. The primary outcome was change in A1C from following tirzepatide treatment. Secondary outcomes included change in body weight and body mass index (BMI) after tirzepatide was initiated. A total of 1896 patient charts were reviewed, and 612 patients were evaluated for the primary outcome. Over a median time period of 10.4 months, treatment with tirzepatide resulted in a mean A1C reduction of 1.02 ± 1.48% (p < 0.001). A total of 570 patients were evaluated for the secondary outcomes. Tirzepatide was associated with a mean reduction in body weight of 7.3 ± 9.3 kg (p < 0.001) and a mean reduction in BMI of 2.5 kg/m2. Greater A1C lowering and weight loss was observed in patients without prior GLP1-RA treatment compared to those switched to tirzepatide from GLP1-RA. In a real-world population of US patients with T2DM, tirzepatide was associated with clinically and statistically significant reductions in A1C and body weight. Greater reductions in both A1C and body weight were observed among patients who were GLP1-RA naïve compared to patients switched from GLP1-RA to tirzepatide.

(051) DEGREE OF WEIGHT LOSS IS ASSOCIATED WITH NEW ERECTILE DYSFUNCTION AFTER GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONIST MEDICATION PRESCRIPTION

Abstract Introduction Glucagon-like peptide receptor agonists (GLP-1ra) such as semaglutide are utilized as an adjunctive to metformin in the treatment of type 2 diabetes when concomitant atherosclerotic disease is present. GLP-1ra’s are also commonly used off-label as a weight loss medication for those with obesity. These drugs have seen an exponential increase in use in recent years. Data on the sexual impact of these medications is limited; however, a recent database study demonstrated an increased relative risk of new-onset erectile dysfunction (ED) in nondiabetic obese patients compared to a matched cohort who had not been treated with GLP-1ra’s. It remains unknown what factors may predict the development of ED after starting these medications. Objective To determine which factors may be associated with a new diagnosis of erectile dysfunction in nondiabetic patients after starting a GLP-1ra. Methods We retrospectively reviewed nondiabetic male patients seen at a large, tertiary care center who had been started on GLP-1ra medications for the indication of being overweight or obese from 2019-2024. We compared those who were on the medication for at least one year with subsequent new diagnosis of erectile dysfunction to a cohort matched for prescription length without diagnosis of ED. Patients were excluded if they had any prior diagnosis of erectile dysfunction or had not been on the medication for at least 1 year. Age, BMI at GLP-1ra start, change in BMI%, and history of hypertension (HTN), hyperlipidemia (HLD), coronary artery disease (CAD), and testosterone deficiency were compared between groups. Multivariable logistic regression for independent prediction of new onset ED was also performed with age, change in BMI%, and history of HTN or HLD as covariates. Results 4037 patients met inclusion criteria. A total of 50 patients (1.24%) developed new-onset ED during the study period while 3987 (98.76%) had no new diagnosis of ED. Those who developed ED were older (58.78 (±11.52) vs 53.95 (±13.71), p = 0.005) when compared to the non-ED cohort on unadjusted analysis. Patients were relatively matched on baseline comorbidities, although HTN occurred more frequently in the ED group (74% vs 52.1%, p = 0.002) (Table 1). On multivariable analysis, change in BMI % was independently associated with new onset ED (aOR 1.027, 95%CI 1.0268– 1.0272, p &amp;lt; 0.0001), signifying that less drop in BMI had higher odds of new onset ED (Table 2). When controlling for age and history of HTN or HLD, initial BMI was not associated with new onset ED (Table 3). Conclusions Older patients and those with a history of HTN may be at higher risk of new-onset ED when starting on GLP-1ra’s for weight loss. Those who experience less weight loss when starting these medications may be at risk for new onset ED irrespective of age, underlying comorbidities, or initial BMI. Further studies are needed to validate these results in a prospective multicentric setting. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Coloplast Corporation; Boston Scientific.

Real world study of GLP-1 receptor agonists in overweight or obese type 2 diabetes by using repeated measurement analysis of variance.

To investigate the safety and efficacy of long-acting glucagon like peptide-1 receptor agonists in overweight or obese patients with type 2 diabetes. Overweight or obese patients with type 2 diabetes from July 2021 to June 2022 were randomly divided into control group (metformin) and experimental group (metformin + dulaglitide or semaglutide). Repeated measures analysis of variance was used to compare Hemoglobin A1c, fasting plasma glucose and body mass index (BMI) of patients before treatment, 6 months and 12 months after treatment. The adverse reactions of patients before treatment and 12 months after treatment were analyzed. The time effect of Hemoglobin A1c, fasting plasma glucose and BMI in the control group (n = 35) and the experimental group (n = 32) were statistically significant (P < .001), and the intergroup effect of BMI was statistically significant (P < .05). The interaction effect of BMI was statistically significant (P < .001). The BMI level of the experimental group was lower than that of the control group at 6 and 12 months after treatment (P < .001). There was no significant difference in the incidence of adverse reactions between the 2 groups (P > .05). Long-acting glucagon like peptide-1 receptor agonists, such as dulaglitide and semaglutide, not only reduce glycosylated hemoglobin levels, but also significantly improve BMI in overweight or obese patients with type 2 diabetes.