Glucagon-like Peptide-1 Receptor Research Articles

Abstract 4145802: Association between Glucagon-like peptide-1 receptor agonists and risk of Arrhythmias or Heart Failure among patients with Type 2 Diabetes: A Meta-Analysis of 29 Randomized Controlled Trials.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a reduction in major adverse cardiovascular events (MACE) among patients with type 2 diabetes mellitus (T2DM). However, their effect on reducing the risk of incidence of arrhythmias and heart failure has not been established, and there is very limited literature to date. Objective: We evaluated the effect of GLP-1 RAs on the incidence of arrhythmias and heart failure among patients with T2DM. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that enrolled patients with type 2 diabetes and compared GLP-1 RAs and control groups. PubMed and ClinicalTrials.gov were systematically searched from inspection till May 2024 without any language restrictions. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using a random-effect model. Results: A total of 29 RCTs with 72,868 patients (35,631 in the GLP-1 RA group and 37,237 in the control group) were included in the analysis. Pooled analysis showed that there is no significant association between GLP-1 RAs and incidence of atrial fibrillation (OR, 0.94(95%CI: 0.75-1.18), P=0.60), atrial flutter (OR, 0.87(95%CI: 0.60-1.26), P=0.46), cardiac arrest (OR, 0.79(95%CI: 0.51-1.23), P=0.30), ventricular tachycardia (OR, 1.37(95%CI: 0.90-2.07), P=0.14), and ventricular fibrillation (OR, 0.91 (95%CI: 0.45-1.84), P=0.80) when compared with control group. However, GLP-RAs reduced the incidence of atrioventricular block complete (OR, 0.58 (95%CI: 0.35-0.97), P=0.04), and heart failure (OR, 0.795 (95%CI: 0.634-0.997), P=0.047). Conclusion: This study shows that GLP-1 RAs reduced the incidence of atrioventricular block complete and incidence of heart failure. However, no significant association has been observed for arrhythmias.

Abstract 4134267: Effects of GLP-1 Receptor Agonists and SGLT2 Inhibitors on In-Hospital Mortality and 30-Day Readmission in Type 2 Diabetic Patients with Acute Coronary Syndrome

Background: The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2is) on reducing cardiovascular events in heart failure patients are well-established; however, less is known about their effects after a myocardial infarction. This study aims to investigate the effects of GLP-1RAs and SGLT2is on in-hospital mortality and 30-day readmission in type 2 diabetic patients with/without heart failure who were hospitalized for acute coronary syndrome (ACS). Methods: We conducted a multicenter retrospective cohort on type 2 diabetic patients who were admitted to the hospital for ACS from 01/01/2020 to 01/31/2024 across 16 West Florida hospitals. Patients receiving a GLP-1RA alone, SGLT2i alone, or both were compared to those taking neither. Chi-square and binary logistic regression were used to predict the clinical outcomes of in-hospital mortality, all-cause readmission within 30 days, and cardiac readmission within 30 days. Results: Among 7,481 type 2 diabetics with ACS, 392 (5.24%) were taking GLP-1RA monotherapy, 577 (7.71%) were taking SGLT2i monotherapy, 144 (1.92%) were taking both, and 6,362 (85.12%) were taking neither. The likelihood of in-hospital mortality was similar among patients on neither medication compared to patients on both (χ 2 = 0.06, p = 0.802), GLP-1RA monotherapy (χ 2 = 0.61, p = 0.435), and SGLT2i monotherapy (χ 2 = 0.002, p = 0.968). The odds of all-cause readmission within 30 days was similar among patients on neither medication compared to patients on both (χ 2 = 0.0004, p = 0.983), GLP-1RAs monotherapy (χ 2 = 0.07, p = 0.791), and SGLT2i monotherapy (χ 2 = 3.10, p = 0.078). The likelihood of cardiac readmission within 30 days was similar among patients on neither medication compared to patients on both medications (χ 2 = 1.63, p = 0.202), GLP-1RA monotherapy (χ 2 = 0.95, p = 0.329), and SGLT2i monotherapy (χ 2 = 0.94, p = 0.332). Conclusion: Our study found no significant differences in the odds of in-hospital mortality or 30-day readmission among type 2 diabetics with ACS who were taking GLP-1RAs, SGLT2is, or both, when compared to those taking neither. These findings further support the outcomes discovered in the EMPACT-MI trial.

Abstract 4135846: Cardiovascular Effectiveness of Glucagon-like Peptide-1 Receptor Agonists and Empagliflozin Combination Therapy in Adults with Type 2 Diabetes

Introduction/Background: Both empagliflozin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular (CV) benefits in clinical trials. However, few trials examined the combination of both therapies and evidence is scarce on whether the addition of empagliflozin to GLP-1RA has further CV benefits. Aim/Goal: We evaluated the risk of CV outcomes in patients with type 2 diabetes (T2D) initiating baseline GLP-1RA therapy that added empagliflozin compared to those that added sulfonylureas (SU). Methods: Using Medicare, Optum, and Marketscan data (2014-22), we identified patients with T2D aged ≥18 years initiating GLP-1RA that subsequently added either empagliflozin or SU. Follow-up began on the date of additional therapy and continued until discontinuation of either drug, a gap in insurance coverage, death, or study end. After propensity score standardized mortality ratio weighting adjusting for 98 covariates, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years evaluating a composite of myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), or all-cause death in the overall population and in patients with history of CV disease. Results: We identified 27,962 patients initiating GLP-1RA + empagliflozin vs 25,137 patients initiating GLP-1RA + SU. After weighting, relative to patients initiating GLP-1RA + SU, those initiating GLP-1RA + empagliflozin had lower risks of MI-stroke [HR 0.70 (0.55, 0.90); RD: -4.3 (-6.6, -2.0)], HHF in the primary hospital discharge position [HR: 0.59 (0.43, 0.81); RD: -3.9 (-5.8, -2.1)]; HHF in any discharge positions [HR: 0.84 (0.72, 0.98); RD: -7.6 (-11.6, -3.6)], and all-cause death [HR: 0.83 (0.62, 1.11); RD: -1.3 (-3.2, 0.56)]. Findings were similar but with larger RDs in patients with baseline CV disease ( Table ). Conclusion: In US clinical practice, patients with T2D initiating GLP-1RA that added empagliflozin had lower risks of MI-stroke, HHF, and death compared to adding SU, which suggests an additive CV benefit when combining GLP-1RA and empagliflozin therapies.

Abstract 4143220: Racial Differences in Prescription of SGLT2 Inhibitors and GLP1 Receptor Agonists Among US Veterans with Type 2 Diabetes and Coronary Artery Disease

Background: Clinical trials have demonstrated that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) reduce cardiovascular (CV) risk in patients (pts) with type 2 diabetes (T2D) with or at high risk for CV disease. Adoption of new therapies has often lagged for Black pts compared with non-Hispanic White pts, contributing to poorer health outcomes. Methods: We identified Veterans with T2D and angiographic CAD between 2015 and 2020 at 84 Veterans Affairs (VA) medical centers who met eligibility criteria for the EMPA-REG OUTCOME or LEADER trials that first established the clinical efficacy of SGLT2i and GLP1RA, respectively. Within each cohort (SGLT2i- and GLP1RA-eligible), we used multivariable logistic regression adjusted for demographic and clinical covariates to estimate associations of race with evidence-based drug prescription. We evaluated patterns of evidence-based prescription of SGLT2i and GLP1RA over time and by race in US Veterans with T2D and coronary artery disease (CAD). Results: Of 63,561 pts with T2D and CAD, 3,527 Black and 18,668 White pts met trial eligibility criteria for SGLT2i treatment and 2,020 Black and 10,103 White pts for GLP1RA treatment. Evidence-based prescription of both classes increased over time for both races ( Figure ) but reached only approximately 40% for SGLT2i and 15% for GLP1RA in 2023. For SGLT2i, race (Black/White) was not associated with evidence-based prescription (adjusted odds ratio [OR] 0.96, 95% CI 0.89-1.04, P=0.3). However, Black pts were less likely than White pts to receive evidence-based prescription of GLP1RA (adjusted OR 0.85, 95% CI 0.74-0.98, P=0.025). Conclusions: Among pts with T2D and CAD in the VA healthcare system, evidence-based prescription of SGLT2i and GLP1RA increased over time, but many eligible pts remained untreated. Prescription of SGLT2i did not differ by race, but Black pts were less likely than White pts to have evidence-based prescription of a GLP1RA. Disparities in evidence-based use of CV treatments may be specific to certain drug classes, even in a healthcare system with few economic barriers. Further investigation is needed to determine underlying causes and solutions for such disparities.

Abstract 4129733: Glucagon-like Peptide 1 Receptor Agonists Effect on Low-Density Lipoprotein Cholesterol and Total Cholesterol Levels Independent of Weight Reduction: A Meta-analysis and Meta-regression of Placebo-controlled Randomized Controlled Trials

Background: The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on lipid components is unclear. The objective of this study was to measure the lipid-lowering effect of GLP-1RAs. Methods: A thorough database search was performed to identify placebo-controlled randomized controlled trials (RCTs) on GLP-1RA therapy through January 2023. From these trials, data was extracted and a robust statistical analysis was performed using a random effects model to determine outcomes with weighted mean difference (MD) in milligrams per deciliter (mg/dL) and 95% confidence intervals (CIs). The primary outcome was the mean difference in low-density lipoprotein cholesterol (LDL-C). Secondary outcomes were mean differences in total cholesterol (TC), triglycerides, high-density lipoprotein-C (HLD-C), and very low-density lipoprotein-C (VLDL-C). To account for covariates, subgroup analyses and meta-regression were performed. Results: A total of 33 studies were included in the final meta-analysis carried out between 2008 and 2023, which were conducted in 26 countries. Of the 5,918 participants, the study population comprised 2,603 (44%) males and 3,315 (56%) females, aged between 33.7 and 65.9 years. GLP-1RAs significantly reduced LDL-C compared to placebo (MD -2.93, 95% CI (-5.01, -0.85), P=0.01). Treatment effect was consistent regardless of duration of treatment;12 weeks or less MD: -5.39, 95% CI (-10.36, -0.42), P=0.03 vs >12 weeks MD: -2.39, 95% CI (-4.70, -0.007), P=0.04, P interaction 0.28). In our analysis, GLP-1RA reduced TC by ~7 mg/dl. There was no significant reduction in triglycerides (MD = -7.19, 95% CI (- 15.01, 0.62], P=0.07) and VLDL-C ~4 mg/dl (MD = -3.99, 95%, CI (-8.73, 0.75), P=0.10). Furthermore, GLP-1RA did not increase HDL-C (MD = -0.12, 95% CI (-0.73, 0.49], P=0.69. Regression analysis determined that weight loss did not affect the treatment effect on LDL-C (tau2=28.38, I2=99.83, R2=0.0, p=0.67), and total cholesterol (tau2=93.6, I2=99.86, R2=0.0, p=0.92). Conclusion: Patients on GLP-1RA experienced modest LDL-C and TC lowering compared to placebo. GLP-1RA did not decrease triglycerides and VLDL-C. GLP-1RA did not increase HDL-C.

Unlocking the potential of glucagon-like peptide-1 receptor agonists in revolutionizing type 2 diabetes management: a comprehensive review.

Diabetes mellitus (DM) is a long-term metabolic disorder caused by inadequate production and resistance to insulin. The prevalence of DM is rapidly increasing, with type 2 diabetes (T2D) accounting for more than 90% of cases. Despite new treatments, many patients with T2D do not meet their glycemic targets due to clinical inertia. This review provides an overview of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the management of T2D. The review synthesizes data from clinical trials and meta-analyses on the efficacy, safety, and cost-effectiveness of GLP-1 RAs. It also discusses the mechanisms of action, classification, and barriers to adherence and persistence in therapy. GLP-1 RAs improve glycemic control by lowering A1C levels and promoting weight loss. They have cardioprotective effects and may reduce endothelial inflammation, oxidative stress, and blood pressure. Adherence to GLP-1 RAs is better with once-weekly injections, though gastrointestinal side effects and cost can affect persistence. Semaglutide and liraglutide have shown significant weight reduction, with semaglutide being particularly effective. GLP-1 RAs are cost-effective due to reduced healthcare costs associated with fewer hospitalizations and lower mortality rates. Safety concerns include gastrointestinal issues, pancreatitis, and rare cases of diabetic retinopathy and thyroid C-cell tumors. For clinical practice, GLP-1 RAs represent a valuable option not only for glycemic control but also for weight management and cardiovascular protection. Incorporating GLP-1 RAs into treatment plans can improve patient outcomes, and optimizing dosing regimens and addressing barriers such as cost and side effects are crucial to enhancing patient adherence and long-term treatment success.

Abstract 4138604: Impact of GLP-1 Agonist on the Incidence of Atrial Fibrillation in Obese Patients Following Heart Failure Hospitalization

Introduction: Atrial fibrillation (AF) in patients with heart failure (HF) is associated with increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) agonists have been shown to reduce cardiovascular risk in patients with obesity and diabetes, respectively. Meta-analysis of prospective trials looking at GLP-1 agonist use on the incidence of AF suggest benefit in patients with diabetes but is of unclear benefit in this regard for patients with obesity. Hypothesis: GLP-1 agonists reduce atrial fibrillation incidence in patients with diabetes and obesity. Aims: The goal of the study is to assess the effects of GLP-1 agonist on incidence of new AF in patients with obesity and diabetes following heart failure hospitalization. Methods: The study included consecutive patients who were admitted to an academic tertiary care center over three years with a primary diagnosis of heart failure exacerbation and no prior diagnosis of AF. The primary outcome was incidence of AF within 12 months after hospitalization. Demographic, comorbidity, echocardiography, and medications were obtained. Cox-regression analysis was performed to identify the predictors of new-onset AF following HF hospitalization. Results: Of the patients included in our study, 1668 (42.9%) have a BMI greater than or equal to 30, 574 (14.5%) have BMI greater than or equal to 40, and 2300 (58.2%) have diabetes mellitus. GLP-1 use is associated with a significantly lower incidence of AF at one year in obese patients (p=0.042; RR 0.73; 95% CI: 0.54-.99) (Figure), while in non-obese individuals, GLP-1 receptor agonist was not associated with a decreased incidence of AF (p=0.674; RR 1.08; 95% CI: 0.76-1.53). In patients with diabetes, GLP-1 receptor agonist use did not reach statistical significance for reduced AF incidence following heart failure hospitalization ( p=0.091; RR 0.80; 95% CI 0.62-1.04 ). Conclusion: GLP-1 receptor agonist use is associated with a statistically significant reduction of incidence of new atrial fibrillation at one year following hospitalization for heart failure in obese patients.

Overview of diabetes agents in cardiovascular disease: it takes an orchestra to play Tchaikovsky in symphony

Purpose of review The aim of this review was to discuss the use and concerns of diabetes agents, clinical targets, and key aspects to be considered in the management of patients with type 2 diabetes mellitus (T2DM), and at high risk or established cardiovascular disease (CVD). Recent findings The recent European and American guidelines recommended SGLT2 inhibitors and GLP-1 receptor agonists as the preferred first-line diabetes agents in patients with T2DM and CVD. This is a paradigm shift from using metformin as first-line therapy. Amid their widespread use, however, there are also concerns about their side effects. With the rapidly growing diabetes regimens available, questions arise about how best to approach the management of patients with T2DM and CVD. Summary To reduce CVD morbidity and mortality in patients with T2DM and at high or very high risk for CVD, the two key diabetes agents SGLT2i and/or GLP1-based therapies should be offered. Although lacking cardiovascular benefit, other diabetes agents remain necessary for many patients with T2DM for their glucocentric effects; Metformin and pioglitazone are useful in severe insulin resistance, while insulin therapy is often necessary in advanced diabetes; GLP1-RA is cautioned in patients with active gastrointestinal and mental health conditions, while DPP4 inhibitor is likely a well tolerated option in a challenging psychosocial setting. Other important aspects that should be considered include obesity, chronic kidney disease, women's cardiovascular health, and psychosocial factors.

Abstract 4141434: Real-World Improvement of Cardiometabolic Risk Factors by Treating Obesity at Scale

Intro: Obesity is a critical risk factor for cardiometabolic disease. A growing body of clinical trial data shows GLP-1 receptor agonist medications (GLP-1s) are not only effective in treating obesity but also demonstrate significant impact on the reduction of cardiovascular risk. Yet current models of care have not been able to reach the >200 million Americans who meet criteria for obesity treatment. To improve access to evidence-based treatment, we established a virtual metabolic health company to provide medically-supervised obesity treatment at scale. Research Question: This real-world evaluation examines the impact of a virtual health program on weight and related cardiometabolic markers. Methods: Data were analyzed for individuals who completed at least 12 months (mos) in the core program and for a subset who continued to 24 mos. Obesity treatment involved GLP-1s combined with a proprietary intensive lifestyle intervention delivered with virtual coaching. Weights were submitted via cellular connected scale. Waist circumference, metabolic labs, and patient-completed surveys were analyzed at baseline and 12 mos. Results: The cohort included 6,766 patients, a subset with structured lab data from a larger population of 16,098 patients who had completed 12 mos in the commercial program. Average weight loss at 12 mos was -16.5% (n=5,932) and -17.8% at 24 os (n=1,171). Improvement was observed for all collected metabolic markers: waist circumference, AST/ALT, lipids, HbA1c, insulin, hs-CRP. Specifically for cardiovascular labs, 12 mos results showed improvement in HDL in 56.3% (n= 3,090), in LDL for 64.8% (n=3,066), in hs-CRP for 82.9% (n=2,446). Of n=825 with abnormal A1c at baseline, 77.1% achieve A1c <5.7%. Average reduction in waist circumference was -5.9 inches (n=3,682). Positive changes were also seen for patient-reported outcomes (PROs). Discussion: In the context of significant obesity and cardiovascular results for GLP-1s in clinical trials, it is important to gather data on the efficacy of approaches to scale treatment in the real world since factors such as medication shortages, gaps in insurance coverage, and challenges with adherence occur with treatment outside of clinical trials. Results from 6,766 patients in a virtual metabolic health program available in 50 states and DC demonstrate clinically significant and sustained weight loss through 24 mos, with improvement in associated key cardiometabolic risk markers, health behaviors, and PROs.

Abstract 4135582: Sociodemographic Trends in Diabetes Medications after Metformin: the BESTMED (oBservational Evaluation of Second line Therapy MEdications in Diabetes) Study

Objective: Though updated American Diabetes Association (ADA) guidelines recommend initiating GLP1 receptor agonists (GLP1) or SGLT2 inhibitors (SGLT2i) for persons with type 2 diabetes mellitus (PWT2DM) with high CV risk, metformin was previously recommended as 1st-line treatment. For PWT2DM at moderate CV risk, it is unknown which 2nd-line drug optimizes CV outcomes. Our multicenter observational study describes US-wide trends in 2nd-line T2DM medication use (DPP4 inhibitors [DPP4i], GLP1s, SGLT2i and sulfonylureas [SU]) overall and in key sociodemographic subgroups between 2014-2023. Methods: This is a secondary analysis of the oBservational Evaluation of Second line Therapy Medications in Diabetes (BESTMED) study, which used a new-user design to evaluate associations between 2nd-line medications and CV events in PWT2DM at moderate CV risk. The database comprised EHRs and insurance claims for 75,224 PWT2DM from 10 health systems and 2 insurance plans on metformin who initiated a 2nd medication from 1/2013 to 1/2023. Data were obtained from orders or prescription fills. Prescription class was regressed on calendar time via multinomial logistic regression to model trends in prescribing patterns, adjusted for sociodemographic variables. Subgroup analyses were performed by adjustment factors; CIs and p-values for differences were calculated via nonparametric bootstrap (B=200). Due to large sample size, statistical significance was interpreted at p<0.05 and annual rate of change >0.5%. Results: We included 75,224 T2DM adults (median A1c 7.8%), of whom 18%,17%, 18%, and 47% initiated DPP4i, GLP1, SGLT2i, SU respectively. From 2014 - 2023, SGLT2i and GLP1 increased: 5.7 to 28.8%, and 3.5 to 30.3%, and DPP4i and SUs decreased: 25.3 to 11.6%, and 65.6 to 29.3%, respectively. Annual rate of change for SGLT2i was higher in men(3.0% vs 2.1%/year; p<0.001) and in > 65 y (3.0% vs 2.4%; p<0.001), and for GLP1s was higher in those <65 y (3.6% vs 2.1%; p<0.001), women (3.5% vs 2.5%; p<0.001), Hispanic ethnicity (3.2% vs 2.7%; p=0.005), and with class II/III obesity (4.1% versus 2.6% per year; p<0.001). There was no evidence that these trends differed by race, insurance, or SDI. Conclusion: In this nationwide study of prescribing patterns PWT2DM at moderate CV risk, prevalences of 2nd-line T2DM therapies are approaching current ADA guidelines for initial therapy for those at high CV risk. Differences between sociodemographic groups appear aligned with clinical expectations.

Abstract 4133830: Uncovering the Gaps: Analyzing Prescribing Patterns of Combination Therapy with SGLT2-inhibitors and GLP-1 Receptor Agonists in Established Atherosclerotic Cardiovascular Disease (ASCVD) and Type 2 Diabetes (T2DM)

Introduction: Combination therapy with SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1RA) reduces major cardiovascular events (MACE) and improves HbA1c, blood pressure, weight, and renal disease progression. The European Society of Cardiology recommends this therapy for ASCVD and T2DM, independent of HbA1c. This study evaluates prescribing patterns in the Internal Medicine Residency Clinics for patients with ASCVD and T2DM. Aims: To investigate demographic and social determinants of health (SDOH) influencing the prescription of combination therapy versus no therapy in an outpatient population and identify factors affecting prescribing patterns and guideline adherence. Methods: We reviewed 828 electronic records of T2DM and ASCVD patients from March 2024. Patients were grouped into combination therapy (SGLT2i and GLP1RA) and no therapy groups. Data on demographics (Table 1) and SDOH (Table 2) were analyzed. Patients on monotherapy or those who did not complete the SDOH questionnaire were excluded. Descriptive statistics were used to summarize demographics. Welch’s t-test compared continuous variables, and chi-square or Fisher’s exact tests compared categorical variables. Analyses were done with SAS 9.4 with significance at 0.05. Results: Age significantly differed between groups (t = 4.56, p < .05), with older patients less likely to receive therapy. Sex was also significant (p < .05); more females were in the no therapy group. No significant association was found between SDOH and combination therapy (p > .05). Conclusion: Over 90% of patients with T2DM and ASCVD were not on optimal medical therapy to reduce MACE, with nearly half on no medications. This highlights the need for increased awareness and targeted interventions to improve outcomes. Future research will explore insurance status and physician awareness to address prescription discrepancies. Limitations: Patients with a GFR <30 are precluded from SGLT2i usage but were not excluded from this study.

Dumping syndrome: Update on pathophysiology, diagnosis, and management.

Dumping syndrome is a complex of gastrointestinal symptoms originally studied in peptic ulcer surgery patients. At present, it is most prevalent in patients who underwent bariatric, upper gastrointestinal cancer or anti-reflux surgery. The symptom pattern comprises early and late dumping symptoms. Several management options have been reported including nutritional, pharmacological and surgical approaches. In this study, we aimed to review the current evidence on dumping syndrome definition, diagnosis and treatment, including preliminary data from newer pharmacological studies. Current pathophysiological concepts and analyses of provocative tests has led to a clear definition of dumping syndrome, including both early and late dumping symptoms. The term postbariatric hypoglycemia represents a limited focus on late dumping only. The diagnosis relies on recognition of symptoms and signs in a patient with appropriate surgical history; and can be confirmed by provocative testing or registration of spontaneous hypoglycemia. The initial treatment focuses on dietary intervention, to which meal viscosity enhancers and/or the glycosidase inhibitor acarbose can be added. The most effective therapy is the use of short- or long-acting somatostatin analogues, which is however expensive and entails side effect issues. In case of refractory hypoglycemia, diazoxide or SGLT2 inhibitors can be considered, based on limited evidence. In refractory patients, continuous enteral feeding or (rarely) surgical reinterventions have been advocated, although not supported by solid evidence. Therapies under current evaluation include the broad-spectrum somatostatin analogue pasireotide, GLP-1 receptor antagonists, GLP-1 receptor agonists and administration of stable forms of glucagon are currently under study. Dumping syndrome is a well-defined but probably under-diagnosed complication of upper gastrointestinal, especially bariatric, and surgeries. Diagnosis is confirmed by a provocative test and incremental therapies starting with diet, adding meal viscosity enhancers or glycosidase inhibitors and adding somatostatin analogues in refractory cases. A number of emerging therapies targeting intestinal propulsion, peptide hormone effects and hypoglycemic events are under evaluation.

Pharmacological management of pediatric metabolic dysfunction-associated steatotic liver disease.

Pediatric obesity, characterized by a body mass index (BMI) at or above the 95th percentile for age, affects a substantial number of children and adolescents worldwide. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, represents a prominent hepatic manifestation of obesity and metabolic syndrome, emerging as the most prevalent hepatic disorder among pediatric patients and a significant contributor to liver transplantation in adults. The escalating prevalence of pediatric MASLD mirrors the alarming rise in childhood obesity rates over recent decades. While lifestyle modifications focusing on dietary changes and increased physical activity constitute the cornerstone of MASLD management, achieving and maintaining significant weight reduction remains challenging. Moreover, disease progression often persists despite standard-of-care interventions, warranting exploration into alternative therapeutic strategies. Pharmacological interventions, particularly, glucagon-like peptide-1 receptor agonists (GLP-1RA), have shown promise in addressing pediatric obesity and its associated comorbidities, including MASLD. Recent studies have demonstrated the efficacy of GLP-1RA in inducing weight loss and improving liver enzyme levels, suggesting a potential role in halting disease progression, and reducing the risk of major adverse liver outcomes. This review provides a comprehensive overview of the current pharmacotherapy landscape for pediatric MASLD, with a focus on novel agents such as GLP-1RA. Furthermore, the manuscript proposes a practical algorithm to assist in integrating GLP-1RA into the clinical management of pediatric patients with obesity and MASLD. Despite promising results, further research is warranted to elucidate the long-term efficacy and safety of GLP-1RA in pediatric populations.

In vivo functional profiling and structural characterisation of the human Glp1r A316T variant.

Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) are a highly effective therapy class for type 2 diabetes (T2D) and obesity, yet there are variable patient responses. Variation in the human Glp1r gene leading to altered receptor structure, signal transduction, and function might be directly linked to variable therapeutic responses in patients. A naturally occurring, low-frequency, gain-of-function missense variant, rs10305492 G>A (A316T), protects against T2D and cardiovascular disease. Here we employ CRISPR/Cas9 technology to generate a humanised knock-in mouse model bearing the homozygous Glp1r A316T substitution. Human Glp1r A316T/A316T mice displayed lower fasting blood glucose levels and improved glucose tolerance, as well as increased plasma insulin levels and improved insulin secretion compared to human Glp1r +/+ littermates, even under metabolic stress. They also exhibited alterations in islet cytoarchitecture and β-cell identity under a high-fat, high-sucrose (HFHS) diet. This was however associated with blunted responses to pharmacological GLP-1RAs in vivo . Further investigations in several rodent and human β-cell models demonstrated that the human Glp1r A316T variant exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Our results are further supported by the cryo-EM analysis and molecular dynamics (MD) simulations of the GLP-1R A316T structure, collectively demonstrating that the A316T Glp1r variant governs basal receptor activity and pharmacological responses to GLP-1R-targeting anti-diabetic therapies, highlighting the importance of the molecular characterisation of human Glp1r variants to predict individual therapy responses.

Tirzepatide – a new hope for type 2 diabetes mellitus and obesity management. A literature review.

INTRODUCTION AND PURPOSE. While obesity and type 2 diabetes mellitus (T2DM) are defined (according to WHO) as civilization diseases we are still searching for the ideal tool to fight them. Recently, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes and weight reduction among obese and overweighted patients. This review evaluates the efficacy and safety of using tirzepatide based on GIP/GLP-1 agonists clinical trials. MATERAILS AND METHODS. Literature available in the PubMeb Database and Google Scholar Databases was reviewed using keywords. RESULTS AND CONCLUSIONS. Tirzepatide is a novel medicine which stands against type 2 diabetes and obesity pandemic. Combining two agonists of GIP and GLP-1 receptors helps decrease glycemic blood levels, HbA1c levels and reducing body weight in more efficient way than the GLP-1 receptor agonists. All these effects have also resulted in minimizing cardiovascular risk which is observed as an improvement in heart failure, hyperlipidemia and hypertension. Beyond that, the recent data present possible positive long-term effect of tirzepatide in such diseases as MAFLD (metabolic associated fatty liver disease) and OSA (obstructive sleep apnea). However, triagonists, achieving a concurrent activation of GLP-1, GIP, and glucagon receptors, normalize body weight in a manner superior to that of monoagonists and dual agonists. Therefore, the triple agonism or other than GIP/GLP-1 combinations could soon represent a new standard for pharmaceutical interventions. KEYWORDS: tirzepatide; obesity; type 2 diabetes; weight reduction; GIP; GLP-1.

A qualitative study of the mental health outcomes in people being treated for obesity and type 2 diabetes with glucagon-like peptide-1 receptor agonists.

Obesity and type 2 diabetes (T2D) are associated with increased rates of mental disorders, particularly depression, anxiety and binge-eating disorder. GLP-1 receptor agonists are a novel class of pharmacological agents for obesity and T2D. We aimed to describe participants' experiences of GLP-1 receptor agonists on their mental health. Qualitative, individual, semi-structured interviews were conducted in nine participants who were prescribed GLP-1 receptor agonists for the treatment of obesity and/or T2D. Mental health status was measured at time of GLP-1 receptor agonist initiation and assessed again at 12-16 weeks when the semi-structured interview took place. Data were analysed using reflexive thematic analysis. Three main themes were generated from the analysis: (1) acceptance of negative side effects for long term physical health benefits; (2) reflections on the diverse impact on mental health; (3) reduced appetite and increased control of eating behaviours. Overall, participants with obesity and/or T2D described a positive impact of GLP-1 receptor agonists on their mental health, especially perception of improved control of eating behaviours. This suggests GLP-1 receptor agonists should be further studied for their potential effectiveness for treatment of binge-eating disorder.

Glucagon-Like Peptide-1 Receptor-Targeted PET/CT With 68 Ga-HBED-CC-Exendin-4 in Localizing Insulinoma : A Head-to-Head Comparison to 68 Ga-NOTA-Exendin-4.

Modifying glucagon-like peptide-1 receptor (GLP-1R)-targeted PET agent to achieve faster renal clearance and preserved high affinity to GLP-1R is clinically relevant. The aim of this study is to assess the performance of a newly developed GLP-1R-targeted agent, 68 Ga-HBED-CC-exendin-4 in localizing insulinoma, and its biodistribution, as compared with previously introduced 68 Ga-NOTA-exendin-4. Nineteen patients with endogenous hyperinsulinemic hypoglycemia were enrolled and referred for 68 Ga-HBED-CC-exendin-4 PET/CT and 68 Ga-NOTA-exendin-4 PET/CT within 2 consecutive days. Diagnostic performance of the 2 tracers in localizing insulinoma was evaluated, and SUV of the lesion, normal pancreas background, kidneys, and bladder were measured. 68 Ga-HBED-CC-exendin-4 and 68 Ga-NOTA-exendin-4 PET/CT exhibited an equivalent efficacy in detection rate (both sensitivity of 100%). Although SUV max of the tumor in 68 Ga-HBED-CC-exendin-4 was significantly lower than that in 68 Ga-NOTA-exendin-4 (20.01 ± 9.41 vs 31.78 ± 15.46, P < 0.001) at 50 minutes postinjection, there was no significant difference in the tumor-to-background ratio between the 2 agents (8.61 ± 3.57 vs 8.18 ± 3.38, P = 0.326), and the lesions could be visible as early as 4 minutes postinjection for both agents in patients who underwent dynamic PET/CT. In addition, 68 Ga-HBED-CC-exendin-4 exhibited approximately 30% decrease of the renal accumulation compared with 68 Ga-NOTA-exendin-4 (SUV mean , 42.21 ± 5.79 vs 58.58 ± 10.06 at 50 minutes, P < 0.001). 68 Ga-HBED-CC-exendin-4 is an effective agent for localizing insulinoma showing similar detectability and tumor-to-background ratio compared with 68 Ga-NOTA-exendin-4. Notably, 68 Ga-HBED-CC-exendin-4 exhibits significantly lower renal uptake than 68 Ga-NOTA-exendin-4, which might potentially benefit the detection of the tumors adjacent to the left kidneys.

High dose of liraglutide impairs renal function in female hypertensive rats.

Glucagon-like peptide-1 (GLP-1) receptor agonists exhibit beneficial cardiovascular effects. However, the renal effects of different doses of liraglutide in an essential hypertension model have not yet been investigated. SHR female rats were treated for 30 days, twice a day, with saline (control) or liraglutide at low (0.06 mg/kg, LL) and high (0.6 mg/kg, LH) doses. Volume intake and excretion were monitored for a period of 24h. In renal tissue, nitrite-NO2-, nitrate-NO3-, advanced protein oxidation products-AOPP, collagen deposition, creatinine (Cr), urea (U), sodium, and potassium were analyzed. liraglutide reduced body weight gain in both groups. However, in the high dose, it increased urinary volume excretion and sodium/potassium ratio. Both doses reduced the urinary U/Cr ratio and LH increased the serum U/Cr ratio. AOPP was reduced only in LL. LH augmented collagen and early markers of kidney injury (blood urea nitrogen-BUN, BUN/Cr). LH increased NO3-, reduced NO2-, and caused an aberrant increase in GFR. Both doses' effects were independent of blood pressure and glycemic control. liraglutide appears to have distinct effects on the hypertensive female kidney depending on the dose, with higher doses impairing kidney function.

Consensus Report on Glucagon-Like Peptide-1 Receptor Agonists as Adjunctive Treatment for Individuals With Type 1 Diabetes Using an Automated Insulin Delivery System.

With increasing prevalence of obesity and cardiovascular diseases, there is a growing interest in the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as an adjunct therapy in type 1 diabetes (T1D). The GLP-1RAs are currently not approved by the US Food and Drug Administration for the treatment of T1D in the absence of randomized controlled trials documenting efficacy and safety of these agents in this population. The Diabetes Technology Society convened a series of three consensus meetings of clinicians and researchers with expertise in diabetes technology, GLP-1RA therapy, and T1D management. The project was aimed at synthesizing current literature and providing conclusions on the use of GLP-1RA therapy as an adjunct to automated insulin delivery (AID) systems in adults with T1D. The expert panel members met virtually three times on January 17, 2024, and April 24, 2024, and August 14, 2024, to discuss topics ranging from physiology and outcomes of GLP-1RAs in T1D to limitations of current sensors, algorithms, and insulin for AID systems. The panelists also identified research gaps and future directions for research. The panelists voted to in favor of 31 recommendations. This report presents the consensus opinions of the participants that, in adults with T1D using AID systems, GLP-1RAs have the potential to (1) provide effective adjunct therapy and (2) improve glycemic and metabolic outcomes without increasing the risk of severe hypoglycemia or diabetic ketoacidosis.

Racial and ethnic disparities in the uptake of SGLT2is and GLP-1RAs among Medicare beneficiaries with type 2 diabetes and heart failure, atherosclerotic cardiovascular disease and chronic kidney disease, 2013-2019.

The aim of this study was to investigate racial and ethnic disparities in the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor antagonists (GLP-1RAs) among older adults with type 2 diabetes and cardiorenal conditions. Using Medicare fee-for-service data (2013-2019), this retrospective cohort study identified older adults (≥65 years) with type 2 diabetes initiating second-line therapies (SGLT2is, GLP1-RAs, dipeptidyl peptidase-4 inhibitors [DPP4is] and sulfonylureas [SUs]) with (1) heart failure (HF), (2) atherosclerotic cardiovascular disease (ASCVD), (3) chronic kidney disease (CKD) and (4) no recorded cardiorenal conditions. Participants were classified as non-Hispanic White, non-Hispanic Black and Hispanic. Multinomial regressions, adjusting for sociodemographic, clinical and county-level characteristics, were used to model the odds of initiating SGLT2is or GLP-1RAs within each cohort. Black participants with HF, ASCVD, CKD or no recorded cardiorenal conditions had 35% (adjusted OR 0.65 [95% CI 0.61, 0.68]), 33% (0.67 [0.64, 0.69]), 32% (0.68 [0.64, 0.72]) and 24% (0.76 [0.74, 0.79]) lower odds of initiating SGLT2is, respectively, than White participants. Disparities ameliorated from 50-60% lower odds in 2013 to 17-18% in 2019. Similar patterns were observed for GLP-1RA uptake among Black participants. By contrast, Hispanic participants had similar odds of SGLT2i initiation in the HF and CKD cohorts as White participants, but 6% (0.94 [0.91, 0.98]) lower odds in the ASCVD cohort. Notable disparities for Hispanic participants compared with White participants were observed for GLP-1RA uptake in the HF, ASCVD, CKD and no cardiorenal conditions cohorts: 11% (0.89 [0.84, 0.94]), 16% (0.84 [0.81, 0.87]), 16% (0.84 [0.80, 0.89]) and 25% (0.75 [0.72, 0.78]) lower odds, respectively. Participants had greater odds than White participants of initiating DPP4is, which confer no cardiorenal benefits, across all cohorts (HF 1.25 [1.19, 1.31]; ASCVD 1.36 [1.32, 1.40]; CKD 1.32 [1.26, 1.38). Adjustment for social determinants of health did not meaningfully change the study findings. Compared with White participants, disparities in the uptake of SGLT2is were evident for Black participants, and in the uptake of GLP-1RAs for both Black and Hispanic participants. This study highlights how type 2 diabetes management is evolving, while underscoring historical imbalances that have shown signs of abatement.