The cost-effectiveness of semaglutide in reducing cardiovascular risk among people with overweight and obesity and existing cardiovascular disease, but without diabetes.

BACKGROUND AND AIMS: The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial demonstrated significant reductions in cardiovascular outcomes in people with cardiovascular disease (CVD) and overweight or obesity (but without diabetes). However, the cost of the medication has raised concerns about its financial viability and accessibility within healthcare systems. This study explored whether use of semaglutide for the secondary prevention of CVD in overweight or obesity is cost-effective from the Australian healthcare perspective. METHODS: A Markov model was developed based on the SELECT trial to model the clinical outcomes and costs of a hypothetical population treated with semaglutide versus placebo, in addition to standard care, and followed up over 20 years. With each annual cycle, subjects were at risk of having non-fatal CVD events or dying. Model inputs were derived from SELECT and published literature. Costs were obtained from Australian sources. All outcomes were discounted by 5% annually. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per year of life saved (YoLS) and cost per quality-adjusted life year (QALY) gained. RESULTS: With an annual estimated cost of semaglutide of A${\$}$4175, the model resulted in ICERs of A${\$}$99 853 (US${\$}$143 504; £40 873) per YoLS and A${\$}$96 055 (US${\$}$138 046; £39 318) per QALY gained. CONCLUSIONS: Assuming a willingness-to-pay threshold of A${\$}$50 000, semaglutide is not considered cost-effective at the current price. A price of ≤ A${\$}$2000 per year or more targeted use in high-risk patients would be needed for it to be considered cost-effective in the Australian setting.

Semaglutide as a promising treatment for hypothalamic obesity: a six-month case series on four females with craniopharyngioma.

PURPOSE: Patients with hypothalamic pathology often develop hypothalamic obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Treatments for hypothalamic obesity have not proven very effective, although the glucagon-like peptide-1 receptor agonist semaglutide has been shown to have positive effects. We examined semaglutide's effect on weight loss in a sample of patients with hypothalamic obesity. METHODS: Four female patients with hypothalamic obesity resulting from treatment of craniopharyngiomas were treated with semaglutide for six months. Whole Body Dual-energy x-ray absorptiometry scans were performed, and blood samples drawn at baseline and after six months. Semaglutide dosages were increased monthly along with tracking of body weight and eating behavior (Three Factor Eating Questionnaire, TFEQ-R18). RESULTS: BMI was reduced in all cases, with an average of 7.9 BMI (range: 6.7 to 10.1) corresponding to a weight loss of 17.0% (range: 11.3-22.4%) or 20.2 kg (range 16.2 kg to 23.4 kg). We found a comparable reduction in total fat mass (17.2%, p = 0.006) and lean mass (16.0%, p = 0.05), whereas bone mass was unchanged (2.6%, p = 0.12). All cases reported an increase in energy levels, improved mobility and physical activity. Unfavorable eating behaviors were reduced after 1 month of treatment (emotional eating - 41 points, p = 0.02, uncontrolled eating - 23 points, p = 0.11). HbA1c and total cholesterol were significantly reduced (p = 0.014 for both). CONCLUSION: Semaglutide is a promising and safe treatment option for HO, that improves eating behavior, reduces weight, and improves metabolic markers.

Chronic cold stress promotes inflammation and ER stress via inhibiting GLP-1R signaling, and exacerbates the risk of ferroptosis in the liver and pancreas.

The cold climates in autumn and winter threatens human health. The aim of this study was to reveal the effects of prolonged cold exposure on the liver and pancreas based on GLP-1R signaling, oxidative stress, endoplasmic reticulum (ER) stress and ferroptosis by Yorkshire pig models. Yorkshire pigs were divided into the control group and chronic cold stress (CCS) group. The results showed that CCS induced oxidative stress injury, activated Nrf2 pathway and inhibited the expression of GLP-1R in the liver and pancreas (P < 0.05). The toll-like receptor 4 (TLR4) pathway was activated in the liver and pancreas, accompanied by the enrichment of IL-1ß and TNF-α during CCS (P < 0.05). Moreover, the kinase RNA-like endoplasmic reticulum kinase (PERK), inositol requiring kinase 1 (IRE1), X-box-binding protein 1 (XBP1) and eukaryotic initiation factor 2α (eIF2α) expression in the liver and pancreas was up-regulated during CCS (P < 0.05). In addition, CCS promoted the prostaglandin-endoperoxide synthase 2 (PTGS2) expression and inhibited the ferritin H (FtH) expression in the liver. Summarily, CCS promotes inflammation, ER stress and apoptosis by inhibiting the GLP-1R signaling and inducing oxidative stress, and exacerbates the risk of ferroptosis in the liver and pancreas.

Weighing your options-intragastric balloon versus semaglutide.

INTRODUCTION: Over half of Americans and up to 78% of US Veteran population meet criteria for obesity. Perioperatively placed intragastric balloon (IGB) can accelerate weight loss goals for safe surgical candidacy, however weight regain is common after removal. Glucagon-like peptide-1-receptor agonists (GLP1RA) may provide a more sustainable weight loss solution after surgery. We hypothesize that weight regain will be less at 1 year after initiation of GLP1RA than IGB placement in Veterans. METHODS: Retrospective review of prospective databases of perioperatively placed intragastric balloon cohort from 1/2019-1/2023 compared to patients who received initiatory GLP1RA from 6/2021-8/2022 at a VA Medical Center(VAMC). All patients were enrolled in the VAMC MOVE! multidisciplinary weight management program for a minimum of 12 weeks. Outcomes measured were patients' weights at 0, 3, 6, and 12 months and weight change for these intervals. Exclusion criteria included history of bariatric surgery and incomplete weight loss data. RESULTS: Two-hundred-twenty-three patients met inclusion criteria; 110 (49%) patients excluded. Mean age was 54 ± 11 years, the majority (78, 69%) were male, and the mean initial BMI was 37 ± 5.9 kg/m2. Seventeen (15%) patients underwent IGB placement and 96 (85%) patients received semaglutide. Weight (kg) change was measured at intervals: 0-3 months:- 11.8(- 17,- 9.5) IGB vs. - 5.1(- 7.4,- 2.3) semaglutide, p < 0.0001; 0-6 months:- 12.7(- 18.4,- 9.9) vs. - 9.4(- 12.6,- 6.1), p = 0.03; 3-6 months:- 0.5(- 2.3,2.3) vs. - 4.3(- 6.8,- 1.6), p < 0.0001; 6-12 months:3(0,7.3) vs. - 1.9(- 4.7,1), p = 0.0006. CONCLUSION: Weight loss occurs more rapidly in the first 6 months after intragastric balloon placement compared to semaglutide (- 12.7 vs. - 9.4 kg, p = 0.03). Despite ongoing attendance in a comprehensive weight loss program, weight regain is common after IGB removal by an average of 3 kg (23.6%) at 1 year. In contrast, patients on GLP1RA (semaglutide) continue to lose weight during this period. Further studies are needed to determine if optimal long-term outcomes may result from combination therapy with intragastric balloon and semaglutide.

Changes in glomerular filtration rate in patients with body mass index ≥35 kg/m2 treated with metabolic and bariatric surgery versus GLP-1 agonist at 1-year follow-up.

Background: Metabolic and bariatric surgery (MBS) reduces glomerular hyperfiltration. The renoprotective effects of GLP-1 analogs were derived from clinical studies in type 2 diabetes (T2D). The objective of this study was to evaluate the changes in glomerular filtration rate (GFR) over time associated with weight loss in patients with a BMI ≥ 35 kg/m2 treated with liraglutide compared with patients treated with MBS. Methods: A longitudinal study derived from a retrospective cohort of patients with BMI ≥ 35 kg/m2 treated with either MBS or liraglutide 3 mg/day, with follow-up ≥1 year. Clinical variables, baseline GFR, and 1-year GFR were analyzed. A generalized estimating equation (GEE) model was used to compare changes in GFR between both groups while controlling for confounding variables. Results: A total of 159 patients were included in the analysis. Of these, 129 patients underwent MBS (median age 60.5 years [IQR 51.8-66.6], body mass index (BMI) 40.9 kg/m2 [IQR 0.68-0.89]), and 30 patients were treated with liraglutide (median age 56 years [IQR 46-62], BMI 37.4 kg/m2 [IQR 0.69-0.93]). No difference in baseline GFR or at 12 months of follow-up was found between the two interventions. GEE analysis revealed an increase of 0.32 mL/min/1.73 m2 per month of follow-up. Factors associated with a greater increase in GFR were the percentage total weight loss (%TWL) (0.12 mL/min/1.73 m2, p = 0.023) and baseline GFR (0.69 mL/min/1.73 m2, p > 0.001) for both interventions, independent of a history of T2D. Conclusion: In patients with BMI ≥ 35 kg/m2, changes in GFR are related to %TWL and baseline GFR, regardless of the presence of diabetes or the type of intervention used.

Effects of Glucagon-Like Peptide 1 Receptor Agonists on Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-analysis.

INTRODUCTION: Despite the technological advancements in catheter ablation strategies, the recurrence of atrial fibrillation (AF) post-ablation remains a concern that requires further investigation. Glucagon-like peptide 1 (GLP-1) receptor agonists have shown a significant effect on weight reduction, which in turn is associated with freedom from AF recurrence in both patients who are obese and not obese undergoing ablation. Therefore, we aimed to summarize the available evidence on the efficacy of GLP-1 receptor agonists in maintaining sinus rhythm post-ablation. METHODS: Medline, Cochrane Library, and Scopus were searched until June 9, 2024. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled using DerSimonian-Laird random effects meta-analysis. RESULTS: Three propensity score-matched studies (n = 6031 participants) were analyzed. Over a 12-months follow-up, the use of GLP-1 receptor agonists was associated with a significant reduction in AF recurrence compared to controls, hazard ratio (HR) = 0.549, 95% confidence interval (CI) = [0.315, 0.956], P = 0.034; I2 = 57%. No significant heterogeneity was observed (Q statistic = 4.6, heterogeneity P = 0.1). CONCLUSION: The use of GLP-1 receptor agonists is associated with a lower risk of AF recurrence in patients receiving AF ablation therapy. Further large-scale randomized trials are necessary to explore the efficacy of GLP-1 receptor agonists in maintaining ablation outcomes over the long term.

Peptide GLP-1 receptor agonists: From injection to oral delivery strategies.

Peptide glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective drugs for treating type 2 diabetes (T2DM) and have been proven to benefit the heart and kidney. Apart from oral semaglutide, which does not require injection, other peptide GLP-1RAs need to be subcutaneously administered. However, oral semaglutide also faces significant challenges, such as low bioavailability and frequent gastrointestinal discomfort. Thus, it is imperative that advanced oral strategies for peptide GLP-1RAs need to be explored. This review mainly compares the current advantages and disadvantages of various oral delivery strategies for peptide GLP-1RAs in the developmental stage and discusses the latest research progress of peptide GLP-1RAs, providing a useful guide for the development of new oral peptide GLP-1RA drugs.

Hepatic function of glucagon-like peptide-1 and its based diabetes drugs.

Incretins are gut-produced peptide-hormones that potentiate insulin secretion, especially after food intake. The concept of incretin was formed more than 100 years ago, even before insulin was isolated and utilized in the treatment of subjects with type 1 diabetes. The first incretin, glucose-dependent insulinotropic polypeptide (GIP), was identified during later 1960's and early 1970's; while the second one, known as glucagon-like peptide-1 (GLP-1), was recognized during 1980's. Today, GLP-1-based therapeutic agents [also known as GLP-1 receptor (GLP-1R) agonists, GLP-1RAs] are among the first line drugs for type 2 diabetes. In addition to serving as incretin, extra-pancreatic functions of GLP-1RAs have been broadly recognized, including those in the liver, despite the absence of GLP-1R in hepatic tissue. The existence of insulin-independent or gut-pancreas-liver axis-independent hepatic function of GLP-1RAs explains why those therapeutic agents are effective in subjects with insulin resistance and their profound effect on lipid homeostasis. Following a brief review on the discovery of GLP-1, we reviewed literature on the exploration of hepatic function of GLP-1 and GLP-1RAs and discussed recent studies on the role of hepatic hormone fibroblast growth factor 21 (FGF21) in mediating function of GLP-1RAs in animal models. This was followed by presenting our perspective views.

Evaluation of glucose-lowering medications in older people: a comprehensive systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population. METHODS: A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool. RESULTS: A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], -3.87 kg; 95% CI, -5.54 to -2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, -1.85 kg; 95% CI, -2.42 to -1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases. CONCLUSIONS: Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes.

Intranasal delivery of glucagon-like peptide-1 to the brain for obesity treatment: opportunities and challenges.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), approved by the US FDA for obesity treatment, are typically administered subcutaneously, an invasive method leading to suboptimal patient adherence and peripheral side effects. Additionally, this route requires the drug to cross the restrictive blood-brain barrier (BBB), limiting its safety and effectiveness in weight management and cognitive addiction disorders. Delivering the drug intranasally could overcome these drawbacks. AREAS COVERED: This review summarizes GLP-1 RAs used as anti-obesity agents, focusing on the intranasal route as a potential pathway to deliver these biomolecules to the brain. It also discusses strategies to overcome challenges associated with nasal delivery. EXPERT OPINION: Nose-to-brain (N2B) pathways can address limitations of the subcutaneous route for GLP-1 RAs. However, peptide delivery to the brain is challenging due to nasal physiological barriers and the drug's physicochemical properties. Innovative approaches, such as cell permeation enhancers, mucoadhesive systems, and nanocarriers in nasal formulations, along with efficient drug delivery devices, show promising preclinical results. Despite this, successful preclinical data does not guarantee clinical effectiveness, highlighting the need for comprehensive clinical investigations to optimize formulations and fully utilize the nose-to-brain interface for peptide delivery.

Impact of a 12-Week Dietary Intervention on Adipose Tissue Metabolic Markers in Overweight Women of Reproductive Age.

The prevalence of overweight and obesity in women of reproductive age leads to significant health risks, including adverse metabolic and reproductive outcomes. Effective dietary interventions are critical to improving health outcomes in this population. This study investigates the impact of a 12-week diet intervention on metabolic markers of adipose tissue in overweight women of reproductive age, determining whether calorie restriction or low-starch diets are more effective, while also accounting for salivary amylase activity. A total of 67 overweight women of reproductive age were enrolled in a randomized controlled trial (RCT). Participants were divided into high-salivary-amylase (HSA) and low-salivary-amylase (LSA) groups based on baseline salivary amylase activity measured using a spectrophotometric method. Each group was further subdivided into two dietary intervention groups: calorie restriction (CR) and low starch (LS), resulting in four subgroups (HSA-CR, HSA-LS, LSA-CR, LSA-LS), along with a control group (CTR) of normal-weight individuals (no intervention). Participants were assigned to a calorie-restricted diet or a low-starch diet for 12 weeks. Key metabolic markers of adipose tissue, including insulin sensitivity, adipokines, cytokines, and lipid profiles, were measured at baseline (T0), 30 min after consuming starch-containing muesli (T1), and 12 weeks after intervention (T2). Active GLP-1, glucagon, and C-peptide levels were assessed to clarify the hormonal mechanisms underlying the dietary effects. Salivary amylase activity was also measured to examine its role in modulating glucose and GLP-1 responses. Both diet interventions led to significant improvements in metabolic markers of adipose tissue, though different ones. Calorie restriction improved insulin sensitivity by effectively reducing visceral fat mass and enhancing insulin signaling pathways. In contrast, the low-starch diet was linked to a reduction in the coefficient of glucose variation influenced partly by changes in GLP-1 levels. Our findings highlight the importance of personalized diet strategies to optimize metabolic health in this demographic.

The incidence of acute pancreatitis with GLP-1 receptor agonist therapy in individuals with a known history of pancreatitis.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been reported to increase the risk of acute pancreatitis (AP). This real-world study did not observe a higher frequency of AP with GLP-1RA exposure in adults with T2D and a prior history of AP regardless of etiology.

The novel chimeric multi-agonist peptide (GEP44) reduces energy intake and body weight in male and female diet-induced obese mice in a glucagon-like peptide-1 receptor-dependent manner.

We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by -1.5 ± 0.6, -1.3 ± 0.4 and -1.9 ± 0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.

Semaglutide in Heart Failure: A Systematic Review of Outcomes of Semaglutide in Heart Failure Patients.

Heart failure (HF) stands as a formidable challenge in global healthcare casting a long shadow over both morbidity and mortality. A significant interplay between HF and type 2 diabetes (T2DM) manifests an elevated risk of adverse cardiovascular events in T2DM patients. Glucagon-like peptide 1 emerges as a pivotal player in T2DM, which is released in response to meals rich in glucose and lipids. We aim to assess the outcomes of using semaglutide in HF. A comprehensive literature search was performed using electronic databases, including PubMed/Medline, the Cochrane Library, and Google Scholar, covering all records up to May 10, 2024. Studies meeting inclusion criteria were selected. Qualitative analysis was conducted to analyze the findings of the studies included. Four studies (three randomized controlled trials and one observational study) were included in our manuscript. There was a significant decrease in the Kansas City Cardiomyopathy Questionnaire clinical summary score (p< 0.001), body weight (p< 0.001), six-minute walk distance (p< 0.001), and CRP levels (p< 0.001). A statistically significant decrease in overall major adverse cardiac events was observed with a hazard ratio of 0.76 (95% CI 0.62, 0.92). Other factors and adverse effects were also discussed in our manuscript. Our study showed that semaglutide resulted in improvement in HF patients. Although adverse effects were observed, they were not as significant as the placebo itself.

Potent and Protease Resistant Azapeptide Agonists of the GLP-1 and GIP Receptors.

The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) play important physiological roles. Stabilized agonists of the GLP-1 receptor (GLP-1R) and the GIP receptor (GIPR) for the management of diabetes and obesity have generated widespread enthusiasm and have become blockbuster drugs. These therapeutics are refractory to the action of dipeptidyl peptidase-4 (DPP4), that catalyzes rapid removal of the two N-terminal residues of the native peptides, in turn severely diminishing their activity profiles.  Here we report that a single atom change from carbon to nitrogen in the backbone of the entire peptide make them refractory to DPP4 action while still retaining full potency and efficacy at their respective receptors.  This was accomplished by use of aza-amino acids, that are bioisosteric replacements for a-amino acids that perturb the structural backbone and local side chain conformations.  Molecular dynamics simulations reveal that aza-amino acid can populate the same conformational space that GLP-1 adopts when bound to the GLP-1R. The insertion of an aza-amino acid at the second position from the N-terminus in semaglutide and in a dual agonist of GLP-1R and GIPR further demonstrates its capability as a viable alternative to current DPP4 resistance strategies while offering additional structural variety.

Distinct Profiles and New Pharmacological Targets for Heart Failure with Preserved Ejection Fraction.

Background: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial condition with a variety of pathophysiological causes and morphological manifestations. The inclusion criteria and patient classification have become overly simplistic due to the customary differentiation regarding the ejection fraction (EF) cutoff. EF is considered a measure of systolic function; nevertheless, it only represents a portion of the true contractile state and has been shown to have certain limits due to methodological and hemodynamic irregularities. Methods: As a result, broader randomized clinical trials have yet to incorporate the most recent criteria for HFpEF diagnosis, leading to a lack of data consistency and confusion in interpreting the results. The primary variations between the bigger clinical trials published in this context concerning patient selection and echocardiographic characteristics were analyzed. For all these reasons, we aim to clarify the main features and clinical impact of HFpEF in a study combining imaging, bio-humoral analysis, and clinical history to identify the specific subgroups that respond better to tailored treatment. Results: Disparate clinical characteristics and a lack of uniform diagnostic standards may cause suboptimal therapeutic feedback. To optimize treatment, we suggest shifting the paradigm from the straightforward EF measurement to a more comprehensive model that considers additional information, such as structural traits, related disorders, and biological and environmental data. Therefore, by evaluating certain echocardiographic and clinical factors, a stepwise diagnostic procedure may be useful in identifying patients at high risk, subjects with early HFpEF, and those with evident HFpEF. Conclusions: The present assessment underscores the significance of the precision medicine approach in guaranteeing optimal patient outcomes by providing the best care according to each distinct profile.

The Effect of Glucagon-Like Peptide-1 Receptor Agonists on Diabetic Retinopathy at a Tertiary Care Center.

Objective: The potential association between diabetic retinopathy (DR) worsening and glucagon-like peptide-1 receptor agonists (GLP-1RA) has affected therapeutic management of diabetic patients but remains controversial. This study compared rates of DR development or progression in patients on GLP-1RA to those on SGLT-2 inhibitors (SGLT-2I). Design: Retrospective cohort study. Subjects: Nine hundred eighty-one patients with diabetes mellitus taking GLP-1RA or SGLT-2I, the latter serving as controls, between 2012 and 2023. Methods: Patients were one-to-one greedy matched by propensity scores on race/ethnicity, age, smoking status, baseline body mass index and hemoglobin A1c %, type of diabetes mellitus, baseline DR status and history of DR procedures, duration of drug use, whether they had taken both drug types, and change in hemoglobin A1c % after 1 year on the drug. Main Outcome Measures: The primary outcome was clinical DR development or progression (termed "worsening") detected by International Classification of Diseases (ICD), 10th edition codes, confirmed by manual review, on GLP-1RA compared with SGLT-2I after propensity score matching. Secondary outcomes included DR worsening indicated by need for procedures due to complications, and time-to-first DR worsening event. Results: The study included 692 GLP-1RA users and 289 SGLT-2I users. The mean follow-up periods for GLP-1RA versus SGLT-2I use were 1.54 (standard deviation [SD] 1.82) years and 1.38 (SD 1.56) years, respectively. The rates of clinical worsening were 2.3% and 2.8%, respectively. After propensity score matching, an association was not identified between GLP1-RA and DR worsening neither clinically by ICD-10 codes (odds ratio [OR] = 0.33, 95% confidence interval [CI]: 0.11-1.03) nor by indication for procedures (OR = 0.50, 95% CI 0.13-2.00). Time-to-first DR worsening did not differ between the groups in Kaplan-Meier analysis. The most common type of clinical worsening event for both drug types was vitreous hemorrhage (43.7% and 50% of worsening events in GLP-1RA and SGLT-2I users, respectively). The most common DR procedure indicated was anti-VEGF injections (34% and 35% of GLP-1RA and SGLT-2I events, respectively). Conclusions: Diabetic retinopathy worsening, either clinically or by procedures, was not associated with GLP-1RA compared with SGLT-2I, both before and after propensity score matching on all analyses, including time-to-first worsening event. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Regulator of G-protein signaling expression in human intestinal enteroendocrine cells and potential role in satiety hormone secretion in health and obesity.

BACKGROUND: Gut L-type enteroendocrine cells (EECs) are intestinal chemosensory cells that secrete satiety hormones GLP-1 and PYY in response to activation of G-protein coupled receptors (GPCRs) by luminal components of nutrient digestion and microbial fermentation. Regulator of G-protein Signaling (RGS) proteins are negative regulators of GPCR signaling. The expression profile of RGS in EECs, and their potential role in satiety hormone secretion and obesity is unknown. METHODS: Transcriptomic profiling of RGS was completed in native colonic EECs was completed using single-cell RNA sequencing (scRNA-Seq) in lean and obesity, and human jejunal EECs with data obtained from a publicly available RNAseq dataset (GSE114853). RGS validation studies were completed using whole mucosal intestinal tissue obtained during endoscopy in 61 patients (n = 42 OB, n = 19 Lean); a subset of patients' postprandial plasma was assayed for GLP-1 and PYY. Ex vivo human intestinal cultures and in vitro NCI-H716 cells overexpressing RGS9 were exposed to GLP-1 secretagogues in conjunction with a nonselective RGS-inhibitor and assayed for GLP-1 secretion. FINDINGS: Transcriptomic profiling of colonic and jejunal enteroendocrine cells revealed a unique RGS expression profile in EECs, and further within GLP-1+ L-type EECs. In obesity the RGS expression profile was altered in colonic EECs. Human gut RGS9 expression correlated positively with BMI and negatively with postprandial GLP-1 and PYY. RGS inhibition in human intestinal cultures increased GLP-1 release from EECs ex vivo. NCI-H716 cells overexpressing RGS9 displayed defective nutrient-stimulated GLP-1 secretion. INTERPRETATION: This study introduces the expression profile of RGS in human EECs, alterations in obesity, and suggests a role for RGS proteins as modulators of GLP-1 and PYY secretion from intestinal EECs. FUNDING: AA is supported by the NIH(C-Sig P30DK84567, K23 DK114460), a Pilot Award from the Mayo Clinic Center for Biomedical Discovery, and a Translational Product Development Fund from The Mayo Clinic Center for Clinical and Translational Science Office of Translational Practice in partnership with the University of Minnesota Clinical and Translational Science Institute.

Alpha-cyclodextrin increases glucagon-like peptide-1 secretion in multiple models and improves metabolic status in mice.

Alpha-cyclodextrin (α-CD) is a non-absorbable and soluble fiber that causes weight loss. We studied whether this is due to an effect on GLP-1 secretion. In GLUTag cells, α-CD increased GLP-1 secretion up to 170% via adenylyl cyclase, phospholipase C, and L-type calcium channels dependent processes. In rat isolated colon perfusions, luminal α-CD increased GLP-1 secretion with 20%. In lean mice, once daily α-CD versus saline caused weight loss and lowered the peak in glucose after an oral glucose tolerance test (OGTT). In obese mice, α-CD added to high-fat diet caused weight loss similar to the control group (receiving cellulose). However, compared to cellulose, the α-CD group ate less. During an OGTT, no differences were observed in glucose, insulin and GLP-1. Thus, α-CD increases GLP-1 secretion in a dose-dependent manner and could be a safe and easy addition to food products to help reduce body weight.