Glucagon-like Peptide-1 Receptor Agonists Research Articles

Semaglutide Treatment Effects on Liver Fat Content in Obese Subjects with Metabolic-Associated Steatotic Liver Disease (MASLD)

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. Methods: In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. Results: After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. Conclusions: The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis.

Semaglutide effects on safety and cardiovascular outcomes in patients with overweight or obesity: a systematic review and meta-analysis.

Semaglutide is a GLP-1 receptor agonist that provides a reduction in glycated hemoglobin and weight. The objective was to evaluate whether the use of semaglutide, in individuals with overweight or obesity, reduces cardiovascular outcomes and adverse effects (AE). The data bases Pubmed, Lilacs, Scielo, Scopus, Web of Science and Cochrane Library were surveyed. Initially, 3333 articles were found, of which 19 articles were included. An additional search included 19 studies, totaling 38 articles. Relative risk (RR) values were significant for hospitalization due to heart failure (HF) 0.24 95% CI 0.12-0.57 (n = 2; 1045 participants; I² = 0.18), death due to cardiovascular causes 0.83 95% CI 0.71-0.98 (n = 3; 24 084 participants; I² = 0.21), death from any cause 0.79 95% CI 0.70-0.89 (n = 3; 24 084 participants; I² = 0.07), coronary revascularization 0.76 95% CI 0.69-0.85 (n = 2;20 951 participants; I² = 0.41), and non-fatal myocardial infarction 0.76 95%CI 0.66-0.88 (n = 3; 24 084 participants; I² = 0.21), with a difference between the subgroups (p = 0.05), favoring the subcutaneous administration route. The RR of stroke was 0.65 95% CI 0.44-0.97 for patients with diabetes (n = 2; 6480 participants; I² = 0.66). There was no difference between the frequency of constipation and routes of administration, as well as between doses of oral semaglutide. The RR of adverse effects was only not significant for discontinuation of treatment for oral semaglutide. The use of semaglutide reduced 76% in hospitalization due to HF, 17% deaths due to cardiovascular causes, 21% deaths due to any cause, 24% non-fatal myocardial infarction, 24% coronary revascularization and 35% stroke (in patients with diabetes). The use of semaglutide was associated with a higher relative risk and frequency of most adverse effects evaluated.

Effect of glucagon-like peptide-1 receptor agonists on prostate cancer: A review.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) is widely used in the treatment of type 2 diabetes mellitus (T2DM) for its significant hypoglycemic effect, weight loss and small side effects. Some studies have shown that GLP-1RA has an inhibitory effect on prostate cancer, and its application will produce adverse effects associated with an increased or decreased risk of some tumors. GLP-1R is widely expressed by various types of cells and tissues in the human body, so GLP-1RA has attracted wide clinical attention to the occurrence, development and prognosis of tumors, which brings more new directions and hopes for the treatment of prostate cancer. This paper describes the expression of glucagon-like peptide-1 receptor (GLP-1R) in prostate cancer and the effects of glucagon-like peptide-1 receptor agonist (GLP-1RA) on prostate cancer.

Obesity Management in Youth with Duchenne Muscular Dystrophy: A Review of Metformin and Alternative Pharmacotherapies.

Background: Individuals with Duchenne muscular dystrophy (DMD) have increased risk of obesity from prolonged glucocorticoid use and progressive muscle weakness. Over 50% have obesity by the teenage years. Objectives: The current study examines literature on obesity management in DMD and describes how obesity pharmacotherapy can be used in this high-risk cohort. Methods: This review was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. A Pubmed Database search was conducted from January 2000 to May 2024. Included terms were DMD and topiramate, phentermine, metformin, glucagon-like peptide-1 receptor agonist, semaglutide, and liraglutide. Eligible studies were cataloged to examine obesity pharmacotherapy, side effect profiles, and clinical outcomes. Results: Twenty studies met inclusion criteria, 18 on metformin. Reviewed studies varied in duration from 4 to 24 weeks, ages 6.5-44 years old, with 112 participants total (range: 1-30 participants). Included studies were: eight animal studies, six clinical trials, four reviews, one cohort study, and one case report. Primary outcomes varied among studies: muscular degeneration and function (15 articles), cardiac function (2 articles), weight loss (2 articles), and general endocrine care (1 article). Conclusions: Adjunct obesity pharmacotherapy use in youth with DMD is promising but needs to be confirmed. Large gaps include appropriate agent selection, side effect monitoring, and dose escalation. The overall quality of pediatric-specific evidence for the use of obesity pharmacotherapy in youth with DMD is low. Future research is needed to investigate how to safely utilize these agents.

Tirzepatide, GIP(1-42) and GIP(1-30) display unique signaling profiles at two common GIP receptor variants, E354 and Q354.

Type 2 diabetes (T2D) and obesity are prevalent metabolic disorders affecting millions of individuals worldwide. A new effective therapeutic drug called tirzepatide for the treatment of obesity and T2D is a dual agonist of the GIP receptor and GLP-1 receptor. Tirzepatide is clinically more effective than GLP-1 receptor agonists but the reasons why are not well understood. Tirzepatide reportedly stimulates the GIP receptor more potently than the GLP-1 receptor. However, tirzepatide signaling has not been thoroughly investigated at the E354 (wildtype) or Q354 (E354Q) GIP receptor variants. The E354Q variant is associated increased risk of T2D and lower body mass index. To better understand GIP receptor signaling we characterized the activity of endogenous agonists and tirzepatide at both GIP receptor variants. Using Cos7 cells we examined wildtype and E354Q GIP receptor signaling, analyzing cAMP and IP1 accumulation as well as AKT, ERK1/2 and CREB phosphorylation. GIP(1-42) and GIP(1-30)NH2 displayed equipotent effects on these pathways excluding CREB phosphorylation where GIP(1-30)NH2 was more potent than GIP(1-42) at the E354Q GIP receptor. Tirzepatide favored cAMP signaling at both variants. These findings indicate that tirzepatide is a biased agonist towards Gαs signaling and suggests it equally activates the wildtype and E354Q GIP receptor variants. We also observed differences between the pharmacology of the GIP receptor variants with endogenous peptides, which may help to explain differences in phenotype. These findings contribute to a comprehensive understanding of GIP receptor signaling, and will aid development of therapies combating T2D and obesity.

Obesity Nephropathy: A Current Overview

The obesity pandemic is a public health problem that is evolving at high speed with both functional and vital outcomes. Recently, many studies have shown that obesity is a driver of chronic kidney disease onset and progression. The mechanisms underlying this fact are multiple including inflammation, oxidative stress, insuline resistance and hemodynamic change with inappropriate RAAS and SNS activation; occuring on a particularly genetic basis of individual predisposition. In this field, Obesity-related glomerulopathy is characterized by glomerulomegaly with localized and segmental glomerulosclerosis lesions. Main symptoms are non specific, dominated by microproteinuria, rarely nephrotic syndrome and a slowed decline in glomerular filtration rate. As for treatment, it starts essentially with lifestyle interventions targeting a meaningful and sustainable weight loss, accompanied by antiobesity medications (AOMS) including RAAS blockers, SGLT2inhibitors and since very recently, long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RA) which were shown to be effective in managing weight loss in non-chronic kidney disease (CKD) patients. Preliminary results of more definitive studies in CKD patients are currently being finalized. Bariatric surgery could reduce the risk of mortality in obese CKD patients; it is recommended for patients with severe morbid obesity, poor tolerance to AOMS, particularly GLP RA, or those whose long-term medication costs represent a barrier to sustainable results. In this review, we summarize epidemiological data on obesity nephropathy, its pathophysiological mechanisms, clinical features and perspectives on its treatment.

Glucagon-like peptide-1 receptor agonists significantly affect the quality of bowel preparation for colonoscopy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) affect gastrointestinal motility, slowing gastric emptying and colonic transit. GLP-1RAs have an impact on gastric residue before endoscopy, but only limited data are available regarding its effect on the adequacy of colonic preparation. We investigated the association between GLP-1RA use and inadequate bowel preparation (IBP) for colonoscopy. We performed a multicenter retrospective study with GLP-1RA cases matched with controls (using propensity scores for age, sex, diabetes mellitus [DM], obesity, and co-morbidities). Data on demographics, medication use, procedural indications, and colonoscopy findings were collected. IBP ("poor preparation" on Aronchik scale or Boston Bowel preparation scale <5) was the primary outcome. 4876 patients treated with GLP-1RAs were included in the analysis and compared with 4876 controls selected from 333 648 patients without GLP-1RA use. Among the GLP-1RA patients, 10% (n = 487) had IBP compared with 197 (4%) of the control group (P<0.001). Subgroup analysis showed a higher rate of IBP among diabetic patients treated with GLP-1RA (284/2364 [12%]) than among diabetic patients without GLP-1RA treatment (118/2364 [5%]; P<0.001). Additionally, 203/2512 nondiabetic patients treated with GLP-1RAs had IBP (8%) compared with 79 of the nondiabetic non-GLP-1RA group (3%; P<0.001). On multivariate analysis, diabetes and GLP-1RA use were both found to be independent risk factors for IBP (odds ratio [OR] 1.4 and OR 2.7, respectively; both P<0.001). Our findings highlight the necessity for special attention and tailored recommendations for both diabetic and nondiabetic patients treated with GLP-1RAs in terms of colonic preparation prior to colonoscopy.

A retrospective evaluation of glucagon-like peptide-1 receptor agonists in systemic lupus erythematosus patients.

Glucagon-like peptide-1 receptor agonists (GLP1-RA) are an emerging class of medications with demonstrated promise in improving cardiometabolic outcomes. Whether these drugs may be useful in mitigating the cardiac risk associated with SLE remains unknown, and a recent case of drug induced lupus secondary to GLP1-RA use calls the safety of GLP1-RAs in SLE patients into question. Accordingly, this retrospective analysis was initiated to evaluate outcomes of GLP1-RAs in SLE. All patients in the NYU Lupus Cohort who had used a GLP1-RA were eligible for inclusion. Patient characteristics were assessed at baseline (most recent rheumatology visit prior to starting GLP1-RA), 1-4 months, and 6-10 months after GLP1-RA initiation. Of the 1211 patients in the cohort, only 24 had received a GLP1-RA. Six were excluded due to insufficient documentation regarding duration of medication use. Of the remaining 18 (median age 50), 17 (94%) were female and 9 (50%) were white. There was one mild-to-moderate flare at 6-10 months, but no patients accumulated new SLE criteria during the follow up period. Compared with baseline, median BMI was reduced by 3% at 1-4 months (p= 0.002) and 13% at 6-10 months (p= 0.001). Nine (50%) patients were initially denied insurance coverage for a GLP1-RA. While limited by a small sample size, this descriptive study showed that GLP1-RAs did not trigger flares above expected background rates and were associated with significantly decreased BMI. Future studies exploring the potential benefits of GLP1-RAs in patients with SLE are warranted.

Glucagon-like peptide-1 receptor agonists improve outcomes in individuals with type 2 diabetes with and without heart failure

BackgroundThe effectiveness of glucagon-like peptide-1 receptor agonists (GLP1Ras) for prevention of heart failure (HF) in patients with type 2 diabetes (T2DM) without HF and for risk of death in patients with T2DM with HF has not been fully elucidated in routine clinical practice. MethodsUsing the real-world global electronic medical record TriNetX database, individuals with T2DM and with or without HF who initiated either GLP1Ras or sitagliptin from 2017 to 2020 were retrospectively analyzed. In individuals with T2DM without HF, the primary outcome was a composite of all-cause mortality and a new diagnosis of HF within three years. In individuals with T2DM with HF, the primary outcome was all-cause mortality within three years. Propensity-score (PS) matching was used to adjust for over 100 baseline characteristics. ResultsA total of 65,598 individuals with T2DM without HF starting a GLP1Ras were PS matched with 65,598 starting sitagliptin. GLP1Ras were associated with a lower incidence of the composite endpoint (10.5 % versus 11.8 %, hazard ratio [HR] 0.82, [0.80–0.85], p < 0.001), mortality (HR 0.66 [0.63–0.69]) and new diagnosis of HF (HR 0.92 [0.88–0.96]). There were 6002 individuals in each group matched for T2DM and HF. Mortality was lower in the GLP1Ras group (17.6 % versus 22.8 %, HR 0.70 [0.65–0.76], p < 0.001). Results were consistent across subgroups. ConclusionsIn this global real-world data analysis, GLP1Ra use was associated with a lower risk of death and HF in individuals with T2DM without HF, and lower risk of death in those with HF.

The Cardiometabolic Risk in Women with Polycystic Ovarian Syndrome (PCOS): From Pathophysiology to Diagnosis and Treatment.

Polycystic Ovarian Syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age, with significant variations in presentation characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. Beyond reproductive health, it may also pose crucial long-term cardiometabolic risks, especially for women with specific types of PCOS, contributing to early subclinical cardiovascular atherosclerotic alterations such as endothelial dysfunction, increased arterial stiffness, and coronary artery calcium levels, respectively. Moreover, the precise relationship between clinical cardiovascular disease (CVD) and PCOS remains debated, with studies demonstrating an elevated risk while others report no significant association. This review investigates the pathophysiology of PCOS, focusing on insulin resistance and its link to subclinical and clinical cardiovascular disease. Diagnostic challenges and novel management strategies, including lifestyle interventions, medications like metformin and glucagon-like peptide-1 receptor agonists (GLP-1RAs), hormonal contraceptives, and bariatric surgery, are further discussed. Recognizing the cardiometabolic risks associated with PCOS, a comprehensive approach and early intervention should address both the reproductive and cardiometabolic dimensions of the syndrome.

Weight Loss Therapies and Hypertension Benefits.

Obesity and hypertension have become an international health issue, with detrimental consequences on patients. Obesity and hypertension share common pathophysiological mechanisms, such as overactivity of the renin-angiotensin-aldosterone and the sympathetic nervous systems, insulin resistance, and disruption of the leptin pathway. Approved therapies for obesity and overweight include phentermine/topiramate, orlistat, naltrexone/bupropion, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide, tirzepatide, and bariatric surgery. This review gives the clinical data in a thorough manner and explains in detail how each of the previously mentioned therapies affects blood pressure levels.

Taming the hunger hormones

GLP-1 receptor agonists, initially developed to manage type 2 diabetes, are now widely used for weight loss due to their ability to manage hunger. As their use expands rapidly, nurses need to be informed about these drugs and their impact on various health conditions.

In adults with type 2 diabetes, what are the comparative benefits and risks of sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists?

In adults with type 2 diabetes, what are the comparative benefits and risks of sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors versus glucagon-like peptide-1 (GLP-1) receptor agonists?

Kidney Outcomes with GLP-1RAs, SGLT2 Inhibitors, DPP-4 Inhibitors, and Sulfonylureas in Type 2 Diabetes and Moderate Cardiovascular Risk

Background: Chronic kidney disease (CKD) is a serious diabetes-related complication. While guidelines recommend use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists to mitigate cardiorenal risk in high-risk patients, the benefit of early initiation of these agents relative to other commonly prescribed glucose-lowering agents in patients at lower baseline cardiovascular disease (CVD) risk remains less clear. Methods: This retrospective observational study emulated an idealized target trial using claims data from OptumLabs® Data Warehouse to test the comparative association of treatment with a dipeptidyl peptidase-4 (DPP-4) inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or sulfonylurea on a primary kidney composite outcome of incident CKD stages 3-5, kidney failure, or need for kidney replacement therapy (KRT) in patients with type 2 diabetes (T2D) and moderate CVD risk. A secondary composite outcome included all components of the primary composite outcome plus death. Results: A total of 364,714 adults ≥21 years of age initiating treatment with a DPP-4 inhibitor (N=78,843), GLP-1 receptor agonist (N=42,049), SGLT2 inhibitor (N=45,466), or sulfonylurea (N=198,356) were identified. Relative to DPP-4 inhibitor, SGLT2 inhibitor (HR: 0.71; 95% CI: 0.67-0.74; P˂0.001) and GLP-1 receptor agonist (HR: 0.87; 95% CI: 0.83-0.92; P˂0.001) treatment was superior for the primary composite outcome. Similarly, SGLT2 inhibitor (HR: 0.69; CI: 0.66-0.73) and GLP-1 receptor agonist (HR: 0.86; CI: 0.82-0.91) treatment was associated with risk reductions for the primary outcome relative to sulfonylurea treatment. When comparing SGLT2 inhibitor to GLP-1 receptor agonist therapy, SGLT2 inhibitors were superior for the primary composite outcome (HR: 0.81; 95% CI: 0.75-0.76; P˂0.001). Similar findings were observed for the secondary composite outcome across all comparisons. Conclusions: SGLT2 inhibitors and GLP-1 receptor agonists were superior to DPP-4 inhibitors and sulfonylurea for preventing kidney complications in a T2D population with moderate baseline CVD risk.

Establishing a Relationship between In Vitro Potency in Cell-Based Assays and Clinical Efficacious Concentrations for Approved GLP-1 Receptor Agonists.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases.

Novel treatment options in patients with maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes that are important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While GCK-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY such as HNF1A-MODY (formerly MODY-3) and HNF4A (formerly MODY-1) usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports.

Retrospective Analysis Comparing the Efficacy of GLP-1 Receptor Agonists Dulaglutide and Semaglutide

Background: Glucagon-like peptide-1 receptor agonists have gained popularity in recent years because of their well-established benefits of increased glycemic control, weight loss, cardiovascular protection, and renal protection, with minimal adverse effects, and low risk for hypoglycemia in patients with type 2 diabetes. This study explored the effectiveness of the GLP-1 receptor agonist semaglutide and dulaglutide on body weight and hemoglobin A1c in patients with type 2 diabetes. Methods: In this retrospective cohort study, 244 patients diagnosed with type 2 diabetes and prescribed semaglutide or dulaglutide were identified through Lourdes Hospital electronic medical records. Over a 12-month period, in set intervals every 3 months, patients were assessed for changes in their hemoglobin A1c and body weight measured as a reduction in their body mass index (BMI). These primary outcomes were compared using linear mixed models from the lme4 package in R (v. 4.2.2). Results: Semaglutide and dulaglutide showed comparable effectiveness in reducing hemoglobin A1c compared with baseline. Both medications also led to a reduction in BMI. However, semaglutide showed statistically significant improvements in weight loss compared with dulaglutide at 3-6 months ( P = 0.01), 6-9 months ( P = 0.01), and 9-12 months ( P = 0.01). Conclusions: These findings suggest that in type 2 diabetes, semaglutide and dulaglutide show comparable effectiveness in reducing hemoglobin A1c. However, semaglutide was shown to be more effective in promoting weight loss. While these findings may be beneficial when treating patients with type 2 diabetes and obesity, treatment should be individualized to the patient, considering all factors before treatment choice.

The First Triple Agonist for Antiobesity: Retatrutide

The prevalence of individuals with overweight and obesity has increased by 18% since 1990 and it is projected that by 2030, nearly 50% of US adults will have obesity. Lifestyle modifications, such as diet and exercise, typically lead to approximately 3–5% weight loss, whereas 5–15% weight loss is necessary to significantly impact obesity-associated comorbidities and improve overall health outcomes. In addition to lifestyle modifications, pharmacotherapy has been utilized as an adjunctive treatment to increase weight loss and improve health outcomes. The Food and Drug Administration has currently approved 6 drugs to treat overweight and obesity, with the recently approved drugs surging in popularity after demonstrating superior weight loss outcomes. Additionally, a number of agents are in the pipeline, offering promise of unprecedented degrees of weight loss. One such drug is retatrutide, which is a triple agonist targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor, and glucagon receptor. Phase 1 and 2 clinical trials have demonstrated the safety, tolerability, and pharmacokinetics of retatrutide in patients with obesity and/or type 2 diabetes. The pharmacokinetics of retatrutide were dose proportional and its mean half-life of approximately 6 days supported a once-weekly dosing. The safety profile was similar to GLP-1R agonists and glucose-dependent insulinotropic polypeptide receptor/GLP-1R co-agonists, with gastrointestinal disorders being the most common adverse effects reported. Each trial demonstrated greater weight loss with retatrutide treatment in comparison to placebo, with greatest efficacy at higher doses. Overall, these clinical trials have demonstrated the superior efficacy of retatrutide as a weight loss medication in patients with overweight and obesity.

A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low-dose liraglutide in otherwise healthy men with overweight or obesity.

Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight. This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD. In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m2) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying. BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive.

Individualized treatment of diabetes mellitus in older adults.

The population of older adults with diabetes mellitus is growing but heterogeneous. Because geriatric syndromes, comorbidity or multimorbidity, the complexity of glucose dynamics, and socioeconomic conditions are associated with the risk of severe hypoglycemia and mortality, these factors should be considered in individualized diabetes treatment. Because cognitive impairment and frailty have similar etiologies and risk factors, a common strategy can be implemented to address them through optimal glycemic control, management of vascular risk factors, diet, exercise, social participation, and support. To prevent frailty or sarcopenia, optimal energy intake, adequate protein and vitamin intake, and resistance or multi-component exercise are recommended. For hypoglycemic drug therapy, it is important to reduce hypoglycemia, to use sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, taking into account the benefits for cardiovascular disease and the risk of adverse effects, and to simplify treatment to address poor adherence. Glycemic control goals for older adults with diabetes should be set according to three categories, based on cognitive function and activities of daily living, using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items. This categorization can be used to determine treatment strategies for diabetes when combined with the Comprehensive Geriatric Assessment (CGA). Based on the CGA, frailty prevention, treatment simplification, and social participation or services should be implemented for patients in Category II and above. Measures against hypoglycemia and for the prevention of cardiovascular disease and chronic kidney disease should also be promoted. Treatment based on categorization and CGA by multidisciplinary professionals would be an individualized treatment for older adults with diabetes. Geriatr Gerontol Int 2024; ••: ••-••.