Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature.

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic ß-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins' physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.

Potent incretin-based therapy for obesity: A systematic review and meta-analysis of the efficacy of semaglutide and tirzepatide on body weight and waist circumference, and safety.

Potent incretin-based therapy shows promise for the treatment of obesity along with reduced incidence of cardiovascular events in patients with preexisting cardiovascular disease and obesity. This study assessed the efficacy and safety of the incretin-based obesity treatments, once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg, in people with obesity without diabetes. Of the 744 records identified, seven randomized controlled trials (n = 5140) were included. Five studies (n = 3288) investigated semaglutide and two studies (n = 1852) investigated tirzepatide. The treatment effect, shown as placebo-subtracted difference, on body weight was -15.0% (95% CI, -17.8 to -12.2) with -12.9% (95% CI, -14.7 to -11.1) for semaglutide and -19.2% (95% CI, -22.2 to -16.2) for tirzepatide. The treatment effect on waist circumference was -11.4 cm (95% CI, -13.7 to -9.2) with -9.7 cm (95% CI, -10.8 to -8.5) for semaglutide and -14.6 cm (95% CI, -15.8 to -13.4) for tirzepatide. The adverse events related to semaglutide and tirzepatide were primarily of mild-to-moderate severity and mostly gastrointestinal, which was more frequent during the dose-titration period and leveled off during the treatment period. This emphasizes that once-weekly subcutaneous semaglutide 2.4 mg and tirzepatide 10 or 15 mg induce large reductions in body weight and waist circumference and are generally well-tolerated.

Duodenal enteroendocrine cells and GIP as treatment targets for obesity and type 2 diabetes.

The duodenum is an important source of endocrine and paracrine signals controlling digestion and nutrient disposition, notably including the main incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Bariatric procedures that prevent nutrients from contact with the duodenal mucosa are particularly effective interventions to reduce body weight and improve glycaemic control in obesity and type 2 diabetes. These procedures take advantage of increased nutrient delivery to more distal regions of the intestine which enhances secretion of the other incretin hormone glucagon-like peptide-1 (GLP-1). Preclinical experiments have shown that either an increase or a decrease in the secretion or action of GIP can decrease body weight and blood glucose in obesity and non-insulin dependent hyperglycaemia, but clinical studies involving administration of GIP have been inconclusive. However, a synthetic dual agonist peptide (tirzepatide) that exerts agonism at receptors for GIP and GLP-1 has produced marked weight-lowering and glucose-lowering effects in people with obesity and type 2 diabetes. This appears to result from chronic biased agonism in which the novel conformation of the peptide triggers enhanced signalling by the GLP-1 receptor through reduced internalisation while reducing signalling by the GIP receptor directly or via functional antagonism through increased internalisation and degradation.

Pharmacological Advances in Incretin-Based Polyagonism: What We Know and What We Don't.

The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.

Brain access of incretins and incretin receptor agonists to their central targets relevant for appetite suppression and weight loss.

New incretin-based pharmacotherapies provide efficient and safe therapeutic options to curb appetite and produce weight loss in patients with obesity. Delivered systemically, these molecules produce pleiotropic metabolic benefits, but the target sites mediating their weight-suppressive action are located within the brain. Recent research has increased our understanding of the neural circuits and behavioral mechanisms involved in the anorectic and metabolic consequences of glucagon-like peptide 1 (GLP-1)-based weight loss strategies, yet little is known about how these drugs access their functional targets in the brain to produce sustained weight loss. The majority of brain cells expressing incretin receptors are located behind the blood-brain barrier, shielded from the circulation and fluctuations in the availability of peripheral signals, which is a major challenge for the development of CNS-targeted therapeutic peptides. GLP-1 receptor (GLP-1R) agonists with increased half-life and enhanced therapeutic benefit do not cross the blood-brain barrier, yet they manage to access discrete brain sites relevant to the regulation of energy homeostasis. In this review, we give a brief overview of the different routes for peptide hormones to access the brain. We then examine the evidence informing the routes employed by incretins and incretin receptor agonists to access brain targets relevant for their appetite and weight-suppressive actions. We highlight existing controversies and suggest future directions to further establish the functionally relevant access routes for GLP-1-based weight loss compounds, which might guide the development and selection of the future generation of incretin receptor polypharmacologies.

Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF.

PURPOSE OF REVIEW: Incretin-based drugs are potent weight-lowering agents, emerging as potential breakthrough therapy for the treatment of obesity-related phenotype of heart failure with preserved ejection fraction (HFpEF). In this review article, we will discuss the contribution of weight loss as part of the benefits of incretin-based medications in obese patients with HFpEF. Furthermore, we will describe the potential effects of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists on the heart, particularly in relation to HFpEF pathophysiology. RECENT FINDINGS: In the STEP-HFpEF trial, the GLP-1 receptor agonist semaglutide significantly improved quality of life outcomes in obese HFpEF patients. Whether the beneficial effects of semaglutide in obese patients with HFpEF are merely a consequence of body weight reduction is unclear. Considering the availability of other weight loss strategies (e.g., caloric restriction, exercise training, bariatric surgery) to be used in obese HFpEF patients, answering this question is crucial to provide tailored therapeutic options in these subjects. SUMMARY: Incretin-based drugs may represent a milestone in the treatment of obesity in HFpEF. Elucidating the contribution of weight loss in the overall benefit observed with these drugs is critical in the management of obese HFpEF patients, considering that other weight-lowering strategies are available and might represent potential alternative options for these patients.

The effects of incretin-based therapies on weight reduction and metabolic parameters in children with obesity: A systematic review and meta-analysis.

BACKGROUND: Growing evidence indicates that incretin-based therapies (IBTs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and dipeptidyl peptidase-4 inhibitors (DPP4is) are effective and safe for treating pediatric obesity patients with or without type 2 diabetes. Therefore, we aimed to perform a systematic review and meta-analysis for updating current evidence. METHODS: We searched the PubMed, the Cochrane Library, and the EMBASE database for articles published until September 15, 2023, and limited to randomized control trials. The primary outcomes were changed from baseline in weight metrics and the cardiometabolic profile. A random effects model will be used, as high heterogeneity is expected. All analyses were performed using STATA 17.0. RESULTS: Fifteen trials with a total number of 1286 participants were included in our meta-analysis. Overall, the mean difference in weight change between the IBTs group and the control group was -2.89 kg (95% confidence interval, -5.12 to -0.65, p = 0.011). Additionally, IBTs significantly reduced the HbA1c level and fasting plasma glucose by 0.37% and 6.99 mg/dl, compared with control groups. IBTs showed a little increased risk of GI side effects and hypoglycemia events, but none of the severe hypoglycemia events were occurred in IBTs group. CONCLUSIONS: Our study results have proved that GLP-1 RAs are safe, acceptable, and effective in weight reduction and sugar control for children with obesity. In addition, DPP-4is seems to have no effect on glycemic control and weight loss in childhood obesity. Further research is needed to confirm these findings, especially in younger children.

Review article: Pharmacologic management of obesity - updates on approved medications, indications and risks.

BACKGROUND: Obesity has reached epidemic proportions, with >40% of the US population affected. Although traditionally managed by lifestyle modification, and less frequently by bariatric therapies, there are significant pharmacological advancements. AIMS: To conduct a narrative review of the neurohormonal and physiological understanding of weight gain and obesity, and the development, clinical testing, indications, expected clinical outcomes, and associated risks of current FDA-approved and upcoming anti-obesity medications (AOMs). METHODS: We conducted a comprehensive review in PubMed for articles on pathophysiology and complications of obesity, including terms 'neurohormonal', 'obesity', 'incretin', and 'weight loss'. Next, we searched for clinical trial data of all FDA-approved AOMs, including both the generic and trade names of orlistat, phentermine/topiramate, bupropion/naltrexone, liraglutide, and semaglutide. Additional searches were conducted for tirzepatide and retatrutide - medications expecting regulatory approval. Searches included combinations of terms related to mechanism of action, indications, side effects, risks, and future directions. RESULTS: We reviewed the pathophysiology of obesity, including specific role of incretins and glucagon. Clinical data supporting the use of various FDA-approved medications for weight loss are presented, including placebo-controlled or, when available, head-to-head trials. Beneficial metabolic effects, including impact on liver disease, adverse effects and risks of medications are discussed, including altered gastrointestinal motility and risk for periprocedural aspiration. CONCLUSION: AOMs have established efficacy and effectiveness for weight loss even beyond 52 weeks. Further pharmacological options, such as dual and triple incretins, are probable forthcoming additions to clinical practice for combating obesity and its metabolic consequences such as metabolic dysfunction-associated steatotic liver disease.

Recent advances in peptide-based therapies for obesity and type 2 diabetes.

Options for the treatment of type 2 diabetes mellitus (T2DM) and obesity have recently been expanded by the results of several large clinical trials with incretin-based peptide therapies. Most of these studies have been conducted with the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide, which is available as a once weekly subcutaneous injection and once daily tablet, and the once weekly injected dual agonist tirzepatide, which interacts with receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In individuals with T2DM these therapies have achieved reductions of glycated haemoglobin (HbA1c) by > 2% and lowered body weight by > 10%. In some studies, these agents tested in non-diabetic, obese individuals at much higher doses have lowered body weight by > 15%. Emerging evidence suggests these agents can also offer cardio-protective and potentially reno-protective effects. Other incretin-based peptide therapies in early clinical development, notably a triple GLP-1/GIP/glucagon receptor agonist (retatrutide) and a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), have shown strong efficacy. Although incretin therapies can incur adverse gastrointestinal effects these are for most patients mild-to-moderate and transient but result in cessation of treatment in some cases. Thus, the efficacy of new incretin-based peptide therapies is enhancing the opportunity to control body weight and blood glucose and improve the treatment of T2DM and obesity.

Tirzepatide in Hispanic/Latino Patients With Type 2 Diabetes: A Subgroup Analysis of the SURPASS Program.

CONTEXT: Efficacy and safety of tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, have been studied in patients with type 2 diabetes in the global phase 3 SURPASS program. OBJECTIVE: This work aimed to assess the efficacy and safety of tirzepatide in Hispanic/Latino and non-Hispanic/Latino patients in SURPASS-1 to -4 clinical trials. METHODS: A total of 5679 patients were included, 2895 of self-reported Hispanic/Latino ethnicity, in this exploratory analysis of SURPASS-1 to -4 trial data. Interventions included tirzepatide 5, 10, or 15 mg, placebo, or active comparator (semaglutide 1 mg, insulin degludec, and insulin glargine). Change in glycated hemoglobin A1c (HbA1c) and body weight from baseline to week 40 (SURPASS-1 and -2) and to week 52 (SURPASS-3 and -4), and other efficacy and safety outcomes were evaluated within Hispanic/Latino and non-Hispanic/Latino subgroups. RESULTS: Among Hispanic/Latino and non-Hispanic/Latino patients treated with tirzepatide, respectively, HbA1c decreased significantly from baseline, ranging from 1.9% to 2.7% and 1.7% to 2.5%, and body weight decreased significantly from baseline, ranging from 5.3 kg to 12.4 and 6.5 kg to 17.1 kg (both P < .05) vs comparators across all trials. Subgroup trends were consistent with the overall trial populations. Treatment-emergent adverse events were reported in similar proportions across the subgroups and were primarily gastrointestinal disorders. The incidence of hypoglycemia was low. CONCLUSION: Tirzepatide significatively reduced HbA1c and body weight in Hispanic/Latino and non-Hispanic/Latino patients. Tirzepatide was generally well tolerated in both subgroups. Efficacy and safety trends were comparable between subgroups and within the overall trial populations.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Risk of thyroid cancer associated with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes: A population-based cohort study.

AIMS: To determine the potential association between the use of either glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 (DPP-4) inhibitors, and the risk of thyroid cancer in individuals with type 2 diabetes. MATERIALS AND METHODS: This population-based cohort study used claims data from the Korean National Health Insurance Database, 2014-2020. Two distinct cohorts were established to compare each incretin-based drug with sodium-glucose cotransporter-2 (SGLT2) inhibitors, chosen as active comparators because of their previous non-association with thyroid cancer, and their common usage as add-on therapy to metformin along with GLP-1RAs and DPP-4 inhibitors. The first cohort included 21 722 new users of GLP-1RAs and 326 993 new users of SGLT2 inhibitors, whereas the second cohort included 904 300 DPP-4 inhibitor new users and 112 017 SGLT2 inhibitor new users. The outcome was the time to incident thyroid cancer. Weighted Cox proportional models were used to estimate hazard ratios of thyroid cancer incidence associated with incretin-based drugs of interest. RESULTS: The use of GLP-1RAs was not associated with an increased risk of thyroid cancer (weighted hazard ratio 0.98, 95% confidence interval 0.62-1.53) compared with that of SGLT2 inhibitors. Using DPP-4 inhibitors was also not associated with an increased risk of thyroid cancer (0.95, 0.79-1.14) compared with that of SGLT2 inhibitors. No significant effect modifications were observed across subgroup analyses. Sensitivity analyses, including alternative outcome definition analysis of medullary thyroid cancer, were consistent with the primary analysis results. CONCLUSIONS: GLP-1RAs and DPP-4 inhibitors were not associated with an increased risk of thyroid cancer in individuals with type 2 diabetes.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

A Review of Incretin Therapies Approved and in Late-Stage Development for Overweight and Obesity Management.

OBJECTIVE: To review clinical trial data for incretin therapies that are approved or in late-stage development for overweight or obesity management, along with clinical implications of these therapies and future directions. METHODS: We searched for clinical trials involving incretin therapies studied specifically for overweight or obesity management in ClinicalTrials.gov and PubMed from registry inception through December 2023. RESULTS: Glucagon-like peptide-1 (GLP-1) receptor agonism, alone and in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonism or glucagon agonism, leads to significant weight reduction in people with overweight or obesity. Newer incretin therapies have demonstrated weight reduction between 15% to 25%, far outpacing non-incretin therapies for weight management and achieving levels of weight loss that may prevent weight-related complications. However, the discontinuation of incretin therapies is associated with weight regain. The main side effects of incretin therapies are transient, mild-to-moderate gastrointestinal side effects - nausea, diarrhea, constipation, and vomiting - that commonly occur in the first 4 to 8 weeks of treatment. There is a rich late-stage pipeline of incretin therapies for weight management, consisting of oral GLP-1 receptor agonists, dual GLP-1/GIP receptor agonists, dual GLP-1/glucagon receptor agonists, triple GLP-1/GIP/glucagon receptor agonists, and combination therapies with nonincretin drugs. CONCLUSION: Newer incretin therapies for weight management have the potential to improve the treatment for overweight and obesity, the treatment and prevention of weight-related complications, and the individualization of weight management. Ensuring that these therapies are accessible - and that treatment with them is consistent and sustainable - is necessary to translate findings from trials into the real world.

The discovery of peptides used for the treatment of diabetes/obesity: A personal journey.

The aim of this personal reminiscence is to acquaint the reader with seminal workwork carried out in 1960 s and 1970 s that made possible the subsequent development of highly effective long-acting GLP-1R agonists and GLP-1R/GIPR co-agonists that are now in clinical practice for the treatment of Type 2 diabetes and obesity. The article highlights the particular contributions of the author's collaborators Ellis Samols and Desmond Turner in elucidating the nature and significance of gut glucagon-like immunoreactivity (enteroglucagon) and GIP. The potent incretin GLP-1(7-36)amide identified in the 1980 s met the criteria for a glucagon-like-substance with incretin like properties postulated to exist by Samols and others in 1966.

[The role of antidiabetic drugs in the treatment of Alzheimer's disease: systematic review].

Recent studies show that Alzheimer's disease (AD) has many common links with conditions associated with insulin resistance, including neuroinflammation, impaired insulin signaling, oxidative stress, mitochondrial dysfunction and metabolic syndrome. The authors conducted an electronic search for publications in the PubMed/MEDLINE and Google Scholar databases using the keywords "amyloid beta", "Alzheimer type-3-diabetes", "intranasal insulin", "metformin", "type 2 diabetes mellitus", "incretins" and "PPARy agonists¼. A systematic literature search was conducted among studies published between 2005 and 2022. The authors used the following inclusion criteria: 1) Subjects who received therapy for AD and/or DM2, if the expected result concerned the risk of cognitive decline or the development of dementia; 2) The age of the study participants is > 50 years; 3) The type of studies included in this review were randomized clinical trials, population-based observational studies or case-control studies, prospective cohort studies, as well as reviews and meta-analyses; 4) The included articles were written in English. In recent years, there has been considerable interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in AD. Human studies involving patients with mild cognitive impairment and Alzheimer's disease have shown that the administration of certain antidiabetic drugs, such as intranasal insulin, metformin, incretins and thiazolidinediones, can improve cognitive function and memory. The purpose of this study is to evaluate the effectiveness of antidiabetic drugs in the treatment of AD. According to the results of the study, metformin, intranasal insulin, thiazolidinediones and incretins showed a positive effect both in humans and in animal models. Recent studies show that thiazolidinediones can activate pathways in the brain that are regulated by IGF-1; however, rosiglitazone may pose a significant risk of side effects. The results of clinical studies on the use of metformin in AD are limited and contradictory.

Paradigm Shift in the Management of Metabolic Diseases-Next-Generation Incretin Therapy.

Recently impressive weight loss has been reported for novel incretin therapies based on dual-and triple-hormone receptor coagonists. These agents have potential as being positioned as early therapeutics for metabolic diseases for which weight loss is preferred, such as type 2 diabetes, obesity, cardiovascular diseases, and nonalcoholic liver disease. This development will change the landscape of future therapy and also place weight reduction at the centerpiece for therapy of metabolic diseases.

Novel cannabinoid receptor 1 inverse agonist CRB-913 enhances efficacy of tirzepatide, semaglutide, and liraglutidein the diet-induced obesity mouse model.

OBJECTIVE: Incretin receptor agonists are now standard of care in treating obesity. Their efficacy and tolerability might be further improved by combining them with compounds that offer orthogonal mechanisms of action. The cannabinoid type 1 receptor (CB1R) is a clinically validated therapeutic target in obesity, and several experimental CB1R inverse agonists have been shown to induce weight loss. METHODS: This study characterizes a novel CB1R inverse agonist (CRB-913) with similar preclinical potency to rimonabant but markedly reduced brain penetration. CRB-913 was tested as monotherapy and in combination with tirzepatide, semaglutide, or liraglutide in the diet-induced obesity (DIO) mouse model for body weight reduction. RESULTS: CRB-913 demonstrated enhanced plasma exposure (3.8-fold larger area under the curvelast ) and reduced brain levels (9.5-fold lower area under the curvelast ) than rimonabant. CRB-913 monotherapy yielded a dose-dependent decrease in body weight in DIO mice reaching -22% within 18 days. In further DIO studies in combination with tirzepatide, semaglutide, or liraglutide, CRB-913 (2.5 mg/kg) resulted in -32.6%, -28.8%, and -16.8% decreases in body weight on Day 18, respectively, with concomitant improvements in body fat content, liver triglycerides, and liver fat deposits. CONCLUSIONS: CRB-913 in combination with incretin analogues could deliver meaningful improvements over current standards of care for obesity and related conditions.