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International Journal of Molecular... Nov 2022Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and... (Review)
Review
Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.
Topics: Humans; Glucagon-Like Peptide 1; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Incretins; Glucagon-Like Peptide-1 Receptor; Glucose; Hypoglycemic Agents
PubMed: 36498958
DOI: 10.3390/ijms232314631 -
Molecules (Basel, Switzerland) Apr 2020Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the... (Review)
Review
Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90-95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Design; Drug Discovery; Drug Evaluation, Preclinical; Glucose; Humans; Hypoglycemic Agents; Incretins; Ligands; Molecular Targeted Therapy; Structure-Activity Relationship
PubMed: 32340373
DOI: 10.3390/molecules25081987 -
Cell Metabolism Jun 2013Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and... (Review)
Review
Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies.
Topics: Animals; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Incretins; Islets of Langerhans; Mice; Receptors, Gastrointestinal Hormone; Signal Transduction
PubMed: 23684623
DOI: 10.1016/j.cmet.2013.04.008 -
Molecular Metabolism Dec 2018A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).
METHODS
LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.
RESULTS
LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.
CONCLUSIONS
Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
Topics: Adult; Animals; Appetite; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Diarrhea; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incretins; Male; Mice; Mice, Inbred C57BL; Middle Aged; Receptors, Gastrointestinal Hormone; Vomiting
PubMed: 30473097
DOI: 10.1016/j.molmet.2018.09.009 -
Pharmacological Research Dec 2022Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However,... (Review)
Review
Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.
Topics: Humans; Neurodegenerative Diseases; Incretins; Diabetes Mellitus, Type 2; Neuroinflammatory Diseases; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide 1; Parkinson Disease; Alzheimer Disease
PubMed: 36372278
DOI: 10.1016/j.phrs.2022.106550 -
Lancet (London, England) Feb 2016Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.
METHODS
This multicentre, double-blinded, randomised, placebo-controlled phase 2 trial was conducted in four UK medical centres to assess subcutaneous injections of liraglutide (1·8 mg daily) compared with placebo for patients who are overweight and show clinical evidence of non-alcoholic steatohepatitis. Patients were randomly assigned (1:1) using a computer-generated, centrally administered procedure, stratified by trial centre and diabetes status. The trial was designed using A'Hern's single-group method, which required eight (38%) of 21 successes in the liraglutide group for the effect of liraglutide to be considered clinically significant. Patients, investigators, clinical trial site staff, and pathologists were masked to treatment assignment throughout the study. The primary outcome measure was resolution of definite non-alcoholic steatohepatitis with no worsening in fibrosis from baseline to end of treatment (48 weeks), as assessed centrally by two independent pathologists. Analysis was done by intention-to-treat analysis, which included all patients who underwent end-of-treatment biopsy. The trial was registered with ClinicalTrials.gov, number NCT01237119.
FINDINGS
Between Aug 1, 2010, and May 31, 2013, 26 patients were randomly assigned to receive liraglutide and 26 to placebo. Nine (39%) of 23 patients who received liraglutide and underwent end-of-treatment liver biopsy had resolution of definite non-alcoholic steatohepatitis compared with two (9%) of 22 such patients in the placebo group (relative risk 4·3 [95% CI 1·0-17·7]; p=0·019). Two (9%) of 23 patients in the liraglutide group versus eight (36%) of 22 patients in the placebo group had progression of fibrosis (0·2 [0·1-1·0]; p=0·04). Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, transient, and similar in the two treatment groups for all organ classes and symptoms, with the exception of gastrointestinal disorders in 21 (81%) of 23 patients in the liraglutide group and 17 (65%) of 22 patients in the placebo group, which included diarrhoea (ten [38%] patients in the liraglutide group vs five [19%] in the placebo group), constipation (seven [27%] vs none), and loss of appetite (eight [31%] vs two [8%]).
INTERPRETATION
Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
FUNDING
Wellcome Trust, National Institute of Health Research, and Novo Nordisk.
Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Incretins; Injections, Subcutaneous; Liraglutide; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; Young Adult
PubMed: 26608256
DOI: 10.1016/S0140-6736(15)00803-X -
Obesity Reviews : An Official Journal... Feb 2022Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is... (Review)
Review
Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.
Topics: Animals; Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity
PubMed: 34713962
DOI: 10.1111/obr.13372 -
Diabetologia Oct 2023Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along... (Review)
Review
Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.
Topics: Humans; Incretins; Diabetes Mellitus, Type 2; Blood Glucose; Glucagon-Like Peptide-1 Receptor; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Body Weight; Weight Loss; Insulin
PubMed: 37430117
DOI: 10.1007/s00125-023-05956-x -
Frontiers in Endocrinology 2022The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity... (Review)
Review
The incretin hormone glucagon-like peptide-1 (GLP-1) has received enormous attention during the past three decades as a therapeutic target for the treatment of obesity and type 2 diabetes. Continuous improvement of the pharmacokinetic profile of GLP-1R agonists, starting from native hormone with a half-life of ~2-3 min to the development of twice daily, daily and even once-weekly drugs highlight the pharmaceutical evolution of GLP-1-based medicines. In contrast to GLP-1, the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) received little attention as a pharmacological target, because of conflicting observations that argue activation or inhibition of the GIP receptor (GIPR) provides beneficial effects on systemic metabolism. Interest in GIPR agonism for the treatment of obesity and diabetes was recently propelled by the clinical success of unimolecular dual-agonists targeting the receptors for GIP and GLP-1, with reported significantly improved body weight and glucose control in patients with obesity and type II diabetes. Here we review the biology and pharmacology of GLP-1 and GIP and discuss recent advances in incretin-based pharmacotherapies.
Topics: Diabetes Mellitus, Type 2; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Incretins; Obesity
PubMed: 35299971
DOI: 10.3389/fendo.2022.838410 -
International Journal of Molecular... Aug 2020Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) represents the most common form of chronic liver disease worldwide. Due to its association with obesity and diabetes and the fall in hepatitis C virus morbidity, cirrhosis in NAFLD is becoming the most frequent indication to liver transplantation, but the pathogenetic mechanisms are still not completely understood. The so-called gut-liver axis has gained enormous interest when data showed that its alteration can lead to NAFLD development and might favor the occurrence of non-alcoholic steatohepatitis (NASH). Moreover, several therapeutic approaches targeting the gut-pancreas-liver axis, e.g., incretins, showed promising results in NASH treatment. In this review, we describe the role of incretin hormones in NAFLD/NASH pathogenesis and treatment and how metagenomic/metabolomic alterations in the gut microbiota can lead to NASH in the presence of gut barrier modifications favoring the passage of bacteria or bacterial products in the portal circulation, i.e., bacterial translocation.
Topics: Animals; Gastrointestinal Microbiome; Gastrointestinal Tract; Humans; Incretins; Liver; Non-alcoholic Fatty Liver Disease; Pancreas
PubMed: 32823659
DOI: 10.3390/ijms21165820