Agonists For Treatment Of Type Research Articles

Harnessing the Incretin System with Multi-Agonists

The scientific community has made great strides in responding to the huge public health problems of obesity and diabetes with the discovery of the incretin system and the development of glucagon-like peptide 1 analogues. These have shown clinical efficacy in randomised controlled trials and observational data from real-world evidence; however, a ‘treatment gap’ remains between the therapeutic success of these molecules and the outcomes achieved with bariatric surgery. To help address this, dual incretins are being developed. These combine glucagon-like peptide 1 action with that of either glucose-dependent insulinotropic peptide or glucagon. This narrative review charts the development of incretin therapy, and the dual agonists for treatment of Type 2 diabetes and obesity.

93-LB: Preferences and Health State Utilities Associated with Routes of Administration for Oral Semaglutide, Injectable Semaglutide, and Dulaglutide

Objective: Previous studies have examined health state utilities (which are preference weightings for use in cost-effectiveness analyses) associated with injectable GLP-1 receptor agonists for treatment of type 2 diabetes (T2D). An oral formulation of semaglutide (sema) has recently become available. This study estimates health state utilities representing preferences associated with routes of administration for daily oral sema and two weekly injectable GLP-1 receptor agonists. Methods: Participants with T2D in the UK valued four health state vignettes (drafted based on drug labels and device instructions for use) in time trade-off interviews to estimate preference-based utility scores. The vignettes had identical descriptions of T2D, but differed in treatment process: (1) daily simple oral treatment (tablets without specific administration requirements), (2) daily oral sema (tablet with administration requirements per product label), (3) weekly dulaglutide (dula) injection, (4) weekly sema injection. Results: Interviews were completed by 201 participants (52.7% male; mean age=58.7). Preferences among routes of administration varied widely. Mean utilities were 0.890 for simple oral, 0.880 for oral sema, 0.878 for dula injection, and 0.859 for sema injection (with higher scores indicating greater preference). All pairwise comparisons found statistically significant differences among the four utility scores (p<0.01), except the comparison between oral sema and dula which was not significant (p=0.49). Conclusions: While some participants preferred daily oral treatment, others preferred one of the weekly injections. Results suggest that patient preferences for routes of administration cannot be compared using only the simplest descriptions (e.g., “oral” vs. “injectable”). The details of treatment administration and treatment frequency have an impact on preference and should be considered. Disclosure K. Boye: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Eli Lilly and Company. K. Cutts: Employee; Self; Evidera. K. Stewart: Employee; Self; Evidera. K. Norrbacka: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L.E. García-Pérez: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. L.S. Matza: Employee; Self; Evidera.

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R).

The therapeutic success of peptidic GLP-1 receptor agonists for treatment of type 2 diabetes mellitus (T2DM) motivated our search for orally bioavailable small molecules that can activate the GLP-1 receptor (GLP-1R) as a well-validated target for T2DM. Here, the discovery and characterization of a potent and selective positive allosteric modulator (PAM) for GLP-1R based on a 3,4,5,6-tetrahydro-1H-1,5-epiminoazocino[4,5-b]indole scaffold is reported. Optimization of this series from HTS was supported by a GLP-1R ligand binding model. Biological in vitro testing revealed favorable ADME and pharmacological profiles for the best compound 19. Characterization by in vivo pharmacokinetic and pharmacological studies demonstrated that 19 activates GLP-1R as positive allosteric modulator (PAM) in the presence of the much less active endogenous degradation product GLP1(9-36)NH2 of the potent endogenous ligand GLP-1(7-36)NH2. While these data suggest the potential of small molecule GLP-1R PAMs for T2DM treatment, further optimization is still required towards a clinical candidate.

Design and synthesis of a novel series of orally active, selective somatostatin receptor 2 agonists for the treatment of type 2 diabetes

The discovery of a novel series of β-methyltryptophan (β MeTrp) derivatives as selective and orally active non-peptide somatostatin receptor 2 (SSTR2) agonists for the treatment of Type 2 diabetes is described. In our previous research, Compound A, β-MeTrp derivative with highly potent and selective SSTR2 agonistic activity IC50 (SSTR2/SSTR5)=0.3/>100 (nM), was identified asa drug candidate for treatment of Type 2 diabetes which lowers significantly plasma glucose level in Wistar fatty rats in its oral administrations. However, as serious increase in AUC and phospholipidosis (PLsis) were observed in its toxicological studies in rats, follow-up compounds were searched to avoid risk of PLsis with reference to their in vitro PLsis potentials evaluated on the basis of accumulation of phospholipids in HepG2 cells exposed to the compounds.It has been found that introduction of a carbonyl group onto the piperidine and piperazine or aniline moiety of compounds A and B reduced markedly the in vitro PLsis potentials. And further modification of the compounds and their evaluation led to a discovery of compounds 3k with lower in vitro PLsis potentials exhibiting lowering effect of hypoglycemia-induced glucagon secretion in SD rats (ED50=1.1mg/kg) and glucose excursion in meal tolerance test in Wistar fatty diabetic rats (MED=3.0mg/kg) in oral administrations.Compound 3k was selected asa new drug candidate of selective and orally active non-peptide SSTR2 agonists for treatment of Type 2 diabetes with low in vivo PLsis potential.

In silico approaches to explore structure of new GPR 119 agonists for treatment of type 2 diabetes mellitus

The G protein coupled receptor 119 is an exciting and promising target for the treatment of type 2 diabetes mellitus. In this study, three dimensional quantitative structure activity relationships i.e. a comparative molecular field analysis and comparative molecular field analysis region focusing have been carried out on a novel series of G protein coupled receptor 119 agonists. A quality pharmacophore model was built by Hip-Hop algorithm. The best pharmacophore model indicated which feature of hydrogen-bond acceptor and hydrophobic existed around active compounds. As the quality of the pharmacophore model is satisfactory, it was utilized to search the ZINC database for a virtual screening task. The obtained compounds subjected to Lipinski filter at first, were docked with Gold algorithm to discover potent hits. The energy difference between the highest occupied molecular orbital and lowest unoccupied molecular orbital (“gap”) implies high reactivity of the most active molecule in the active site of protein. In addition, the molecular electrostatic potential energy at density functional theory level confirms the results from molecular docking. In silico absorption, distribution, metabolism, and excretion and toxicity risk assessment analysis were carried out on the seven hits with the highest Gold score fitness. Six of the new hits from virtual screening had diverse structures and are reported as new scaffold candidates for G protein coupled receptor 119 agonists.

Evaluating the Long-Term Cost-Effectiveness of Daily Administered GLP-1 Receptor Agonists for the Treatment of Type 2 Diabetes in the United Kingdom.

IntroductionThe glucagon-like peptide-1 (GLP-1) receptor agonist class has grown in the last decade, with several agents available in the UK. However there is currently a paucity of evidence regarding the relative cost-effectiveness of liraglutide 1.2 mg versus other daily administered GLP-1 receptor agonists, due to a lack of head-to-head trial data. Therefore the present analysis was performed, using results from a network meta-analysis (NMA), to compare the cost-effectiveness of three currently available daily administered GLP-1 receptor agonists for treatment of diabetes in the UK setting.MethodsA validated and published diabetes model was used to make long-term projections of clinical outcomes and direct costs (2015 GBP) for patients receiving liraglutide 1.2 mg once-daily, exenatide 10 μg twice daily and lixisenatide 20 μg once-daily. Treatment effects were taken from an NMA evaluating the efficacy of GLP-1 receptor agonists and were applied in a cohort based on the Liraglutide Effect and Action in Diabetes 6 (LEAD-6) trial. Costs and utilities were based on published sources.ResultsLiraglutide 1.2 mg was associated with improved quality-adjusted life expectancy versus exenatide [9.19 versus 9.17 quality-adjusted life years (QALYs)] and lixisenatide (9.19 versus 9.12 QALYs). Improvements were driven by benefits in glycemic control, leading to a reduced incidence of diabetes-related complications. Liraglutide 1.2 mg was associated with reduced costs versus exenatide (GBP 36,394 versus GBP 36,547) and lixisenatide (GBP 36,394 versus GBP 36,496), with cost savings as a result of complications avoided entirely offsetting increased acquisition costs. Based on the projected outcomes, liraglutide was found to be dominant over both exenatide and lixisenatide.ConclusionLiraglutide 1.2 mg is likely to be considered cost-effective versus alternative daily administered GLP-1 receptor agonists for treatment of type 2 diabetes in the UK.

Physician perceptions of GLP-1 receptor agonists in the UK

Objectives Glucagon-like peptide-1 (GLP-1) receptor agonists have been used to treat type 2 diabetes for almost a decade, and new treatments in this class have recently been introduced. The purpose of this study was to examine perceptions of GLP-1 receptor agonists among physicians who treat patients with type 2 diabetes in the UK.Methods A total of 670 physicians (226 diabetes specialists; 444 general practice [GP] physicians) completed a survey in 2014.Results Almost all physicians had prescribed GLP-1 receptor agonists (95.4% total sample; 99.1% specialists; 93.5% GP), most frequently to patients whose glucose levels are not adequately controlled with oral medications (85.9% of physicians) and obese/overweight patients (83.7%). Physicians’ most common reasons for prescribing a GLP-1 receptor agonist were: associated with weight loss (65.8%), good efficacy (55.7%), less hypoglycemia risk than insulin (55.2%), not associated with weight gain (34.5%), and better efficacy than oral medications (32.7%). Factors that most commonly cause hesitation when prescribing this class were: not considered first line therapy according to guidelines (56.9%), injectable administration (44.6%), cost (36.7%), gastrointestinal side effects (33.4%), and risk of pancreatitis (26.7%). Almost all specialists (99.1%) believed they had sufficient knowledge to prescribe a GLP-1 receptor agonist, compared with 76.1% of GPs.Conclusions Results highlight the widespread use of GLP-1 receptor agonists for treatment of type 2 diabetes in the UK. However, almost a quarter of GPs reported that they do not have enough knowledge to prescribe GLP-1s, suggesting a need for increased dissemination of information to targeted groups of physicians. Study limitations were that the generalizability of the clinician sample is unknown; survey questions required clinicians to select answers from multiple response options rather than generating the responses themselves; and responses to this survey conducted in 2014 do not reflect perceptions of the most recently introduced GLP-1 receptor agonists.

Advances in Small-Molecule GPR40 Agonists for Treatment of Type 2 Diabetes Mellitus

Advances in Small-Molecule GPR40 Agonists for Treatment of Type 2 Diabetes Mellitus

In vitro and mouse in vivo characterization of the potent free fatty acid 1 receptor agonist TUG-469

Activation of the G protein-coupled free fatty acid receptor 1 (FFA1; formerly known as GPR40) leads to an enhancement of glucose-stimulated insulin secretion from pancreatic β-cells. TUG-469 has previously been reported as a potent FFA1 agonist. This study was performed to confirm the higher in vitro potency of TUG-469 compared to the reference FFA1 agonist GW9508 and to prove in vivo activity in a pre-diabetic mouse model. The in vitro pharmacology of TUG-469 was studied using Ca(2+)-, cAMP-, and impedance-based assays at recombinant FFA1 and free fatty acid receptor 4, formerly known as GPR120 (FFA4) expressing 1321N1 cells and the rat insulinoma cell line INS-1. Furthermore, we investigated the systemic effect of TUG-469 on glucose tolerance in pre-diabetic New Zealand obese (NZO) mice performing a glucose tolerance test after intraperitoneal administration of 5 mg/kg TUG-469. In comparison to GW9508, TUG-469 showed a 1.7- to 3.0-times higher potency in vitro at 1321N1 cells recombinantly expressing FFA1. Both compounds increased insulin secretion from rat insulinoma INS-1 cells. TUG-469 is > 200-fold selective for FFA1 over FFA4. Finally, a single dose of 5 mg/kg TUG-469 significantly improved glucose tolerance in pre-diabetic NZO mice. TUG-469 turned out as a promising candidate for further drug development of FFA1 agonists for treatment of type 2 diabetes mellitus.

GLP1 and cancer: friend or foe?

The new incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) receptor agonists are widely used for the treatment of type 2 diabetes because of their glucose-lowering capacity with low risk of hypoglycemia. As they are weight neutral or induce weight loss in this mostly overweight population, they are popular among clinicians and patients alike. Nonetheless, concerns have been raised about GLP1's trophic effects. While increased β cell mass observed in rodents sounds appealing for treatment of diabetes, there was also an increased incidence of medullary thyroid cancer (MTC) in some species. We reviewed literature available in the Medline database until March 2012. Safety signals have emerged for MTC and pancreatic carcinoma from adverse event databases in the United States and Europe. Considering the relatively short duration of these studies, it is more likely that premalignant lesions are stimulated in presence of GLP1, rather than new neoplasms induced. Moreover, interpreting results of animal studies is difficult because of species-specific differences in presence and density of GLP1 receptors. Furthermore, data are emerging suggesting beneficial effects of GLP1 on colon and breast cancer. In conclusion, presently, the benefits of using DPP4 inhibitors or GLP1 receptor agonists for treatment of type 2 diabetes outweigh the risks. Nonetheless, their safety profile should be monitored and their indications should be widened cautiously. At present they remain contra-indicated in patients with a personal or family history of MTC or multiple endocrine neoplasia type 2.