Glucagon-like peptide 1 agonists for type 2 diabetes, weight loss, or both?

ABSTRACT: Glucagon-like peptide 1 agonists (GLP1s) and the novel glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 agonist are effective drugs for reducing A1C and weight in patients with type 2 diabetes. However, clinicians may find it difficult to discern which drug to prescribe in specific clinical scenarios. This article discusses evidence-based clinical use of these drugs.

At ObesityWeek, More Data and Questions About Semaglutide, Tirzepatide, and Retatrutide.

This Medical News article discusses weight-loss medications highlighted at ObesityWeek 2023.

Impact of a dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta-analysis.

AIMS: To evaluate the impact of a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide (TZP), and its potential dose-response effect, on heart rate. METHODS: Articles were searched from PubMed, Web of Science, Embase, Cochrane Library, and clinical trials registries (ClinicalTrials.gov) databases. Randomized controlled trials (RCTs) comparing TZP at doses of 5, 10 and 15 mg in adults with type 2 diabetes were included. Six study arms were summarized from original research (TZP 5, 10 and 15 mg, GLP-1 receptor agonists [GLP-1RAs], insulin, placebo). The GLP-1RA and non-GLP-1RA groups were combined to form a control group. Two reviewers independently extracted data and assessed the quality of each study. Mean differences (MDs) were calculated as effect estimates for continuous outcomes. Pairwise meta-analyses and network meta-analyses were conducted. The study protocol was prospectively registered (PROSPERO ID: CRD42023418551). RESULTS: Eight articles were included in this systematic review and meta-analysis. The mean baseline heart rate ranged from 65.2 to 75.7 beats per minute. Pairwise meta-analysis showed that, compared with combined the control group, there were significantly greater increases in heart rates in the TZP group (MD 1.82, 95% confidence interval [CI] 0.75, 2.89). Similar significant rises were identified when comparing TZP with GLP-1RAs and non-GLP-1RAs (GLP-1 RAs: MD 2.29, 95% CI 1.00, 3.59; non-GLP-1RAs: MD 1.58, 95% CI 0.26, 2.91). TZP 5 mg was associated with smaller increases in heart rates compared to TZP 10 mg and TZP 15 mg (TZP 10 mg: MD -0.97, 95% CI -1.79, -0.14; TZP 15 mg: MD -2.57, 95% CI -3.79, -1.35). TZP 10 mg increased heart rate less than TZP 15 mg (MD -1.5, 95% CI -2.38, -0.82). Network meta-analysis indicated that TZP 15 mg was associated with significant increases in heart rate compared with TZP 5 mg (MD 2.53, 95% CI 1.43, 3.62), TZP 10 mg (MD 1.44, 95% CI 0.35, 2.53), GLP-1RAs (MD 3.46, 95% CI 1.67, 5.25), insulin (MD 2.86, 95% CI 1.32, 4.41) and placebo (MD 2.96, 95% CI 1.36, 4.57). CONCLUSIONS: Our study showed not only that there was a greater increase in heart rate in the TZP group than in the control, GLP-1RA and non-GLP-1RA groups, but also that the 15-mg dose of TZP had the strongest impact on increasing heart rates compared with the other five inventions, with a TZP dose-response impact on heart rate. Further research on the effects of TZP treatment-related increases in heart rate is required.

Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.

BACKGROUND: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. METHODS: We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. RESULTS: We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. CONCLUSIONS: In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).

A systematic review of the safety of tirzepatide-a new dual GLP1 and GIP agonist - is its safety profile acceptable?

Aims: Tirzepatide is a novel dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA). At present, there is no controversy over its effectiveness, but its safety. We conducted a systematic review to assess the safety of tirzepatide. Methods: We searched PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs) of tirzepatide from databases inception to August 28, 2022 and used the Cochrane Systematic Assessment Manual Risk of Bias Assessment Tool (version 5.1) and modified Jadad scale to assess risk of bias. The systematic review was conducted via Revman5.4. Results: Nine RCTs with a total of 9818 patients were included. The overall safety profile of tirzepatide is similar to GLP-1RAs, except for the hypoglycemia (tirzepatide 15mg, pooled RR=3.83, 95% CI [1.19- 12.30], P=0.02) and discontinuation (tirzepatide 10mg, pooled RR=1.75,95%CI[1.16-2.63], P=0.007 and 15mg, pooled RR=2.03, 95%CI [1.37-3.01], P=0.0004). It also showed that the dose escalation could not rise the occurrence rates of total, severe, gastrointestinal adverse events and hypoglycemia (P>0.05); Compared with 5mg, tirzepatide 10mg and 15mg were associated with more frequent nausea (P<0.001), discontinuation (P<0.05) and injection-site reaction (P<0.01); The rates of vomiting and diarrhea were dose-dependence at the range of 5-15mg. Conclusion: The safety profile of tirzepatide is generally acceptable, similar to GLP-1 RAs. It is necessary to pay attention to its specific adverse events (hypoglycemia and discontinuation) at high doses (10mg or higher). Nausea, vomiting, diarrhea, discontinuation and injection-site reaction were dose-dependence among specific dose ranges.As the heterogeneity in different studies by interventions, the results may be with biases and the further confirmation is needed. Meanwhile, more well-designed trials are needed to control the confounding factors and ensure adequate sample size.

Treatment of Type 2 Diabetes and Obesity on the Basis of the Incretin System: The 2021 Banting Medal for Scientific Achievement Award Lecture.

In my lecture given on the occasion of the 2021 Banting Medal for Scientific Achievement, I briefly described the history of the incretin effect and summarized some of the developments leading to current therapies of obesity and diabetes based on the incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In the text below, I discuss in further detail the role of these two hormones for postprandial insulin secretion in humans on the basis of recent studies with antagonists. Their direct and indirect actions on the ß-cells are discussed next as well as their contrasting actions on glucagon secretion. After a brief discussion of their effect on insulin sensitivity, I describe their immediate actions in patients with type 2 diabetes and emphasize the actions of GLP-1 on ß-cell glucose sensitivity, followed by a discussion of their extrapancreatic actions, including effects on appetite and food intake in humans. Finally, possible mechanisms of action of GIP-GLP-1 coagonists are discussed, and it is concluded that therapies based on incretin actions are likely to change the current hesitant therapy of both obesity and diabetes.

Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes.

CONTEXT: Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. OBJECTIVE: Explore mechanisms of glucose control by tirzepatide. DESIGN: Post hoc analyses of fasting biomarkers and multiple linear regression analysis. SETTING: Forty-seven sites in 4 countries. PATIENTS OR OTHER PARTICIPANTS: Three hundred and sixteen subjects with type 2 diabetes. INTERVENTIONS: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. MAIN OUTCOME MEASURES: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. RESULTS: Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. CONCLUSIONS: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

Characterizing Effects of Antidiabetic Drugs on Heart Rate, Systolic and Diastolic Blood Pressure.

A model-based meta-analysis was performed with reported data from obese subjects and patients with type 2 diabetes (T2DM) to characterize the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, gastric inhibitory polypeptides (GIPs), glucagon-like peptide-1 (GLP1), and dual GIP/GLP1 agonists, or a combination of these antidiabetic drugs (ADs) on heart rate (HR), diastolic blood pressure (DBP), and systolic blood pressure (SBP). A systematic literature search and review after the Cochrane method identified sources for investigational and approved ADs resulted in a comprehensive database with data from 178 clinical studies in obese subjects and patients with T2DM. Results indicated that there were AD class-dependent effects on HR and SBP, whereas no clear AD-related effects on DBP were found. All AD classes, except for DPP4 inhibitors, increased HR. The largest increase of 12 bpm was seen with GLP1 receptor agonists. All AD classes appeared to decrease SBP. DPP4 inhibitors were associated with a marginal decrease of ~ 1 mmHg, whereas GLP1 and GIP/GLP1 dual agonists exhibited the largest decrease of ~ 3 mmHg in SBP. AD-related effects were similar in obese subjects and patients with T2DM. In conclusion, there are clinically relevant AD-related effects on both HR and SBP, but not on DBP. DPP4 inhibitors are associated with the smallest (if at all) effects on HR and SBP, whereas GLP1 inhibitors exhibited the largest effects on these two cardiovascular end points. Additional studies are warranted to further investigate how AD-related SBP decreases combined with HR increases affect long-term cardiovascular mortality.

Rational design of a GLP-1/GIP/Gcg receptor triagonist to correct hyperglycemia, obesity and diabetic nephropathy in rodent animals.

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.

Enhanced agonist residence time, internalization rate and signalling of the GIP receptor variant [E354Q] facilitate receptor desensitization and long-term impairment of the GIP system.

In patients with type 2 diabetes mellitus (T2DM), the insulinotropic action of the GIP system is desensitized, whereas this is not the case for the GLP-1 system. This has raised an interesting discussion of whether GIP agonists or antagonists are most suitable for future treatment of T2DM together with GLP-1-based therapies. Homozygous carriers of the GIP receptor (GIPR) variant, [E354Q], display lower bone mineral density, increased bone fracture risk and slightly increased blood glucose. Here, we present an in-depth molecular pharmacological phenotyping of GIPR-[E354Q]. In silico modelling suggested similar interaction of the endogenous agonist GIP(1-42) to [E354Q] as to GIPR wt. This was supported by homologous competition binding in COS-7 cells revealing GIPR wt-like affinities of GIP(1-42) with Kd values of ~2 nmol/L and wt-like agonist association rates (Kon ). In contrast, the dissociation rates (Koff ) were slower, resulting in 25% higher agonist residence time for GIPR-[E354Q]. Moreover, in Gαs signalling (cAMP production) GIP(1-42) was ~2-fold more potent and more efficacious on GIPR-[E354Q] compared to wt with 17.5% higher basal activity. No difference from GIPR wt was found in the recruitment of ß-arrestin 2, whereas the agonist-induced internalization rate was 2.1- to 2.3-fold faster for [E354Q]. Together with the previously described impaired recycling of [E354Q], our findings with enhanced signalling and internalization rate possibly explained by an altered ligand-binding kinetics will lead to receptor desensitization and down-regulation. This could explain the long-term functional impairment of the GIP system in bone metabolism and blood sugar maintenance for [E354Q] carriers and may shed light on the desensitization of the insulinotropic action of GIP in patients with T2DM.

Neurotrophic and neuroprotective effects of a monomeric GLP-1/GIP/Gcg receptor triagonist in cellular and rodent models of mild traumatic brain injury.

A synthetic monomeric peptide triple receptor agonist, termed "Triagonist" that incorporates glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (Gcg) actions, was previously developed to improve upon metabolic and glucose regulatory benefits of single and dual receptor agonists in rodent models of diet-induced obesity and type 2 diabetes. In the current study, the neurotrophic and neuroprotective actions of this Triagonist were probed in cellular and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in both the young and elderly. Triagonist dose- and time-dependently elevated cyclic AMP levels in cultured human SH-SY5Y neuronal cells, and induced neurotrophic and neuroprotective actions, mitigating oxidative stress and glutamate excitotoxicity. These actions were inhibited only by the co-administration of antagonists for all three receptor types, indicating the balanced co-involvement of GLP-1, GIP and Gcg receptors. To evaluate physiological relevance, a clinically translatable dose of Triagonist was administered subcutaneously, once daily for 7 days, to mice following a 30 g weight drop close head injury. Triagonist fully mitigated mTBI-induced visual and spatial memory deficits, evaluated at 7 and 30 days post injury. These results establish Triagonist as a novel neurotrophic/protective agent worthy of further evaluation as a TBI treatment strategy.

Selection and progression of unimolecular agonists at the GIP, GLP-1, and glucagon receptors as drug candidates.

The continued global growth in the prevalence of obesity coupled with the limited number of efficacious and safe treatment options elevates the importance of innovative pharmaceutical approaches. Combinatorial strategies that harness the metabolic benefits of multiple hormonal mechanisms have emerged at the preclinical and more recently clinical stages of drug development. A priority has been anti-obesity unimolecular peptides that function as balanced, high potency poly-agonists at two or all the cellular receptors for the endocrine hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon. This report reviews recent progress in this area, with emphasis on what the initial clinical results demonstrate and what remains to be addressed.

Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes.

Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor-directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1's activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic islet ß cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.

DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP-1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP-1/GIP dual agonist DA5-CH that activates the incretin hormone GLP-1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5-CH administration effectively improved working-memory and long-term spatial memory of 9-month-old AD mice in Y-maze and Morris water maze tests; (2) DA5-CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5-CH basically reversed the deficits in hippocampal late-phase long-term potentiation; (4) DA5-CH up-regulated the levels of p-PI3K and p-AKT growth factor kinases and prevented excessive activation of p-GSK3ß in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5-CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5-CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

Do we know the true mechanism of action of the DPP-4 inhibitors?

The prevalence of type 2 diabetes is increasing, which is alarming because of its serious complications. Anti-diabetic treatment aims to control glucose homeostasis as tightly as possible in order to reduce these complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors are a recent addition to the anti-diabetic treatment modalities, and have become widely accepted because of their good efficacy, their benign side-effect profile and their low hypoglycaemia risk. The actions of DPP-4 inhibitors are not direct, but rather are mediated indirectly through preservation of the substrates they protect from degradation. The two incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, are known substrates, but other incretin-independent mechanisms may also be involved. It seems likely therefore that the mechanisms of action of DPP-4 inhibitors are more complex than originally thought, and may involve several substrates and encompass local paracrine, systemic endocrine and neural pathways, which are discussed here.

Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects.

AIMS: To evaluate the pharmacodynamics, pharmacokinetics and safety of single subcutaneous (s.c.) injection of ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in healthy subjects. METHODS: A total of 51 healthy volunteers were enrolled in this double-blind, placebo-controlled study investigating RG7697 doses ranging from 0.03 to 5 mg. Adverse events (AEs) were monitored and drug concentrations, fasting glycaemic variables, vital signs, ECG, antibody formation and routine laboratory variables were assessed. A meal tolerance test (MTT) was performed at the same time on day -1 (baseline) and day 1. RESULTS: RG7697 was generally well tolerated in healthy participants after s.c. injections up to 3.6 mg. Tolerability was limited by gastrointestinal AEs (nausea and vomiting) at the highest dose. There was a small dose-dependent increase in heart rate. No episodes of hypoglycaemia occurred. RG7697 concentrations peaked at 2 to 4 hours post-dose with a half-life of 19 to 25 hours. During MTT, RG7697 at doses ≥1.8 mg, reduced glucose maximum plasma concentration (Cmax ; -46%) without affecting overall glucose area under the curve (AUC). Its effect on insulin was more pronounced, with reductions in both Cmax (-64%) and AUC (-51%). Pharmacodynamic variables were well correlated to RG7697 average plasma concentration during MTT, with IC50 (average concentration required for 50% reduction) values of 49 and 24.5 ng/mL for glucose and insulin, respectively. CONCLUSION: Single s.c. injections of RG7697 up to 3.6 mg were generally well tolerated. Evidence of glycaemic effect and pharmacokinetic profiles consistent with once-daily dosing render this drug candidate suitable to be further tested in multiple-dose clinical trials in patients with type 2 diabetes.

Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus.

AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of RG7697, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist, in patients with type 2 diabetes mellitus (T2D). METHODS: A total of 56 patients with T2D received once-daily subcutaneous (s.c.) injection of RG7697 (0.25-2.5 mg) or placebo for 14 days in a randomized, double-blind, dose-escalation study. Adverse events (AEs), vital signs, ECGs and routine laboratory variables were intensively monitored. Drug concentrations, fasting glycaemic variables, 24-hour glucose profiles, glycated haemoglobin (HbA1c) and antibody formation were measured. Several meal tolerance and gastric emptying tests were performed during the study. RESULTS: Daily s.c. injections of RG7697 were well tolerated by the majority of participants with T2D. The most frequently reported AEs with RG7697 were diarrhoea, nausea and decreased appetite. Asymptomatic events of hypoglycaemia were relatively uniformly distributed across dose groups including placebo. Pharmacokinetic steady-state was achieved within 1 week. Meaningful reductions in fasting, postprandial and 24-hour plasma glucose profile were observed at doses ≥0.75 mg, and were associated with numerical decreases in HbA1c (-0.67% [2.5-mg dose] vs -0.21% [placebo]). Decrease in postprandial insulin at doses ≥1.1 mg suggested improvement in insulin sensitivity. Minimum delay in gastric emptying and body weight reductions numerically greater than placebo (- 3.0 kg vs -0.9 kg) were seen at the highest dose of 2.5 mg. CONCLUSIONS: Daily doses of RG7697 for 2 weeks were well tolerated by the majority of patients with T2D. Pharmacokinetic data supported once-daily dosing and pharmacodynamic effect displayed dose-dependent reductions in fasting and postprandial plasma glucose, without increasing the risk of hypoglycaemia.

Benefits and challenges of a QSP approach through case study: Evaluation of a hypothetical GLP-1/GIP dual agonist therapy.

Quantitative Systems Pharmacology (QSP) is an emerging science with increasing application to pharmaceutical research and development paradigms. Through case study we provide an overview of the benefits and challenges of applying QSP approaches to inform program decisions in the early stages of drug discovery and development. Specifically, we describe the use of a type 2 diabetes systems model to inform a No-Go decision prior to lead development for a potential GLP-1/GIP dual agonist program, enabling prioritization of exploratory programs with higher probability of clinical success.

Glucagon receptor antagonist and GIP agonist combination for diet-induced obese mice.

Ablation of glucagon receptor signaling represents a potential treatment option for type 2 diabetes (T2DM). Additionally, activation of glucose-dependent insulinotropic polypeptide (GIP) receptor signaling also holds therapeutic promise for T2DM. Therefore, this study examined both independent and combined metabolic actions of desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon (glucagon receptor antagonist) and d-Ala(2)GIP (GIP receptor agonist) in diet-induced obese mice. Glucagon receptor binding has been linked to alpha-helical structure and desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon displayed enhanced alpha-helical content compared with native glucagon. In clonal pancreatic BRIN-BD11 beta-cells, desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon was devoid of any insulinotropic or cAMP-generating actions, and did not impede d-Ala(2)GIP-mediated (P<0.01 to P<0.001) effects on insulin and cAMP production. Twice-daily injection of desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon or d-Ala(2)GIP alone, and in combination, in high-fat-fed mice failed to affect body weight or energy intake. Circulating blood glucose levels were significantly (P<0.05 to P<0.01) decreased by all treatments regimens, with plasma and pancreatic insulin elevated (P<0.05 to P<0.001) in all mice receiving d-Ala(2)GIP. Interestingly, plasma glucagon concentrations were decreased (P<0.05) by sustained glucagon inhibition (day 28), but increased (P<0.05) by d-Ala(2)GIP therapy, with a combined treatment resulting in glucagon concentration similar to saline controls. All treatments improved (P<0.01) intraperitoneal and oral glucose tolerance, and peripheral insulin sensitivity. d-Ala(2)GIP-treated mice showed increased glucose-induced insulin secretion in response to intraperitoneal and oral glucose. Metabolic rate and ambulatory locomotor activity were increased (P<0.05 to P<0.001) in all desHis(1)Pro(4)Glu(9)(Lys(12)PAL)-glucagon-treated mice. These studies highlight the potential of glucagon receptor inhibition alone, and in combination with GIP receptor activation, for T2DM treatment.