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Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors ("multi-agonists"), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1)-based drugs have been approved by the United States Food and Drug Administration (FDA) and are widely used to treat type 2 diabetes mellitus (T2DM) and obesity. More recent developments of unimolecular peptides targeting multiple incretin-related receptors (“multi-agonists”), including the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and the glucagon (Gcg) receptor (GcgR), have emerged with the aim of enhancing drug benefits. In this study, we utilized human and mouse microglial cell lines, HMC3 and IMG, respectively, together with the human neuroblastoma SH-SY5Y cell line as cellular models of neurodegeneration. Using these cell lines, we studied the neuroprotective and anti-inflammatory capacity of several multi-agonists in comparison with a single GLP-1 receptor (GLP-1R) agonist, exendin-4. Our data demonstrate that the two selected GLP-1R/GIPR dual agonists and a GLP-1R/GIPR/GcgR triple agonist not only have neurotrophic and neuroprotective effects but also have anti-neuroinflammatory properties, as indicated by the decreased microglial cyclooxygenase 2 (COX2) expression, nitrite production, and pro-inflammatory cytokine release. In addition, our results indicate that these multi-agonists have the potential to outperform commercially available single GLP-1R agonists in neurodegenerative disease treatment.

Unlabelled: Highly effective antiobesity and diabetes medications such as glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide/GLP-1 (dual) receptor agonists (RAs) have ushered in a new era of treatment of these highly prevalent, morbid conditions that have increased across the globe. However, the rapidly escalating use of GLP-1/dual RA medications is poised to overwhelm an already overburdened health care provider workforce and health care delivery system, stifling its potentially dramatic benefits. Relying on existing systems and resources to address the oncoming rise in GLP-1/dual RA use will be insufficient. Generative artificial intelligence (GenAI) has the potential to offset the clinical and administrative demands associated with the management of patients on these medication types. Early adoption of GenAI to facilitate the management of these GLP-1/dual RAs has the potential to improve health outcomes while decreasing its concomitant workload. Research and development efforts are urgently needed to develop GenAI obesity medication management tools, as well as to ensure their accessibility and use by encouraging their integration into health care delivery systems., (© Elizabeth R Stevens, Arielle Elmaleh-Sachs, Holly Lofton, Devin M Mann. Originally published in JMIR Diabetes (https://diabetes.jmir.org).)

Aim: To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes. Materials and Methods: The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS‐2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin‐only treated patients were used for primary analysis. Results: The SURPASS‐2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin‐only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of −0.36% (95% confidence interval [CI] −0.63, −0.09) and −0.4% (95% CI −0.67, −0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of −3.15 kg (95% CI −4.84, −1.46) and −5.15 kg (95% CI −6.85, −3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight. Conclusions: In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head‐to‐head clinical trial. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) receptor agonist-based drugs (incretin mimetics) have meaningfully impacted current treatment of type 2 diabetes mellitus (T2DM), and their actions on satiety and weight loss have led to their use as an obesity medication. With multiple pleotropic actions beyond their insulinotropic and weight loss ones, including anti-inflammatory and anti-insulin-resistant effects selectively mediated by their receptors present within numerous organs, this drug class offers potential efficacy for an increasing number of systemic and neurological disorders whose current treatment is inadequate. Among these are a host of neurodegenerative disorders that are prevalent in the elderly, such as Parkinson's and Alzheimer's disease, which have bucked previous therapeutic approaches. An increasing preclinical, clinical, and epidemiological literature suggests that select incretin mimetics may provide an effective treatment strategy, but 'which ones' for 'which disorders' and 'when' remain key open questions. • GLP-1 receptor agonists (RA) have become widely prescribed drugs (type 2 diabetes/weight loss). • GLP-1RA repurposing is being clinically evaluated in neurodegenerative disorders of the elderly. • Clinical trials of GLP-RAs are promising in Parkinson's disease – Alzheimer studies are ongoing. • GLP-1RAs with action on GIP and other receptors are available and may offer greater benefit. • Selection of the best GLP-1RAs, most likely patients to respond and best time to treat is critical. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions.

Type-2 diabetes mellitus (T2DM) is a complicated long-term disorder associated with metabolism that is identified by insulin resistance, imbalance in glucose regulation and reduced secretion of insulin. GLP-1(Glucagon-like peptide-1) is an incretin mimetic that has excellent effects on the regulation of blood glucose levels and also the management of disorders associated with vital organs. GLP-1 agonist is an effective class of drug for the treatment of type-2 diabetes mellitus and associated complications. Liraglutide is one of the potent drugs of this class having similar effects as biological GLP-1. This review includes clinical trials and patents related to the pharmaceutical formulation, synthesis and biological action of liraglutide.

Abstract Traumatic brain injury (TBI) is a neurodegenerative disorder for which no effective pharmacological treatment is available. Glucagon-like peptide 1 (GLP-1) analogues such as Exenatide have previously demonstrated neurotrophic and neuroprotective effects in cellular and animal models of TBI. However, chronic or repeated administration was needed for efficacy. In this study, the pharmacokinetics and efficacy of PT302, a clinically available sustained-release Exenatide formulation (SR-Exenatide) were evaluated in a concussive mild (m)TBI mouse model. A single subcutaneous (s.c.) injection of PT302 (0.6, 0.12, and 0.024 mg/kg) was administered and plasma Exenatide concentrations were time-dependently measured over 3 weeks. An initial rapid regulated release of Exenatide in plasma was followed by a secondary phase of sustained-release in a dose-dependent manner. Short- and longer-term (7 and 30 day) cognitive impairments (visual and spatial deficits) induced by weight drop mTBI were mitigated by a single post-injury treatment with Exenatide delivered by s.c. injection of PT302 in clinically translatable doses. Immunohistochemical evaluation of neuronal cell death and inflammatory markers, likewise, cross-validated the neurotrophic and neuroprotective effects of SR-Exenatide in this mouse mTBI model. Exenatide central nervous system concentrations were 1.5% to 2.0% of concomitant plasma levels under steady-state conditions. These data demonstrate a positive beneficial action of PT302 in mTBI. This convenient single, sustained-release dosing regimen also has application for other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy and multiple sclerosis where prior preclinical studies, likewise, have demonstrated positive Exenatide actions. Highlights • PT302 is a sustained-release formulation of Exenatide that generates steady-state plasma levels. • PT302 post-treatment mitigates neuronal loss induced by mild TBI in mice. • PT302 post-treatment mitigates neuroinflammation induced by mild TBI in mice. • PT302 post-treatment mitigates behavioral impairments induced by mild TBI in mice. • All the above was achieved at clinically translatable doses of PT302. [ABSTRACT FROM AUTHOR]

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

The prevalence of diabetes continues to rise worldwide. Over the past five years, available treatment options have expanded to allow individualized management of patients with diabetes. The glucagon-like peptide-1 (GLP-1) receptor agonists have become an essential tool in the management of type 2 diabetes mellitus (T2DM). This class provides several advantages for glycemic control with minimal risk of hypoglycemia. Based on the most recent guidelines for T2DM, GLP-1 receptor agonists can be prescribed as monotherapy or in combination with oral antidiabetic agents or insulin for the management of T2DM. Dulaglutide has become the most recent and available GLP-1 receptor agonist on the market. Dulaglutide is a once-weekly GLP-1 receptor agonist that can be used as monotherapy or as a second-line agent for T2DM. This review article summarizes the efficacy, safety, and clinical attributes of dulaglutide among patients with T2DM. [ABSTRACT FROM PUBLISHER]

Insulin therapy in the management of Type 2 diabetes is often postponed and/or not adequately intensified to maintain glycemic control because of the risk of weight gain and hypoglycemia. A fixed combination of the long-acting insulin degludec and liraglutide has recently been accepted by the EMA for the management of Type 2 diabetes. The incentive for this combination is to exploit the advantages of each of the drugs while counterbalancing the side effects. Insulin degludec effectively reduces fasting plasma glucose, but carries the risk of hypoglycemia and body weight gain. Liraglutide, on the other hand, exerts glycemic control with a minimal risk of hypoglycemia and, at the same time, reduces appetite and body weight. [ABSTRACT FROM AUTHOR]

Introduction: As the prevalence of type 2 diabetes mellitus (T2DM) is anticipated to continue to rise worldwide, so too are the treatment options also continuing to expand. Current guidelines recommend individualized treatment plans which allow for provider choice and diversity of pharmacotherapeutic regimens. The glucagon-like peptide-1 receptor agonist (GLP-1 RA) class is rapidly expanding, with dulaglutide (Trulicity™) as a once-weekly agent recently approved. Aims: This article examines the evidence currently available on the efficacy and safety of dulaglutide for use in T2DM. Evidence review: Dulaglutide has been shown to have similar efficacy and safety to other newer GLP-1 RAs, and better glycemic control than placebo. It lowers glycated hemoglobin (A1c), fasting and postprandial glucose levels, and promotes weight loss when used as first-, second-, or third-line therapy. It has also been shown to improve β-cell function and provide cardiovascular benefits, such as lower blood pressure and improved lipid levels. Dulaglutide also has a low risk for hypoglycemia and a similar adverse effect profile to other GLP-1 RAs in the class, with transient gastrointestinal problems and potential risk for pancreatitis. Place in therapy: While long-term data on safety and efficacy are forthcoming, dulaglutide is positioned to be placed at the same level as other GLP-1 RAs in the class: as second-line therapy in addition to diet and exercise in those patients who cannot achieve glycemic control on monotherapy metformin. It may also be useful as first-line therapy instead of metformin. Conclusion: Dulaglutide is a once-weekly GLP-1 RA approved for the treatment of T2DM that has shown similar efficacy to other agents in this class. [ABSTRACT FROM AUTHOR]

Background: Dyslipidemia and type 2 diabetes are two of the most significant risk factors for the development of cardiovascular disease. Measurement of lipoprotein subclasses provides important information about derangements in lipid metabolism and helps refine cardiovascular risk assessment. Exenatide, a glucagon-like peptide 1 receptor agonist, improved glycemic control, obesity, hypertension, and dyslipidemia in patients with type 2 diabetes in clinical trials. Methods: In the DURATION-1 trial, patients with type 2 diabetes were treated with exenatide once weekly or twice daily for 30 weeks. This post hoc analysis evaluated the impact of exenatide on lipoprotein subclasses in 211 DURATION-1 patients using vertical auto profile methodology and the Statistical Package for the Social Sciences general linear model adjusted for glycosylated hemoglobin (HbA1c) and weight. Results: Baseline lipids and high sensitivity C-reactive protein were normal overall based on the standard lipid panel. Once-weekly exenatide reduced apolipoprotein B and the apolipoprotein B to apolipoprotein A1 ratio (P < 0.05), independent of glycemic improvement and weight loss. A significant shift in lipoprotein pattern away from small, dense low-density lipoprotein-4 cholesterol was also observed (P < 0.05). Exenatide once weekly increased high-density lipoprotein-2 cholesterol, even after adjustment for changes in HbA1c and weight (P < 0.05). Triglycerides, very low-density lipoprotein cholesterol, and high sensitivity C-reactive protein were reduced with both the once-weekly and twice-daily exenatide regimens (P < 0.05). Conclusion: In this post hoc analysis, exenatide significantly improved a number of cardiovascular risk markers. Continuous exenatide exposure with exenatide once weekly elicited a greater response than did immediate-release exenatide twice daily, generally independent of glycemic improvement and weight loss. Thus, in addition to improving glycemic control, exenatide induced favorable changes in lipid and lipoprotein metabolism and decreased systemic inflammation. [ABSTRACT FROM AUTHOR]

To determine the insulinotropic effects of an incretin mimetic, exenatide, a hyperglycemic clamp was used to evaluate three different doses (0.1, 0.24, and 1 μg/kg) administered subcutaneously to healthy cats. Subsequently, drug safety during chronic administration was evaluated during 4 weeks of twice daily exenatide treatment. Administration of exenatide at the highest dose tested, 1 μg/kg, increased plasma insulin concentration during hyperglycemia from 15 to 120, and also at 240 minutes post administration, as compared to a saline control. Exenatide at lower doses (0.1 and 0.24 μg/kg) had lesser effects on plasma insulin concentrations, thus insulin release was stimulated in a dose-dependent manner. Chronic administration of 1 μg/kg exenatide did not lead to apparent adverse effects, but significant weight loss was observed in cats during this period. Exenatide's insulinotropic action combined with its safety profile in healthy cats suggests that study in diabetic cats is warranted [ABSTRACT FROM AUTHOR]

Abstract: Exendin-4 is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. EXf is an available carboxy-terminal truncated fragment of exendin-4 with two amino acid substitutions. The purpose of these studies was to evaluate the biological activity of EXf. After a single subcutaneous injection, EXf significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge both in non-diabetic (ICR), monosodium l-glutamate induced insulin resistance (MSG-IR) and diabetic KK-ay mice. Meanwhile, EXf resulted in an increase of first-phase insulin secretion in normal mice and KK-ay mice following the glucose challenge. EXf was also shown to inhibit small intestinal transit in rodent models. EXf activated the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1) GFP-construct in a dose-dependent manner in the cultured mouse insulinoma cell line, termed NIT-1, and this agonist activity was blocked by the glucagon-like peptide 1 (GLP-1) receptor antagonist exendin(9–39). In summary, EXf, an analogue of exendin-4, has agonist activity to GLP-1 receptor in vitro and glucoregulatory activities in vivo, thus it can be considered as a new candidate for the treatment of type 2 diabetes. [Copyright &y& Elsevier]

What is already known about this subject • Nonclinical studies have shown that exenatide is primarily cleared by the renal system. • It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI). What this study adds • Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide. • However, exenatide is not recommended in patients with severe RI or end-stage renal disease. Aims To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). Methods Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end-stage renal disease (ESRD) requiring haemodialysis ( n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. Results Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.). Conclusions Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD. [ABSTRACT FROM AUTHOR]

Abstract: Background: Exenatide was approved by the US Food and Drug Administration (FDA) in April 2005 as adjunctive therapy to metformin or a sulfonylurea for the treatment of type 2 diabetes mellitus (DM). Objective: We evaluated whether use of exenatide soon after its approval was consistent with the FDA- approved indications. Methods: We assembled a retrospective cohort of patients with DM using data from a population of employed persons and their dependents, including pharmacy claims and claims for inpatient and outpatient services, provided by i3 Innovus. The data set included patients aged between 18 and 64 years with a diagnosis of DM or a claim for a DM drug from June 1, 2004, to December 31, 2005. Laboratory data were available for a subgroup of patients tested at specific commercial laboratories from June 1, 2003, to December 31, 2005. In addition, we requested data for patients with a diagnosis of obesity, regardless of a diagnosis of DM, to assess early off-label use of this medication. Patients were categorized by DM medication use and by their first fill date for exenatide, and their clinical characteristics were described. Early use was defined as filling a prescription for exenatide in the first 3 months after its approval. For descriptive purposes, we reported the means and percentages for the variables described. Results: The study included data for 206,345 individuals (mean age, 51.3 years), of whom 54.0% were male. Starting in June 2005, prescriptions for exenatide were filled by 3225 (1.6%) individuals. Fifty-three percent of early users were women. Among those who filled a prescription for exenatide, 21.9% were obese, compared with 10.9% to 15.1% of those filling prescriptions for other DM medications. The proportion of patients filling a prescription for exenatide who had not received a prescription for any other DM medication in the preceding year was 14%, suggesting that exenatide was their initial therapy. A prescription for a thiazolidinedione was filled by 29.9% of patients within 60 days of filling a prescription for exenatide. Conclusions: Soon after its approval, exenatide was frequently used as monotherapy or in combination with a thiazolidinedione, neither of which is an FDA- approved indication. The observation that those filling a prescription for exenatide had a higher prevalence of obesity than those receiving prescriptions for other therapies may reflect awareness of the weight-lowering effects of exenatide. (Clin Ther. 2007;29:1784-1794) Copyright © 2007 Excerpta Medica, Inc. [Copyright &y& Elsevier]

Abstract: Exenatide, the active ingredient of BYETTA® (exenatide injection), is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. Exenatide binds to and activates the known GLP-1 receptor with a potency comparable to that of the mammalian incretin GLP-1(7-36), thereby acting as a glucoregulatory agent. AC3174 is an analog of exenatide with leucine substituted for methionine at position 14, [Leu14]exendin-4. The purpose of these studies was to evaluate the glucoregulatory activity and pharmacokinetics of AC3174. In RINm5f cell membranes, the potency of AC3174 for the displacement of [125I]GLP-1 and activation of adenylate cyclase was similar to that of exenatide and GLP-1. In vivo, AC3174, administered as a single IP injection, significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge in both non-diabetic (C57BL/6) and diabetic db/db mice (P <0.05 vs. vehicle-treated). The magnitude of glucose lowering of AC3174 was comparable to exenatide. The ED50 values of AC3174 for glucose lowering (60 minute post-dose) were 1.2 μg/kg in db/db mice and 1.3 μg/kg in C57BL/6 mice. AC3174 has insulinotropic activity in vivo. Administration of AC3174 resulted in a 4-fold increase in insulin concentrations in normal mice following an IP glucose challenge. AC3174 was also shown to inhibit food intake and decrease gastric emptying in rodent models. AC3174 was stable in human plasma (>90% of parent peptide was present after 5 h of incubation). In rats, the in vivo half-life of AC3174 was 42–43 min following SC administration. In summary, AC3174 is an analog of exenatide that binds to the GLP-1 receptor in vitro and shares many of the biological and glucoregulatory activities of exenatide and GLP-1 in vivo. [Copyright &y& Elsevier]

The aim of this 52-week, open-label, non-inferiority trial was to compare the safety and efficacy of exenatide (an incretin mimetic) with that of biphasic insulin aspart. Patients on metformin and a sulfonylurea were randomised to exenatide ( n = 253; 5 μg twice daily for 4 weeks, 10 μg thereafter) or biphasic insulin aspart ( n = 248; twice-daily doses titrated for optimal glucose control), while continuing with metformin and sulfonylurea treatment. Glycaemic control achieved with exenatide was non-inferior to that achieved with biphasic insulin aspart (mean±SEM, HbA1c change: exenatide −1.04 ± 0.07%, biphasic insulin aspart −0.89 ± 0.06%; difference −0.15 [95% CI −0.32 to 0.01]%). Exenatide-treated patients lost weight, while patients treated with biphasic insulin aspart gained weight [between-group difference −5.4 (95% CI −5.9 to −5.0) kg]. Both treatments reduced fasting serum glucose (exenatide −1.8 ± 0.2 mmol/l, p < 0.001; biphasic insulin aspart −1.7 ± 0.2 mmol/l, p < 0.001). Greater reductions in postprandial glucose excursions following morning ( p < 0.001), midday ( p = 0.002) and evening meals ( p < 0.001) were observed with exenatide. The withdrawal rate was 21.3% (54/253) for exenatide and 10.1% (25/248) for biphasic insulin aspart. Nausea (33% incidence, 3.5% discontinuation) was the most common adverse event observed with exenatide. Exenatide treatment resulted in HbA1c reduction similar to biphasic insulin aspart and provided better postprandial glycaemic control, making it a potential alternative for the treatment of type 2 diabetes. Treatment with biphasic insulin aspart was associated with weight gain and lower risk of adverse gastrointestinal events. Although the availability of glucose-lowering agents associated with weight reduction may be considered a therapeutic advance, the long-term implications of progressive weight reduction observed with exenatide have yet to be defined. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA1c) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide ‘real-world’ exenatide clinical experience. Objective:: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. Methods:: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-pg exenatide, 10-pg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. Results:: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100 119 kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m2; mean [SD] HbA1c, 8.3% [1.0%1] completed 2 years of exenatide treatment. Reductions in mean (SE) HbA1c from baseline to week 30 (−0.9% [0.1%]) were sustained through 2 years (−1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA1c ≤ 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (−2.1 [0.2] kg), with progressive reductions after 2 years (−4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female ≤19 IU/L; male ≤30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (−11 [1] IU/L from baseline 38 [1] IU/1,; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = −0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the β-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. Conclusions: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA1c, progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT. [Copyright &y& Elsevier]

Aim: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30-week placebo-controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82-week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET). Methods: This interim analysis is of 314 patients who received exenatide in the 30-week placebo-controlled trials and subsequently in 52 weeks of open-label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout. Results: Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 ± 10 years, weight 99 ± 21 kg, body mass index 34 ± 6 kg/m2, A1C 8.3 ± 1.0% (mean ± SD)]. Reduction in A1C from baseline to week 30 [−0.9 ± 0.1% (mean ± SE)] was sustained to week 82 (−1.1 ± 0.1%), with 48% of patients achieving A1C ≤ 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (−2.1 ± 0.2 kg), with progressive reduction at week 82 (−4.4 ± 0.3 kg). Similar results were observed for the intent-to-treat population (n = 551), with reductions in A1C and weight at week 82 of −0.8 ± 0.1% and −3.5 ± 0.2 kg respectively. The 82-week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild-to-moderate nausea and hypoglycaemia. Conclusion: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Background: Exenatide is a subcutaneously injected incretin mimetic. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) who are already receiving therapy with metformin, a sulfonylurea, or both but continue to have suboptimal glycemic control. Objective: This article reviews available information on the clinical pharmacology, comparative efficacy, tolerability, drug interactions, contraindications and precautions, dosage and administration, availability and storage, and cost of exenatide. Methods: MEDLINE (1966–April 2006) and Web of Science (1995–April 2006) were searched for original research and review articles published in the English language. The search terms used were exenatide, exendin-4, glucagon-Like peptide-1, GLP-1, and incretin mimetic. The reference lists of identified articles were also consulted, as was selected information from the package insert for exenatide. All relevant comparative efficacy studies that were available in published form were included in the review. Results: Naturally occurring incretins, such as glucagon-like peptide-1 (GLP-1), exhibit insulinotropic properties after release into the circulation from the gut. As a GLP-1 agonist, exenatide improves glucose homeostasis by mimicking the actions of naturally occurring GLP-1. It improves glycemic control by reducing fasting and postprandial glucose concentrations through a combination of known mechanisms, including glucose-dependent insulin secretion, restoration of first-phase insulin response, regulation of glucagon secretion, delaying gastric emptying, and decreasing food intake. Three Phase III comparative efficacy trials were identified that enrolled a total of 1446 patients who received exenatide 5 pg SC BID, exenatide 10 μg SC BID, or placebo for 30 weeks in addition to their existing therapy with metformin, sulfonylurea, or both. In these trials, the addition of exenatide was associated with significant reductions in glycosylated hemoglobin (HbA1c) values (P < 0.001–P < 0.002), greater proportions of patients achieving an HbA1c ≤7%, significant decreases in fasting plasma glucose concentrations (P < 0.001–P < 0.005), and a dose-dependent progressive weight loss compared with placebo. Nausea (43.5%) was the most commonly reported adverse event in the combined exenatide groups. Other adverse events occurring in >10% of patients receiving exenatide were hypoglycemia (19.6%), diarrhea (12.8%), and vomiting (12.8%). Conclusions: During clinical trials, exenatide added to existing metformin and/or sulfonylurea therapy in patients with T2DM reduced fasting and postprandial glucose concentrations, with improvements in HbA1c and modest weight loss. The main adverse effect associated with exenatide therapy was nausea. [Copyright &y& Elsevier]

The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies--including the newly approved incretin mimetic exenatide--that elicit actions similar to those of GLP-1. [ABSTRACT FROM AUTHOR]

Exenatide, (BYETTA TM), is the first in a new class of agents termed incretin mimetics, which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1 (GLP-1). Currently approved (April 2005) in the United States as an injectable adjunct to metformin and/or sulphonylurea therapy, exenatide improves glycaemic control through multiple mechanisms of action including: enhancement of glucose-dependent insulin secretion, restoration of first-phase insulin response, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying and reduction in food intake. Subcutaneous exenatide injected twice-daily before morning and evening meals shows immediate and sustained effects on both postprandial and fasting glucose concentrations and is accompanied by reductions in body weight. Since the actions of exenatide on insulin and glucagon secretion are glucose dependent, the risk of hypoglycaemia is minimised except when exenatide is used in conjunction with agents that induce hypoglycaemia, such as sulphonylureas. Mild-to-moderate nausea is the most common side effect, which can be reduced with dose titration upon initiation of therapy. The incretin mimetic, exenatide, is a novel therapeutic option to improve glycaemic control with potential weight reduction in patients with type 2 diabetes suboptimally controlled with metformin or a sulphonylurea. [ABSTRACT FROM PUBLISHER]

Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic the actions of incretin hormones such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. Several incretin mimetics and DPP-IV inhibitors are undergoing late-stage clinical trials for the treatment of type 2 diabetes. These agents appear to have multiple mechanisms of action, including some or all of the following: enhancement of glucose-dependent insulin secretion; suppression of inappropriately elevated glucagon secretion; slowing of gastric emptying; and decreased food intake (i.e. appetite suppression). Based on preliminary clinical data, incretin mimetics and DPP-IV inhibitors show potential for treating type 2 diabetes. [Copyright &y& Elsevier]

Abstract: Background:: Exenatide (synthetic exendin-4;AC2993) is a 39-amino acid peptide in the new class of antidiabetic agents known as incretin mimetics. In clinical trials, exenatide exhibited glucoregulatory effects (glucose-dependent stimulation of insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying) in patients with type 2 diabetes mellitus (DM). Objective:: The goal of this study was to determine the relative bioavailability of exenatide injected subcutaneously into the abdomen, arm, or thigh. Methods:: Patients with type 2 DM were randomized in an open-label, crossover study to assess relative bioavailability of exenatide (10 μg) injected into the arm and thigh versus injection into the abdomen. Serial plasma exenatide concentrations were measured for 10 hours after injection. A sample size of >24 patients provided ∼80% power to ensure that 90% CIs were within the 80% to 125% interval for the ratios (geometric least squares [LS] means) of AUC0−∞. Results:: Twenty-eight patients were randomized intothe study (mean age, 56 [8] years; glycosylated hemoglobin, 8.0 [1.7]%; body mass index, 33 [5] kg/m2; all values given as mean [SD]). AUC0−∞ values (geometric LS mean SE for SC injections into the abdomen arm and thigh were 63,935 (6608), 59,573 (6157), and 62,148 (6424) pg·/mL, respectively. The AUC (geometric LS mean ratio for relative bioavailability) for arm versus abdomen was 0.93 (geometric 90% CI, 0.82–1.05); for thigh versus abdomen it was 0.97 (geometric 90% CI, 0.86–1.10). Consistent with the observed data, intrasubject variability of AUC0−∞ was low among the 3 treatments (coefficient of variation, 26%). Cmax values (geometric LS mean [SE]) were 220 (24) pg/mL, abdomen; 218 (23) pg/mL, arm; and 193 (21) pg/mL, thigh. The Cmax (geometric LS mean ratio) for arm versus abdomen was 0.99 (geometric 90% CI, 0.85–1.15), and for thigh versus abdomen it was 0.88 (geometric 90% CI, 0.75–1.02). The most common treatment-emergent adverse events were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Three patients received an inadvertent 10-fold overdose and were withdrawn from the study immediately. All experienced severe nausea and vomiting, and 1 patient experienced severe hypoglycemia requiring aid. All recovered without mishap and were excluded from statistical and tolerability results. There were no adverse events related to the injection or the injection site. Conclusion:: In this study of patients with type 2DM, SC administration of exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability. [Copyright &y& Elsevier]

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. Unlabelled Image • The GLP-1, GIP, Gcg Triagonist is neurotrophic in neuronal SH-SY5Y cultures. • Triagonist is neuroprotective against oxidative stress and glutamate excitotoxicity. • Triagonist neurotrophic/protective actions are balanced across receptors. • Triagonist reduces microglial cell inflammation. • Triagonist mitigates mild TBI-induced visual and spatial memory impairments. [ABSTRACT FROM AUTHOR]

Background: Traditional diabetes therapies have been associated with weight gain, hypoglycemia, and/or high secondary failure rates. Glucagon-like peptide-1 (GLP-1) analog use is associated with a minimal risk of hypoglycemia, a persistent average weight loss of 2 to 3 kg, and sustained efficacy even after 3 years of use. Presently, 3 GLP-1 analogs are commercially available in the United States. Objective: To evaluate the real-world clinical utility of once weekly exenatide in type 2 diabetes mellitus (T2DM) patients who previously received once or twice daily GLP-1 therapy. Methods: In this pre-post observational study, electronic medical records (EMRs) were reviewed to identify patients meeting all study criteria. Data collected included baseline patient demographic information, duration of diabetes, disease states, medications, pertinent laboratory data, blood pressure, height, weight, and reported adverse drug events. Primary (changes in A1C and percentage of patients reporting adverse effects of therapy) and secondary (percentage of patients with A1C of <7% and changes in weight, blood pressure, and lipids) outcomes were evaluated using appropriate statistical analysis. Results: EMRs of 78 patients met all study criteria. Baseline patient demographic information included an average age of 61 ± 12 years, an average duration of T2DM of 14 ± 6 years, 59% of patients were male, and 93.6% were Caucasian. The baseline average body mass index was 39 ± 9.2, and mean A1C was 7.47 ± 1.45%. After a minimum of 3 months (average = 5.6 months) switchover, there were significant decreases in A1C (-0.35%; P = .0067) and weight (-1.6 kg; P = .0151). There were no significant changes in blood pressure or lipid levels. Two patients (2.5%) discontinued once weekly exenatide due to adverse reactions. Conclusion: Once weekly exenatide was generally well tolerated and significantly reduced A1C levels and body weight in patients with T2DM when switched from a shorter-acting GLP-1 analog., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michael P. Kane, PharmD, FCCP, BCPS, BCACP, received an investigator-initiated grant from Bristol Myers Squibb Company, makers of Bydureon, for the conduction of this study. Robert S. Busch, MD, has received speaking honoraria from Bristol Myers Squibb. Sara J Micale, PharmD, Shahab Khatounabadi, Gary Bakst, MD, Jill M. Abelseth, MD, and Robert A. Hamilton, PharmD, MPH, report no relevant conflicts of interest., (© The Author(s) 2014.)

Lixisenatide (trade name Lyxumia®), a short-acting glucagon-like peptide 1 receptor (GLP-1R) agonist, was approved for the treatment of type 2 diabetes by the European Medicines Agency in early 2013. In preclinical investigations, acceptable toxicity and carcinogenicity profiles were demonstrated, as well as pancreatic beta cell-preserving actions and favorable effects on glycemic control. Following subcutaneous administration in humans, lixisenatide displays linear pharmacokinetics and an absorption-dependent elimination half-life of 2-3 hours. In clinical trials of up to 1 year duration in patients with type 2 diabetes, treatment with lixisenatide alone and in combination with insulin and various oral antidiabetics conferred significant reductions in HbA1c, fasting and postprandial plasma glucose. In direct comparison with the other GLP-1R agonists on the market (exenatide and liraglutide), lixisenatide appears to be less efficient, or at best non-inferior in terms of reducing HbA1c, fasting plasma glucose and body weight. Nevertheless, lixisenatide confers fewer adverse events than the other currently marketed GLP-1R agonists, while exhibiting a clinically valuable effect on postprandial hyperglycemia., (Copyright 2013 Prous Science, S.A.U. or its licensors. All rights reserved.)

Liraglutide is a long-acting analog of GLP-1, being developed by Novo Nordisk and currently undergoing regulatory review for the treatment of type 2 diabetes. Upon injection, liraglutide binds non-covalently to albumin, giving it a pharmacokinetic profile suitable for once-daily administration. In clinical trials of up to 1 year duration, liraglutide has been demonstrated to have beneficial effects on islet cell function, leading to improvements in glycemic control. Both fasting and postprandial glucose concentrations are lowered, and are associated with lasting reductions in HbA1c levels. Liraglutide is effective as monotherapy and in combination therapy with oral antidiabetic drugs, and reduces HbA1c by up to approximately 1.5% from baseline (8.2%-8.4%). Because of the glucose-dependency of its action, there is a low incidence of hypoglycemia. Liraglutide is associated with body weight loss, and reductions in systolic blood pressure have been observed throughout the clinical trials. The most common adverse events reported with liraglutide are gastrointestinal (nausea, vomiting and diarrhea). These tend to be most pronounced during the initial period of therapy and decline with time. Further clinical experience with liraglutide will reveal its long-term durability, safety and efficacy.