Search

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a potent therapeutic option for the management of obesity, demonstrating exceptional efficacy in several large-scale clinical trials. Despite their promising therapeutic outcomes, the rising popularity of these agents raises significant concerns, particularly regarding their off-label use by individuals seeking weight loss for aesthetic reasons rather than addressing underlying metabolic health conditions. This article critically evaluates the efficacy and safety of GLP-1 RAs in obesity management. Additionally, it explores the economic implications and ethical challenges associated with the increasing demand for GLP-1 RAs. By addressing these dimensions, this article aims to facilitate informed and responsible decision-making in clinical practice, highlighting the need for individualized patient assessments and careful consideration of both short- and long-term safety risks. [ABSTRACT FROM AUTHOR]

Aim: Glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D). However, some studies suggest that their effects in patients with heart failure (HF) may be attenuated. We aimed to explore the effects of the GLP1‐RA albiglutide on HF outcomes in patients with and without HF history enrolled in the Harmony Outcomes trial. Methods and results: Harmony Outcomes enrolled patients with T2D and cardiovascular disease randomized to either albiglutide or placebo over a median follow‐up of 1.6 years. A total of 9462 patients were included, of whom 1922 (20%) had HF history. Patients with HF had more cardiovascular comorbidities, poorer renal function, and had a three to four‐fold higher risk of HF events compared to patients without HF. Compared to placebo, the effect of albiglutide on the composite of cardiovascular death or HF hospitalization was more pronounced among patients without HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56–0.95) than in patients with HF (HR 1.06, 95% CI 0.79–1.43) (interaction p = 0.062). A similar pattern was observed for HF hospitalizations (interaction p = 0.025). The effect of albiglutide on cardiovascular death, sudden death or 'pump failure' death, and all‐cause mortality was also attenuated among patients with HF history, but without significant interaction (p > 0.1). The benefit of albiglutide to reduce atherosclerotic events was consistent regardless of HF history. Conclusions: In patients with T2D and cardiovascular disease, albiglutide appeared to have no effect in reducing HF‐related events among patients with HF history. These findings, placed in the context of other trials, suggest that GLP1‐RA may not improve HF outcomes in patients with HF. [ABSTRACT FROM AUTHOR]

Introduction: Atrial fibrillation and flutter (AF) are common in patients with type 2 diabetes and are associated with worse outcomes., Methods: Harmony Outcomes was a multicenter, event-driven, double-blind, placebo-controlled trial comparing the effects of albiglutide, a glucagon-like peptide-1 (GLP1) receptor agonist, with placebo on a composite of major adverse cardiac events (MACE; non-fatal myocardial infarction; non-fatal stroke and cardiovascular death) in 9,463 patients aged >40years with type-2 diabetes and established cardiovascular disease. Herein, the cardiovascular effects of albiglutide in patients with and without AF, as well as the effects on AF events during follow-up, were analyzed., Results: Patients with a history of AF (8.9%) exhibited a higher event rate for the primary composite MACE endpoint during 1.6 years of follow-up (12.7 vs. 6.3 events/100 person-years, adjusted hazard ratio (aHR)1.41 (95% Confidence Interval (CI)1.14-1.74, p=0.001). Treatment with albiglutide reduced the occurrence of the primary endpoint irrespective of history of AF at baseline (history of AF: aHR0.83 (0.58-1.19), no history of AF: aHR0.77 (0.66-0.90); pinteraction=0.71). During follow-up, 239 patients (2.5%) experienced an AF event. Overall, Albiglutide was associated with numerically fewer AF events (108 vs 131; HR 0.82 (0.63-1.06, p=0.12), irrespective of baseline history of AF (pinteraction=0.92)., Conclusions: In patients with type 2 diabetes, treatment with albiglutide, compared to placebo, reduced the risk of cardiovascular events irrespective of history of AF. Further, albiglutide treatment did not increase AF adverse events but was associated with a trend to a lower rate of AF events during follow-up without reaching statistical significance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery endothelial cells (caECs) through macropinocytosis and acts directly on mouse and human coronary artery smooth muscle cells (caSMCs) and caECs, resulting in soluble adenylyl cyclase Adcy10-dependent (sAC-dependent) increases in cAMP, activation of protein kinase A, and cytoprotection from oxidative injury. GLP-1(28-36) modulates sAC by increasing intracellular ATP levels, with accompanying cAMP accumulation lost in [sAC.sup.-/-] cells. We identify mitochondrial trifunctional protein-[alpha] (MTP[alpha]) as a binding partner of GLP-1(28-36) and demonstrate that the ability of GLP-1(2836) to shift substrate utilization from oxygen-consuming fatty acid metabolism toward oxygen-sparing glycolysis and glucose oxidation and to increase cAMP levels is dependent on MTP[alpha]. NEP inhibition with sacubitril blunted the ability of GLP-1 to increase cAMP levels in coronary vascular cells in vitro. GLP-1(28-36) is a small peptide that targets novel molecular (MTP[alpha] and sAC) and cellular (caSMC and caEC) mechanisms in myocardial ischemic injury., Introduction In myocardial infarction (MI), infarct size is the most determinant cause of morbidity and mortality (1). Although early reperfusion is of unequivocal benefit, this treatment is inherently complicated by [...]

Background: GLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.). Scope of review: To summarize current knowledge about GLP-1 receptor agonist. Major conclusions: At present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.

Aims: Large outcome trials have demonstrated cardiovascular benefits of selected glucagon-like peptide-1 (GLP-1) receptor agonists. We examined coronary disease outcomes in the Harmony Outcomes trial of the GLP-1 receptor agonist albiglutide., Methods and Results: Harmony Outcomes was an event-driven, multicenter, double-blind, and placebo-controlled trial involving 9463 patients >40 years of age with type-2 diabetes and established atherosclerotic cardiovascular disease. It tested the effects of albiglutide on the occurrence of a composite primary endpoint, consisting of cardiovascular death, myocardial infarction (MI), or stroke. Within this post-hoc analysis, the effects of albiglutide on MI subtypes and other ischaemic endpoints were analysed.During the median-follow up of 1.6 years, a total of 421 patients (4.5%) experienced at least one MI, with 72 patients having more than one event. Treatment with albiglutide reduced both first events [hazard ratio (HR) 0.75 (0.62-0.91)] and overall events [HR 0.75 (0.61-0.91)] as well as first type 1 [HR 0.73 (0.57-0.92)] and type 2 myocardial infarctions [HR 0.65 (0.46-0.92)]. The effect of albiglutide treatment was consistent for ST-segment elevation [HR 0.69 (0.38-1.26)] and non-ST elevation (HR 0.86 (0.66-1.2) MI., Conclusion: Treatment with the GLP-1 receptor agonist albiglutide resulted in a 25% relative risk reduction in MI that was consistent for type of infarction and presence or absence of ST elevation. Our findings add novel information about the effects of GLP-1 receptor agonists on ischaemic events in patients with type 2 diabetes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Hamish Courtney,1 Rahul Nayar,2 Chinnadorai Rajeswaran,3 Ravi Jandhyala 4 1Diabetes Department, Royal Victoria Hospital, Belfast, 2City Hospitals Sunderland NHS Foundation Trust, Sunderland, 3Department of Diabetes & Endocrinology, Mid Yorkshire NHS Trust, Dewsbury, 4Medical Affairs, Diabetes, AstraZeneca, Luton, UK Abstract: Continuously reducing excess blood glucose is a primary goal for the management of type 2 diabetes (T2D). Most patients with T2D require glucose-lowering medications to achieve and maintain adequate glycemic control; however, treatment failure may occur, limiting treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an emerging therapeutic class that can be prescribed for patients instead of basal insulin after the failure of oral therapies. Recent studies have focused on the durability and tolerability of long-term GLP-1RA therapy. This review summarizes the key efficacy and safety findings from prospective phase 3 clinical studies of at least 76 weeks’ duration for the GLP-1RAs currently approved in the United States and the European Union (albiglutide, dulaglutide, exenatide twice daily [BID], exenatide once weekly [QW], liraglutide, and lixisenatide). Currently, most of the long-term data are from uncontrolled extension studies, and continuous patient benefit has been observed for up to 3 years with multiple GLP-1RAs. Four-year comparative data demonstrated a longer time to treatment failure for exenatide BID than for sulfonylurea, and 3-year comparative extension data demonstrated greater glycated hemoglobin (HbA1c) reductions and weight loss with exenatide QW than with insulin glargine. Currently, the longest extension study for a GLP-1RA is the DURATION-1 study of exenatide QW, with >7 years of clinical data available. Data from DURATION-1 demonstrated that continuous HbA1c reductions and weight loss were observed for the patients continuing on the treatment, with no unexpected adverse events. Taken together, these data support GLP-1RAs as a long-term noninsulin treatment option after the failure of oral therapies. Keywords: albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, long-term

A meta‐analysis of cardiovascular outcome trials (CVOTs) comparing glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) and placebo concerning cardiorenal outcomes in patients with type 2 diabetes (T2D) is presented. An electronic search without language restrictions up to June 15, 2019 was conducted to determine eligible trials. A meta‐analysis of available trial data was undertaken, using a random‐effects model to calculate overall hazard ratios (HRs) and 95% confidence intervals (CIs). Data from seven CVOTs, comprising 56 004 patients (68.9% with established cardiovascular disease) were included. GLP‐1RA reduced major cardiovascular events (MACE) by 13% (HR, 0.87; 95% CI, 0.80–0.96; P = 0.011) with a non‐significant heterogeneity between subgroups of patients with and without cardiovascular disease (CVD) (P = 0.220). GLP‐1RA also reduced the risk of cardiovascular death by 12%, of non‐fatal stroke by 16%, of hospitalization for heart failure by 9%, of all‐cause mortality by 11%, and the broad composite kidney outcome by 17%; the latter appeared to be driven only by a reduction in macroalbuminuria (HR, 0.76 [0.68–0.86]; P = 0.003). GLP‐1RAs have moderate benefits concerning MACE, and also reduce hospitalization for heart failure and all‐cause mortality; they also robustly reduce the incidence of macroalbuminuria, without affecting the progression of diabetic renal disease. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) still remains a progressive condition that is associated with higher risk of end‐stage kidney disease and significant cardiovascular morbidity and mortality. Twelve cardiovascular outcome trials in type 2 diabetes (T2D) have been published to date. Most trials with dipeptidyl‐peptidase inhibitors (SAVOR‐TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin, and CARMELINA with linagliptin) and with glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) (ELIXA with lixisenatide, LEADER with liraglutide, SUSTAIN‐6 with semaglutide, EXCSEL with exenatide once‐weekly, and HARMONY with albiglutide) pointed towards reduced albuminuria, which is a surrogate endpoint possibly heralding renal function preservation. The three trials with sodium‐glucose co‐transporter‐2 inhibitors (SGLT‐2is) (empagliflozin, canagliflozin and dapagliflozin) also showed a salutary effect on long‐term estimated glomerular filtration rate, suggesting that SGLT‐2is are more effective at mitigating loss of kidney function than incretin‐based therapies; moreover, SGLT‐2is also have the advantage of plausible haemodynamic mechanisms for improved renal outcomes. Despite some residual limitations linked to differences in study populations and patient characteristics, the cardiorenal protective actions of SGLT‐2is, and to a lesser extent some GLP‐1RAs, make them favourable medications for patients with T2D at increased cardiorenal risk. There is room for optimism that their use may change the paradigm of the ineluctable progression of DKD. [ABSTRACT FROM AUTHOR]

Aims: Compare the efficacy and safety of albiglutide from a ready-to-use, single-dose, auto-injector system with the lyophilized product in patients with type 2 diabetes mellitus (T2DM).Methods: In this phase 3 study, 308 patients between 18 and 80 years with T2DM and experiencing inadequate glycemic control on their current regimen of diet/exercise alone or in combination with metformin were randomized 1:1 to weekly injections for 26 weeks with an active albiglutide auto-injector and placebo lyophilized dual-chamber cartridge (DCC) pen injector (n = 154) or active albiglutide lyophilized DCC pen injector and placebo liquid auto-injector (n = 154). Participants received liquid or lyophilized albiglutide 30 mg for 4 weeks, and then 50 mg for the remaining 22 weeks. Change in HbA1c and fasting plasma glucose (FPG), pharmacokinetics, and safety were assessed.Results: In the albiglutide liquid and lyophilized drug product groups, 55.6% (85/153) and 45.5% of patients (70/154) had a baseline HbA1c ≥ 8.0%, respectively. The model-adjusted least squares (LS) mean change in HbA1c from baseline at week 26 was -1.1% (95% CI: -1.3, -1.0) and -1.2% (95% CI: -1.3, -1.0; noninferiority P = 0.0002) in the albiglutide liquid and lyophilized product groups, respectively. Similarly, the model-adjusted LS mean change in FPG from baseline at week 26 in the albiglutide liquid and lyophilized product groups was -2.2 (95% CI: -2.6, -1.8) mmol/L and -1.9 (95% CI: -2.3, -1.5) mmol/L, respectively. No new safety concerns were identified.Conclusion: Change from baseline in HbA1c for albiglutide liquid was noninferior to lyophilized drug product in patients with T2DM. [ABSTRACT FROM AUTHOR]

An excess risk of heart failure (HF) persists in patients with type 2 diabetes (T2D) despite optimal control of an array of conventional risk factors, including hyperglycaemia. Twelve cardiovascular outcome trials (CVOTs) have been published to date, although none, with the exception of the DECLARE trial with dapagliflozin, has included HF as a primary endpoint. The four trials with dipeptidyl‐peptidase inhibitors (DPP‐4i) (SAVOR‐TIMI 53 with saxagliptin, EXAMINE with alogliptin, TECOS with sitagliptin and CARMELINA with linagliptin) failed to show any significant effect on HF risk in patients with T2D, with the notable exception of saxagliptin which was associated with a 27% increased risk. Five completed CVOTs with the GLP‐1 RAs lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN‐6), exenatide once weekly (EXSCEL) and albiglutide (HARMONY) also failed to reveal any significant effect on HF risk. The three trials with sodium glucose co‐transporter‐2 inhibitors (SGLT‐2i) (EMPA‐REG OUTCOME with empagliflozin, CANVAS with canagliflozin and DECLARE with dapagliflozin) all revealed a robust and significant reduction in the hazard ratios of hospitalization for HF, from 27% to 35%, which remained consistent, significant and of similar magnitude regardless of the presence of a history of HF or established atherosclerotic cardiovascular disease. There is no association between reductions in HF risk and haemoglobin A1c (A1C) levels, while there is a significant association between reductions in HR for MACE and A1C levels (Spearman's correlation, r = 0.695; P = 0.013). All of the 12 CVOTs completed to date have provided reassurance of the overall cardiovascular safety of the newer anti‐hyperglycaemic drugs. At present, the robust, consistent and reproducible reduction of approximately 30% in the risk of HF with SGLT‐2i may be considered a class effect. The beneficial effect on MACE outcome observed with the use of some GLP‐1RAs and SGLT‐2i must be interpreted within the frame of the single trial. [ABSTRACT FROM AUTHOR]

Albiglutide, developed for treatment of type 2 diabetes mellitus, is provided in a dual‐chamber cartridge (DCC) single‐dose pen‐injector containing lyophilized drug that must be reconstituted with diluent prior to use. A liquid formulation of albiglutide has been developed that does not require mixing. In this 2‐period, randomized, crossover, double‐blind, phase I study (NCT02660736) in 59 healthy volunteers, pharmacokinetic parameters were determined and the bioequivalence of the 2 formulations was assessed. Participants received injections from each type of pen‐injector, one containing albiglutide 50 mg and one containing placebo, followed by an 8‐week washout period between regimens: albiglutide 50‐mg liquid formulation from an auto‐injector and lyophilized placebo from a DCC pen‐injector (Regimen A), or placebo liquid from an auto‐injector and lyophilized albiglutide 50 mg from a DCC pen‐injector (Regimen B). Geometric mean total exposures (area under the drug concentration–time curve [AUC](0‐t) [1345.4 vs 1426.9 (μg · h/mL)], AUC(0‐∞) [1376.2 vs 1454.6 (μg · h/mL)], and maximum concentration of drug in blood plasma [4968.5 vs 5314.7 ng/mL]) were comparable between Regimens A and B. Ratios of geometric least square means (90% confidence interval) were 95.3% (89.49‐101.52) for AUC(0‐∞), 95.1% (89.12‐101.49) for AUC(0‐t), and 93.2% (86.76‐100.17) for maximum concentration of drug in blood plasma, falling within the 90% confidence interval of 0.80 to 1.25 for bioequivalence. No new safety concerns were observed. [ABSTRACT FROM AUTHOR]

Alan A Martin,1 Daniel Parks2 1Department of Value Evidence Analytics, GlaxoSmithKline, Uxbridge, Middlesex, UK; 2Department of Value Evidence Analytics, GlaxoSmithKline, Collegeville, PA, USA Abstract: No head-to-head comparisons exist between once-weekly (QW) glucagon-like peptide-1 receptor agonists; accordingly, this indirect comparison was conducted to evaluate the comparative efficacy of QW albiglutide vs QW exenatide. Following a systematic literature search, it was determined that HARMONY 7 and DURATION 6, Phase III trials for albiglutide and exenatide, respectively, were similar in study design and baseline characteristics and included a common comparator arm, making them suitable for an indirect comparison using the Bucher method. The primary endpoint of change from baseline in glycated hemoglobin (HbA1c) with albiglutide 50 mg QW and exenatide 2.0 mg QW was compared and tested for noninferiority. The indirect comparison showed a treatment difference of 0.0% (95% confidence interval: -0.189% to 0.189%) in mean change in HbA1c from baseline, and albiglutide 50 mg was noninferior to exenatide 2.0 mg QW at the noninferiority margin of 0.3%. In the absence of a head-to-head trial, these results can be used in pharmacoeconomic analysis and to inform health technology assessment and clinical decision making. Keywords: albiglutide, exenatide 2.0 mg QW GLP-1 RA, Bucher method

The article discusses that seven placebo-controlled cardiovascular outcomes trials (CVOTs) of glucagon-like peptide-1 receptor agonists shown the class of drugs reduces cardiovascular risk and all-cause mortality in people with type 2 diabetes. It mentions that rapidity of glucose control improvement in people with pre-existing retinopathy. It also mentions that hypotheses regarding early worsening of diabetic retinopathy remain to be clarified.

The prevalence of type 2 diabetes is increasing at an astounding rate. Many of the agents used to treat type 2 diabetes have undesirable adverse effects of hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1) receptor agonists represent a unique approach to the treatment of diabetes, with benefits extending outside glucose control, including positive effects on weight, blood pressure, cholesterol levels, and beta-cell function. They mimic the effects of the incretin hormone GLP-1, which is released from the intestine in response to food intake. Their effects include increasing insulin secretion, decreasing glucagon release, increasing satiety, and slowing gastric emptying. There are currently four approved GLP-1 receptor agonists in the United States: exenatide, liraglutide, albiglutide, and dulaglutide. A fifth agent, lixisenatide, is available in Europe. There are important pharmacodynamic, pharmacokinetic, and clinical differences of each agent. The most common adverse effects seen with GLP-1 therapy include nausea, vomiting, and injection-site reactions. Other warnings and precautions include pancreatitis and thyroid cell carcinomas. GLP-1 receptor agonists are an innovative and effective option to improve blood glucose control, with other potential benefits of preserving beta-cell function, weight loss, and increasing insulin sensitivity. Once-weekly formulations may also improve patient adherence. Overall, these are effective agents for patients with type 2 diabetes, who are either uncontrolled on metformin or intolerant to metformin.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are an efficacious and convenient option for the treatment of type 2 diabetes (T2D). This narrative review assesses the mode and mechanism of action of the GLP-1RA class in general and highlights similarities and differences within the class. Published clinical trials and manuscripts of basic scientific research were collated and critically reviewed for information relating to the mode and mechanism of action of GLP-1RAs. The mode and mechanism of action is consistent across the GLP-1RA class, despite differences in sequence homology, formulation, conjugation and device administration. Within the class there are some differences in efficacy with regard to glycemic control. Crucially, cardiovascular benefit with GLP-1RAs cannot at this time be considered as a class effect. Once-weekly GLP-1RAs are a good therapeutic option for patients with T2D, either as monotherapy or as part of a combination therapy. Differences between these agents in terms of efficacy and safety outcomes, as well as convenience of a particular device and regimen, should be considered as part of individualization of therapy for patients unable to achieve glycemic control with metformin alone. [ABSTRACT FROM AUTHOR]

Objective: to evaluate the efficacy and safety of albiglutide compared with placebo and active comparators from an integrated trial subpopulation of Latino/Hispanic patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled on their current regimen of diet and exercise, with or without oral antidiabetic drugs (OADs) and/or insulin.Methods: Latino/Hispanic patient subpopulations (N = 1204) across 7 phase III albiglutide studies (N = 4400) were evaluated post-hoc for efficacy and safety. Comparators were placebo, sulfonylureas, insulin, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors. Glycatedhemoglobin (HbA1c) change from baseline to the time of the primary endpoint assessment (from 26 to 104 weeks) was evaluated in patients on diet and exercise and/or OADs, with or without insulin. Patients were allowed to continue in the study if hyperglycemic rescue was required, according to a prespecified algorithm and at the discretion of the investigator.Results: At baseline in the Latino/Hispanic subpopulation, the mean HbA1c was 8.3%, mean age was 53 years, mean body mass index was 32 kg/m2, and mean duration of T2DM was 8.0 years. The primary endpoint of mean HbA1c difference (albiglutide - placebo) was -0.94% for the Latino/Hispanic subpopulation and -0.86% (p < 0.001) for the overall phase III population. Changes in fasting plasma glucose mirrored those of HbA1c. Weight loss with albiglutide was numerically greater than with OADs and insulin in both populations, but it was smaller than with liraglutide. Within the Latino/Hispanic subpopulation, more injection-site reactions were reported with albiglutide vs all comparators, while gastrointestinal and hypoglycemic adverse events were comparable between the two groups, and the latter was uncommon when used without insulin and/or a sulfonylurea.Conclusions: In the Latino/Hispanic population, albiglutide resulted in effective lowering of glucose and modest weight loss, and it was generally well tolerated. [ABSTRACT FROM AUTHOR]

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 μg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide ( P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time. [ABSTRACT FROM AUTHOR]

Aims: Diabetes therapies that provide durable glycaemic control for people with type 2 diabetes mellitus (T2DM) are needed. We present efficacy results of albiglutide, a glucagon-like peptide-1 receptor agonist, in people with T2DM over a 3-year period.Methods: Five of the 8 HARMONY phase 3 trials, comparing albiglutide with other therapies or placebo across a spectrum of clinical care, lasted for a preplanned 3years. Participants with uncontrolled hyperglycaemia who met predetermined criteria could receive rescue medication. The ability to remain on study medication without needing additional rescue was an efficacy measure. Glycaemic measures and body weight were analysed in 2 populations: those who remained rescue-free and all participants.Results: Participants (n=3132) were randomised to albiglutide or comparator. A greater proportion of participants who received albiglutide remained rescue-free (55-71%) compared with placebo (35-51%; p<0.001 to p=0.002). The proportion of rescue-free participants with albiglutide did not differ from glimepiride or insulin glargine, was higher than with sitagliptin (p=0.013), and lower than with pioglitazone (p=0.045). At 3years, albiglutide was associated with clinically significant reductions in hyperglycaemia (eg, rescue-free participants: HbA1c -0.52% [SE0.11] to -0.98% [0.12]; -5.7mmol/mol [1.2] to -10.7mmol/mol [1.3] and all participants: HbA1c -0.29% [0.11] to-0.92% [0.13]; -3.2mmol/mol [1.2] to -10.1mmol/mol [1.4]). Albiglutide was also associated with modest reductions in body weight vs pioglitazone, glimepiride, and insulin glargine, which were associated with weight gain.Conclusion: These 3-year efficacy data support long-term use of albiglutide in the management of people with T2DM. ClinicalTrials.gov NCT00849056, NCT00849017, NCT00838903, NCT00838916, NCT00839527. [ABSTRACT FROM AUTHOR]

BACKGROUND: It is estimated that 29.1 million people or 9.3% of the US population have diabetes, which contributes to considerable medical and financial burden. Type 2 diabetes mellitus is characterized by insulin resistance and insulin secretion impairment leading to hyperglycemia. The presence of insulin resistance is strongly correlated with obesity. OBJECTIVE: This article reviews the available glucagon-like peptide-1 (GLP-1) receptor agonists and their role in the management of patients with diabetes, to help guide the selection of the most suitable agent for the individualized treatment of patients with type 2 diabetes. DISCUSSION: This article reviews the evidence from phase 3 clinical trials for each of the 5 GLP-1 receptor agonists by comparing them against one another and with other existing therapies, including metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sulfonylureas. Incretin-based therapies have emerged as attractive agents for the treatment of type 2 diabetes. They target the GLP-1 hormone, which is partly responsible for insulin release and for attenuating hyperglycemia during meals (ie, the incretin effect). The 2 classes of incretin-based therapy currently available are GLP-1 receptor agonists and DPP-4 inhibitors, which prevent the breakdown of GLP-1. Both classes are attractive options, given their glucose- lowering effects without the adverse effects of hypoglycemia and weight gain. The different mechanisms of action of these therapies result in generally greater efficacy with GLP-1 receptor agonists, albeit at the expense of slightly increased gastrointestinal symptoms. These agents exert their effects by improving glucose-dependent insulin release, suppressing glucagon release, suppressing hepatic glucose output, and decreasing the rate of gastric emptying, thereby reducing appetite. Currently, 5 GLP-1 receptor agonists are available, including exenatide, liraglutide, albiglutide, dulaglutide, and lixisenatide; semaglutide may soon become available as the newest agent. With the exception of the investigational oral semaglutide, which has shown promising results, the other 5 agents are administered as subcutaneous injections, at different dosing intervals. CONCLUSION: Currently, 5 GLP-1 receptor agonists are available for use in the United States. Although they are all in the same drug class, some significant differences exist among the various GLP-1 receptor agonists. The choice of a specific GLP-1 receptor agonist will depend on the patient preferences, potential adverse effects, and cost. [ABSTRACT FROM AUTHOR]

Objective:To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM). Research design and methods:In this phase 3, 1 year study (NCT01777282), patients (N = 374) received albiglutide 30 mg plus a single OAD (sulfonylurea [n = 120], biguanide [n = 67)], glinide [n = 65], thiazolidinedione [n = 61], or α-glucosidase inhibitor [n = 61]). Albiglutide could be increased to 50 mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbA1cand fasting plasma glucose (FPG), proportion of patients achieving HbA1c≤7.0%, and withdrawals due to hyperglycemia. Results:On-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in >1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide + sulfonylurea (14.2%) and the albiglutide + glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbA1cwas 8.1%. Mean decreases from baseline in HbA1cwere observed with the addition of albiglutide to thiazolidinediones (−1.42%), α-glucosidase inhibitors (−1.39%), sulfonylureas (−1.04%), glinides (−0.95%), and biguanides (−0.94%). HbA1cof <7% in >50% of patients and mean reductions in FPG were achieved in all groups. Mean changes from baseline in body weight ranged from +0.52 kg (albiglutide + thiazolidinedione) to −0.33 kg (albiglutide + biguanide). Limitations of the study included open label treatment that was not randomized. Conclusions:When combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted. [ABSTRACT FROM PUBLISHER]

Gastrointestinal (GI) adverse events (AEs) are the most frequently reported treatment-related AEs associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of type 2 diabetes mellitus. The GI safety of albiglutide, a once-weekly GLP-1RA, was assessed using data from five phase III studies. In a pooled analysis of four placebo-controlled trials, the most common GI AEs were diarrhoea (albiglutide, 14.5% vs. placebo, 11.5%) and nausea (albiglutide, 11.9% vs. placebo, 10.3%), with most patients experiencing 1-2 events. The majority were mild or moderate in intensity and their median duration was 3-4 days. Vomiting occurred in 4.9% of patients in the albiglutide vs. 2.6% in the placebo group. For both albiglutide and placebo, serious GI AEs (2.0% vs. 1.5%) and withdrawals attributable to GI AEs (1.7% vs. 1.5%) were low. In a 32-week trial of albiglutide 50 mg weekly versus liraglutide 1.8 mg daily, nausea occurred in 9.9% of patients in the albiglutide group vs. 29.2% in the liraglutide group. Vomiting occurred in 5.0% in the albiglutide vs. 9.3% in the liraglutide group. In conclusion, albiglutide has an acceptable GI tolerability profile, with nausea and vomiting rates slightly higher than those for placebo but lower than those for liraglutide. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) vary in their structure, duration of action, efficacy, and safety. In order to optimize glycemic control, it is important to target both fasting (FPG) and postprandial plasma (PPG) glucose. Although phase 3 trials document the effect of GLP-1 RAs on glycated hemoglobin, few data are available to assess their effect on PPG. Albiglutide is a once-weekly GLP-1 RA with a half-life of ≈ 5 days. The goal of this review is to summarize the effects of albiglutide on PPG in four phase 2 trials and to describe the PPG-lowering effects of the GLP-1 RAs. At clinically relevant doses (30-64 mg), albiglutide consistently lowered PPG after each meal in addition to its effect on lowering FPG. Multiple weekly subcutaneous injections of albiglutide led to improvements in a variety of glycemic measures, including maximal reductions in PPG from baseline, postmeal glucose excursions, and FPG. Albiglutide, a longer-acting GLP-1 RAs, provides reductions in FPG, PPG following meals, and glucose over 24 hours. [ABSTRACT FROM PUBLISHER]

No head-to-head comparisons exist between once-weekly (QW) glucagon-like peptide-1 receptor agonists; accordingly, this indirect comparison was conducted to evaluate the comparative efficacy of QW albiglutide vs QW exenatide. Following a systematic literature search, it was determined that HARMONY 7 and DURATION 6, Phase III trials for albiglutide and exenatide, respectively, were similar in study design and baseline characteristics and included a common comparator arm, making them suitable for an indirect comparison using the Bucher method. The primary endpoint of change from baseline in glycated hemoglobin (HbA1c) with albiglutide 50 mg QW and exenatide 2.0 mg QW was compared and tested for noninferiority. The indirect comparison showed a treatment difference of 0.0% (95% confidence interval: -0.189% to 0.189%) in mean change in HbA1c from baseline, and albiglutide 50 mg was noninferior to exenatide 2.0 mg QW at the noninferiority margin of 0.3%. In the absence of a head-to-head trial, these results can be used in pharmacoeconomic analysis and to inform health technology assessment and clinical decision making. [ABSTRACT FROM AUTHOR]

Currently, six glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are approved for treating type 2 diabetes. These fall into two classes based on their receptor activation: short‐acting exenatide twice daily and lixisenatide once daily; and longer‐acting liraglutide once daily, exenatide once weekly, albiglutide once weekly and dulaglutide once weekly. The phase III trial of a seventh GLP‐1RA, taspoglutide once weekly, was stopped because of unacceptable adverse events (AEs). Nine phase III head‐to‐head trials and one large phase II study have compared the efficacy and safety of these seven GLP‐1RAs. All trials were associated with notable reductions in glycated haemoglobin (HbA1c) levels, although liraglutide led to greater decreases than exenatide formulations and albiglutide, and HbA1c reductions did not differ between liraglutide and dulaglutide. As the short‐acting GLP‐1RAs delay gastric emptying, they have greater effects on postprandial glucose levels than the longer‐acting agents, whereas the longer‐acting compounds reduced plasma glucose throughout the 24‐h period studied. Liraglutide was associated with weight reductions similar to those with exenatide twice daily but greater than those with exenatide once weekly, albiglutide and dulaglutide. The most frequently observed AEs with GLP‐1RAs were gastrointestinal disorders, particularly nausea, vomiting and diarrhoea. Nauseaoccurred less frequently, however, with exenatide once weekly and albiglutide than exenatide twice daily and liraglutide. Both exenatide formulations and albiglutide may be associated with higher incidences of injection‐site reactions than liraglutide and dulaglutide. GLP‐1RA use in clinical practice should be customized for individual patients, based on clinical profile and patient preference. Ongoing assessments of novel GLP‐1RAs and delivery methods may further expand future treatment options. [ABSTRACT FROM AUTHOR]