Injectable drugs for weight management

New Glucose-Lowering Agents for Diabetic Kidney Disease.

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Current and emerging medications for the management of obesity in adults.

Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial

Ecnoglutide is a cAMP biased GLP-1 analogue developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a randomised, double-blind, placebo-controlled, phase 3 trial (NCT05680155) in Chinese participants with T2DM. Participants were randomised (2:2:1:1) to receive ecnoglutide 0.6 mg or ecnoglutide 1.2 mg or volume-matched placebo for 24 weeks, then all receive ecnoglutide for 28 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline at week 24. 211 participants were randomised to receive ecnoglutide 1.2 mg (n = 71), 0.6 mg(n = 69), or placebo(n = 71). At week 24, HbA1c changed from baseline by -1.96%, -2.43% with 0.6 mg, 1.2 mg ecnoglutide, and − 0.87 with placebo. Bodyweight changed by -3.04 kg, -3.21 kg with 0.6 mg, 1.2 mg ecnoglutide, and − 1.45 kg with placebo. Ecnoglutide was safe and well tolerated, with a safety profile consistent with other approved GLP-1 receptor agonists, representing a potential monotherapy option for T2DM. Type 2 diabetes mellitus (T2DM), a progressive metabolic disease primarily characterised by abnormal glucose metabolism, poses an enormous burden on individuals as well as health systems across the world.1–3 The goal of T2DM management is to reduce the risk of associated complications through optimal glycaemic control. Despite a wide range of available treatment options, a large proportion of patients still cannot achieve glycated haemoglobin (HbA1c) treatment targets.4,5 Furthermore, glycaemic management should consider minimising undesired effects such as hypoglycaemia and bodyweight gain,6 which has proven to be challenging with traditional glucose-lowering medications. The advert of single glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide has transformed the treatment landscape of T2DM. They can control glycaemia effectively without inducing severe hypoglycaemia or bodyweight gain.7–9 Apart from glycaemic control, GLP-1 receptor agonists provide other clinical benefits, including bodyweight loss, cardiovascular risk reduction, and improvement in renal outcomes among others.10–12 Therefore, they are an effective treatment option for T2DM and have been recommended by various guidelines.13–15 Ecnoglutide, also known as XW003, is a novel, potent cyclic adenosine monophosphate (cAMP)-biased GLP-1 analogue, containing an alanine-to-valine substitution at position 8 as well as an 18-C fatty acid conjugation at the lysine 30 side chain.16 cAMP bias is hypothesised to enhance the clinical efficacy of GLP-1 receptor agonists through reducing internalisation of the GLP-1 receptor and enhancing insulin secretion.17 In a preclinical study, ecnoglutide showed a stronger binding affinity towards the GLP-1 receptor and more potent efficacy in reducing blood glucose and bodyweight than semaglutide, an unbiased GLP-1 receptor agonist.16 In phase 1 trials among healthy volunteers, once-weekly injections of ecnoglutide exhibited favourable safety and tolerability profiles and a half-life ranging from 124 to 138 h, indicating its potential as a long-acting regimen.16 In a phase 2 trial among individuals with T2DM, once-weekly injections of ecnoglutide at doses of 0.4, 0.8, and 1.2 mg resulted in more pronounced improvements versus placebo in glycaemic control and bodyweight, supporting its potential as a treatment option for T2DM.18 Here we report the findings from a phase 3 trial, EECOH-1, which investigated the efficacy and safety of once-weekly injections of ecnoglutide at doses of 0.6 mg and 1.2 mg versus placebo in adults with T2DM inadequately controlled with diet and exercise alone or with a single oral hypoglycaemic agent.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are chronic neurodegenerative disorders with few effective drug treatments available. An underrated element of these diseases is that glucose uptake and energy utilization is much reduced in neurons. In the brains of patients, signaling of insulin, insulin-like growth factor 1, and other growth factors is downregulated early on. This leads to reduced glucose utilization and impaired mitochondrial function. In an attempt to compensate for the loss, other pathways are upregulated, e.g., the increased use of ketones produced from fatty acids by astrocytes that are shuttled to neurons. In addition, amino acids are increasingly used to generate energy. Despite this, neurons generate less and less energy over time, leading to impaired synaptic activity, reduced cell repair, mitogenesis, autophagy, the accumulation of misfolded proteins, and finally, to cell death. At the same time, the chronic inflammation response in the brain that is part of these diseases continues to damage neurons. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones and growth factors that have shown neuroprotective effects in animal studies and in clinical trials. GLP-1 and GIP receptor agonists were able to reduce inflammation while normalizing growth factor signaling and energy utilization in the brain. Insulin signaling was improved and energy utilization, glucose uptake, mitogenesis, and mitochondrial functionality was brought back to physiological levels. In addition, the chronic inflammation response and the levels of proinflammatory cytokines in the brain were much reduced. Clinical trials testing GLP-1 receptor agonists in patients with AD or PD have been conducted and have shown first successes, serving as proof of concept that activating GLP-1 receptor is a sensible strategy to treat AD/PD. A phase II study testing liraglutide in patients with AD showed first improvements, and two phase II trials testing exendin-4 (exenatide, Bydureon®) or lixisenatide showed improvements in patients with PD. A recent phase III trial testing exendin-4 did not show an improvement, which may be linked to the lack of insulin desensitization in the study participants. Semaglutide (Rybelsus®; Wegovy®; Ozempic®) is currently in two phase III trials for AD. Current drugs that are on the market have a long half-life in the blood and do not readily cross the blood–brain barrier (BBB). Newer dual GLP-1/GIP receptor agonists have been developed that can more easily cross the BBB and that show improved protection in animal models of AD and PD. Therefore, GLP-1 and GIP receptor agonists that can cross the BBB show promise as treatments for chronic neurodegenerative disorders.

Insulin and glucagon are well-known peptide hormones that keep glucose levels within a healthy range in the body. But they are only part of a complex network that controls concentrations of this ubiquitous sugar in blood and tissues. Other molecules regulate glucose by controlling insulin secretion from the pancreas or protecting pancreatic β cells against stresses that lead to cellular dysfunction or cell death (1). One of these protective regulators is glucagon-like peptide 1 (GLP-1), a 30-amino-acid-long peptide produced in specialized epithelial cells of the intestine, called L cells, and also in the brain and other organs and tissues (2). GLP-1 belongs to a group of peptides that mediate the “incretin effect,” an endocrine response to glucose arising from food digestion in the intestines (2, 3). This response helps regulate food intake and the fate of dietary glucose. Specifically, GLP-1 is released from the intestinal cells when food is ingested and then binds to and activates the GLP-1 receptor (GLP-1R), a G protein–coupled receptor on many cell types, including β cells in which GLP-1R signaling stimulates insulin synthesis and secretion (3). Notably, the incretin effect stimulates insulin secretion from pancreatic β cells more strongly than exposure to glucose alone. An article published in the Journal of Biological Chemistry (4), recognized as a Classic here, added to our understanding of the incretin effect by showing that GLP-1R signaling protects β cells from cell death (Fig. 1). This finding was significant for preventing or managing type 2 diabetes, in which β-cell apoptosis occurs (5) and may contribute to insufficient pancreatic insulin production (6). Open in a separate window Figure 1. Li et al. (4) have shown that binding of the receptor agonist exendin-4 to GLP-1R on pancreatic β cells protects the cells from cellular injury and cytokine-induced apoptosis and thereby preserves glucose homeostasis in mice. Binding of GLP-1 to its cognate receptor on pancreatic β cells up-regulates intracellular cAMP levels, in turn reducing streptozotocin-induced β-cell death. Images of exendin-4 and GLP-1R (with GLP-1 bound) are from Ref. 7; image of cAMP is from Wikimedia, used under Creative Commons.

New Medications for the Treatment of Diabetes

The incretin system plays an important role in glucose homeostasis, largely through the actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Unlike GIP, the actions of GLP-1 are preserved in patients with type 2 diabetes mellitus, which has led to the development of injectable GLP-1 receptor (GLP-1R) agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1R agonists—which can be dosed to pharmacologic levels—act directly upon the GLP-1R. In contrast, DPP-4 inhibitors work indirectly by inhibiting the enzymatic inactivation of native GLP-1, resulting in a modest increase in endogenous GLP-1 levels. GLP-1R agonists generally lower the fasting and postprandial glucose levels more than DPP-4 inhibitors, resulting in a greater mean reduction in glycated hemoglobin level with GLP-1R agonists (0.4%–1.7%) compared with DPP-4 inhibitors (0.4%–1.0%). GLP-1R agonists also promote satiety and reduce total caloric intake, generally resulting in a mean weight loss of 1 to 4 kg over several months in most patients, whereas DPP-4 inhbitors are weight-neutral overall. GLP-1R agonists and DPP-4 inhibitors are generally safe and well tolerated. The glucose-dependent manner of stimulation of insulin release and inhibition of glucagon secretion by both GLP-1R agonists and DPP-4 inhibitors contribute to the low incidence of hypoglycemia. Although transient nausea occurs in 26% to 28% of patients treated with GLP-1R agonists but not DPP-4 inhibitors, this can be reduced by using a dose-escalation strategy. Other adverse events (AEs) associated with GLP-1R agonists include diarrhea, headache, and dizziness. The main AEs associated with DPP-4 inhibitors include upper respiratory tract infection, nasopharyngitis, and headache. Overall, compared with other therapies for type 2 diabetes mellitus with similar efficacy, incretin-based agents have low risk of hypoglycemia and weight gain. However, GLP-1R agonists demonstrate greater comparative efficacy and weight benefit than DPP-4 inhibitors.

Mechanisms and possible hepatoprotective effects of glucagon-like peptide-1 receptor agonists and other incretin receptor agonists in non-alcoholic fatty liver disease

Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges.

Spinal fusion is a widely performed surgical procedure for treating various spinal disorders, with lumbar fusion showing remarkably rapid growth worldwide. Despite positive outcomes after the procedure, it carries significant complications, most notably pseudarthrosis. Compromised blood supply is a key factor disrupting normal bone fusion, making optimal vascularization crucial for successful outcomes. Glucagon-like peptide-1 (GLP-1) receptor agonists, primarily used for diabetes management, demonstrate promising effects including enhanced glycemic control, improved vascular endothelial function, and direct enhancement of osteoblastic cell activity through GLP-1 receptors on bone precursor cells. Theoretically, GLP-1 receptor agonists should be beneficial for optimizing spinal fusion outcomes. We aim to systematically review and analyze the current evidence on the efficacy and safety of GLP-1 receptor agonists in promoting bone fusion and reducing complications in patients undergoing spinal fusion surgery.We conducted a comprehensive systematic review following Cochrane guidelines. We searched PubMed, Web of Science, Scopus, Embase, and Cochrane Library for studies examining GLP-1 receptor agonists in spinal fusion procedures. We used the Newcastle-Ottawa Scale for the quality assessment of the included studies. We conducted a statistical analysis using RevMan 5.4 with risk ratios for dichotomous outcomes.In total, 11 studies with a total of 14,344 participants were analyzed. GLP-1 receptor agonists significantly reduced pseudoarthrosis at six months (risk ratio (RR) = 0.63, 95% confidence interval (CI) = 0.54-0.74) and 12 months (RR = 0.64, 95% CI = 0.57-0.72), and significantly increased acute kidney injury (RR = 1.30, 95% CI = 1.03-1.65). No significant differences were observed for pseudoarthrosis at 24 months (RR = 1.03, 95% CI = 0.53-2.03), readmission rates (RR = 0.85, 95% CI = 0.48-1.51), cerebrovascular accidents (RR = 1.01, 95% CI = 0.63-1.62), and deep vein thrombosis (RR = 1.16, 95% CI = 0.78-1.72). Additionally, no significant reoperations or adverse effects were found. We also performed a subgroup analysis considering the diabetic stage, which showed valuable insights.GLP-1 receptor agonists showed promising results in reducing pseudoarthrosis at short- to medium-term follow-up, indicating potential therapeutic benefits in bone healing applications. However, the increased risk of acute kidney injury suggests the need for careful patient monitoring and risk stratification. The lack of sustained benefit at 24 months and significant heterogeneity observed in several outcomes indicate that further investigation is warranted. Future research should focus on conducting larger, well-designed randomized controlled trials with standardized outcome definitions, longer follow-up periods, and comprehensive safety monitoring to establish optimal dosing protocols and patient selection criteria for GLP-1 receptor agonist therapy in orthopedic applications.

Strong associations exist between obstructive sleep apnea (OSA) and obesity. Prior studies have demonstrated that weight reduction in people with OSA and obesity improves severity of OSA. Until recently, there were no approved pharmacotherapies for OSA. We aim to review recent literature on GLP-1 receptor agonists and GIP agonists and their potential role in the management of OSA. Novel pharmacotherapies developed to target obesity include glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. These therapies have proven to be helpful in many comorbid conditions, with published studies suggesting a benefit in OSA. GLP-1 receptor agonists and GIP agonists are emerging potential therapies for OSA and associated cardiometabolic risk.

Objective: Hypertension and type 2 diabetes mellitus (T2DM) are common co-morbidities, with hypertension being twice as frequent in patients with T2DM compared to those without. Blood pressure (BP) control is of utmost importance for subjects with T2DM, in order to minimize the risk for development of cardiovascular and chronic kidney disease. High on treatment BP levels also correlate with the incidence of major adverse cardiovascular outcomes and all-cause death. Recently, novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists have been developed for patients with T2DM. Therefore, we sought to determine whether dual GIP and GLP-1 receptor agonists have a significant effect on BP in subjects with T2DM. Design and method: We searched PubMed and Cochrane Library databases for relevant published randomized controlled trials up to 13th November 2021. We assessed the change in office systolic BP (SBP) and diastolic BP (DBP) with dual GIP and GLP-1 receptor agonists compared to placebo or active comparator in subjects with T2DM. Results: We finally pooled data from 5 trials for a total of 5,060 patients with T2DM. We demonstrated that dual GIP/GLP-1 receptor agonists compared to control induced a significant decrease in SBP by 3.6 mm Hg (MD = -3.6, 95% CI; -5.54 to -1.65, I2 = 83%, p = 0.0003), along with a significant decrease in DBP by 1.29 mm Hg (MD = -1.29, 95% CI; -2.30 to -0.28, I2 = 74%, p = 0.01). Conclusions: Dual GIP/GLP-1 receptor agonists might provide a significant decrease, and thus a better control of BP in patients with T2DM. Whether this preliminary observation is translated into a significant cardiovascular benefit has to be further confirmed in well-designed trials, such as the forthcoming SURPASS-CVOT (NCT04255433). Moreover, the effects of dual agonists on out-of-office BP values need to be evaluated.