Peptides represent a rapidly expanding class of drugs with broad therapeutic potential. However, due to their large molecular weight and susceptibility to degradation in the gastrointestinal tract, most peptide drugs are administered via subcutaneous injections. Despite extensive research, a painless broad delivery platform for these drugs is still lacking. Recently, an octopus-inspired buccal patch has shown promise in addressing this challenge by leveraging a synergistic combination of mechanical stretching and permeation enhancers. In this study, the patch and the loaded formulation were optimized to improve ease of use, scalability, and efficacy. Through assessments of mechanical properties, finite element simulations, and ex vivo experiments, we evaluated the effects of patch design and material, as well as the drug matrix composition and the formulation preparation methods on the delivery performance. A patch with a > 9-fold larger effective surface area, produced via mold casting of medical-grade silicone (shore hardness 50) and loaded with a lyophilized drug matrix, emerged as the most promising system. In beagle dogs, 30-min application of this patch resulted in a 14.6 % bioavailability for teriparatide (4118 g mol-1), while bioavailability of semaglutide (4114 g mol-1) was 9.6 times higher than that of the commercial tablet. This work showcases how systematic optimization of this technology can improve and simplify the buccal administration of macromolecular drugs, facilitating the clinical translation of this non-invasive dosage form.

Research on Glucagon-like peptide 1 receptor agonist (GLP-1RA) has mainly focused on the efficacy of weight loss and not the long-term efficacy of weight loss maintenance. This systematic review and meta-analysis aims to evaluate the sustainability of weight loss of patients taking GLP-1RAs following the discontinuation of the drug. EBSCOhost was used to simultaneously search Academic Search Premier, CINHAL Ultimate, Cochrane Central Register of Controlled Trials, MEDLINE with full text, Cochrane Database of Systematic Reviews, and separate PubMed search was systematically investigated using a predetermined search strategy from inception to February 1st, 2024. The authors extracted data regarding body weight change from baseline on treatment and off treatment, change in waist circumference from baseline on and off treatment, and change in BMI from baseline on and off treatment. Meta-analysis was conducted using RevMan (version 5.4) to calculate pooled mean differences using a Der Simonian-Laird Random Effects model. ResultsThe initial search yielded 497 relevant articles and, after screening, retained 8 randomized controlled trials comprised of 2372 participants, all with a BMI ≥ 27 kg/m2. After discontinuing GLP-1RA therapy, weight regain was proportional to the original weight loss. Participants who took liraglutide regained 2.20 kg (95% CI 1.69 to 2.70, P < 0.00001), and participants taking semaglutide/tirzepatide regained 9.69 kg (95% CI 5.78 to 13.60, P < 0.00001). This systematic review and meta-analysis show that significant weight is regained after discontinuing GLP-1RA treatment, which should be discussed when stopping therapy. PRACTITIONER POINTS: Question: Does discontinuation of Glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment lead to significant weight gain? Findings: In this systematic review and meta-analysis, discontinuing GLP-1RA treatment led to a pooled overall mean weight regain of 2.20 kg in participants taking liraglutide and 9.69 kg in those patients prescribed semaglutide/tirzepatide. The proportion of weight regained was proportional to the amount originally lost. Meaning: Discontinuation of GLP-1RA treatment leads to weight regain, regardless of lifestyle interventions, and should therefore be considered a chronic therapy to prevent weight regain and associated undesirable outcomes related to obesity.

We describe changes in HbA1c and body-weight and the relationship between drug adherence and clinical response in a large real-world cohort of patients with type 2 diabetes (T2D) treated with subcutaneous semaglutide for up to three years.

We included adults with T2D registered at Maccabi Healthcare Services, Israel, who initiated subcutaneous semaglutide (August 2019 - June 2022). Adherence, assessed as Proportion of Days Covered (PDC), was based on drug's dispensation. We assessed the absolute change in HbA1c and the relative change in body-weight from baseline.

The 23,442 participants (11,513 women) had a mean age of 62.2 years, HbA1c of 7.6 %, and BMI of 33.7 kg/m2. Compared to baseline, the mean reductions in HbA1c were 0.77 [95 %CI 0.75-0.78], 0.57 [0.53-0.61], and 0.35 [0.27-0.44] %-points at 6 months, 2 years, and 3 years, respectively. The respective body-weight reductions were 4.9 % [4.8-5.0], 5.3% [5.1-5.5], and 4.5 % [3.7-5.2]. Among 6049 patients with ≥2 years of potential follow-up, median PDC between 0-6 months was 83.9 %, and remained relatively stable thereafter, reaching 74.6 % between 18-24 months. Higher PDC was associated with more pronounced HbA1c and body-weight reductions.

Long-term real-world adherence with semaglutide was relatively stable. Semaglutide use was associated with sustained glycemic control and weight reduction in patients with T2D and relatively good baseline glycemic control, especially among those with high adherence, supporting its use for long-term management of T2D.

Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretin hormones playing key roles in the control of food intake, nutrient assimilation, insulin secretion and whole-body metabolism. Recent pharmacological advances and clinical trials show that unimolecular co-agonists that target the receptors for the incretins - GIP and glucagon-like peptide 1 (GLP-1) - offer more effective treatment strategies for obesity and type 2 diabetes mellitus (T2D) compared with GLP-1 receptor (GLP1R) agonists alone, suggesting previously underappreciated roles of GIP in regulating food intake and body weight. The mechanisms by which GIP regulates energy balance remain controversial as both agonism and antagonism of the GIP receptor (GIPR) produce weight loss and improve metabolic outcomes in preclinical models. Recent studies have shown that GIPR signalling in the central nervous system (CNS), especially in regions of the brain that regulate energy balance, is essential for its action on appetite regulation. This finding has sparked interest in understanding the mechanisms by which GIP engages brain circuits to reduce food intake and body weight. In this review, we present key knowledge around the actions of GIP on food intake regulation and the potential mechanisms by which GIPR and GIPR/GLP1R agonists may regulate energy balance.

Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity.

This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate cocaine seeking. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.

With accumulating evidence showing a benefit in the renal and cardiovascular systems, diabetes guidelines recommend that patients with diabetes and chronic kidney disease (CKD) be treated with sodium-glucose cotransporter-2 inhibitor (SGLT2i) and/or glucagon like peptide-1 receptor agonists (GLP-1RAs) for renal protection. The real-world efficacy of the two medications on the urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) remains to be explored.

To evaluate the SGLT2i and GLP-1RA application rates and UACR alterations after intervention in a real-world cohort of patients with diabetes.

A cohort of 5482 patients with type 2 diabetes were enrolled and followed up at the Integrated Care Clinic for Diabetes of Peking University First Hospital for at least 6 months. Propensity score matching was performed, and patients who were not recommended for GLP-1RA or SGLT2i with comparable sex categories and ages were assigned to the control group at a 1:2 ratio. Blood glucose, body weight, UACR and eGFR were evaluated after 6 months of treatment in real-world clinical practice.

A total of 139 (2.54%) patients started GLP-1RA, and 387 (7.06%) received SGLT2i. After 6 months, the variations in fasting blood glucose, prandial blood glucose, and glycosylated hemoglobin between the GLP-1RA group and the SGLT2i and control groups were not significantly different. UACR showed a tendency toward a greater reduction compared with the control group, although this difference was not statistically significant (GLP-1RA vs control, -2.20 vs 30.16 mg/g, P = 0.812; SGLT2i vs control, -20.61 vs 12.01 mg/g, P = 0.327); eGFR alteration also showed no significant differences. Significant weight loss was observed in the GLP-1RA group compared with the control group (GLP-1RA vs control, -0.90 vs 0.27 kg, P < 0.001), as well as in the SGLT2i group (SGLT2i vs control, -0.59 vs -0.03 kg, P = 0.010).

Compared with patients who received other glucose-lowering drugs, patients receiving SGLT2i or GLP-1RAs presented significant weight loss, a decreasing trend in UACR and comparable glucose-lowering effects in real-world settings.

Glucagon-like peptide-1 receptor (GLP-1R) is a well-established target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. The development of orally bioavailable and long-acting small-molecule GLP-1R agonists is a pursuit in both academia and industry. Herein, new selenium (Se)-containing compounds were designed using a Se-oxygen bioisostere strategy on the danuglipron scaffold. Among these, compound 21 was orally bioavailable and exhibited full agonistic efficacy in promoting cyclic adenosine monophosphate (cAMP) accumulation. In hGLP-1R knock-in mice, 21 effectively reduced blood glucose levels and food intake, with the duration of action slightly extended compared to that of danuglipron. Importantly, no significant adverse effects were observed in mice treated with 21 during the subacute toxicity studies. This study delineates the potential of Se-containing compounds as orally bioavailable GLP-1R agonists, with compound 21 emerging as a promising candidate for T2DM and obesity treatment.

A novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist, tirzepatide (LY3298176, TZP), has been developed to treat Type 2 diabetes mellitus (T2DM). In ischaemic heart diseases, TZP is involved in cardiac metabolic processes. However, its efficacy and safety in treating heart failure (HF) following myocardial infarction (MI) remain uncertain.

Herein, 12 week C57BL/6J mice were subjected to MI surgery, followed by administration of TZP. The effects of TZP on cardiac function and metabolism were thoroughly assessed by physiological, histological, and cellular analyses. Downstream effectors of TZP were screened through untargeted metabolomics analysis and molecular docking. Construct a lower branched chain amino acid (BCAA) diet model to determine whether TZP's cardioprotective effect is associated with reducing BCAA levels. Our results demonstrated that TZP reduced mortality following MI, decreased the infarct area, and attenuated cardiomyocyte necrosis. Pathological evaluation of cardiac tissues demonstrated increased fibrosis repair and decreased inflammatory infiltration. Mechanistically, untargeted metabolomics analysis uncovered a positive correlation between TZP and the BCAA catabolism pathway. The molecular docking verified that TZP could bind with branched-chain keto acid dehydrogenase E1 subunit α (BCKDHA). TZP reduced BCKDHA phosphorylation at S293, enhanced BCAA catabolism, and inhibited the activation of metabolism by activating rapamycin (mTOR) signalling pathway. Furthermore, mice fed a low-BCAA diet post-MI demonstrated reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced when used synergistically with TZP.

Taken together, our findings provide new perspectives on the unrecognized role of TZP in cardiac protection. TZP enhanced BCAA catabolism and attenuated BCAA/mTOR signalling pathway in MI mice. Consequently, this study may present novel therapeutic options for patients with HF.

To investigate medication adherence and treatment persistence in patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) in Japan.

Using an anonymized claims database from January 2015 to December 2021, data on adult patients at high risk for atherosclerotic cardiovascular disease or with a history of coronary artery disease (CAD) who had at least 1 prescription for PCSK9-mAbs were retrieved.

In total, 276 patients were analyzed. The cumulative treatment persistence rate after 1 year was 67.0%. A multivariate analysis revealed that better adherence to oral low-density lipoprotein cholesterol (LDL-C)-lowering therapy in the year before starting PCSK9-mAbs (adjusted odds ratio [OR] 2.16) and a history of CAD for secondary prevention (adjusted OR 2.44) were associated with better adherence to PCSK9-mAbs in the first year. Better adherence to oral LDL-C-lowering therapy in the year before starting PCSK9-mAbs (adjusted OR 2.32) and a history of CAD for secondary prevention (adjusted OR 3.03) were also associated with a lower rate of discontinuation of PCSK9-mAbs. Age, sex, comorbidity, number of tablets taken daily (all medications), and number of hospital or clinic visits in the year prior to starting PCSK9-mAbs did not affect the persistence rate or adherence to PCSK9-mAbs in the multivariate analyses.

Better adherence to oral LDL-C-lowering therapy and secondary prevention were identified as factors associated with better medication adherence and treatment persistence in patients receiving PCSK9-mAbs within the first year.

Chronic nausea and vomiting are symptoms of a wide range of gastrointestinal and non-gastrointestinal conditions. Diagnosis can be challenging and requires a systematic and well-structured approach. If the initial investigation for structural, toxic and metabolic disorders is negative, digestive motility and gut-brain interaction disorders should be assessed. United European Gastroenterology (UEG) and the European Society for Neurogastroenterology and Motility (ESNM) identified the need for an updated, evidence-based clinical guideline for the management of chronic nausea and vomiting.

A multidisciplinary team of experts in the field, including European specialists and national societies, participated in the development of the guideline. Relevant questions were addressed through a literature review and statements were developed and voted on according to a Delphi process.

Ninety-eight statements were identified and voted following the Delphi process. Overall agreement was high, although the grade of scientific evidence was low in many areas. Disagreement was more evident for some pharmacological treatment options. A diagnostic algorithm was developed, focussing on the differentiating features between gastrointestinal motility and gut-brain interaction disorders with predominant nausea and vomiting.

These guidelines provide an evidence-based framework for the evaluation and treatment of patients with chronic nausea and vomiting.

The growing popularity of glucagon-like peptide-1 receptor agonists (GLP-1-RAs) for weight loss could significantly impact joint preservation and arthroplasty. While this will in part be driven by the association between obesity, osteoarthritis (OA), and total joint arthroplasty (TJA), recent evidence also indicates that GLP-1-RAs may have direct joint-protective, anti-inflammatory effects.

To evaluate the association between GLP-1-RA use and the onset and progression of hip and knee OA in an obese population.

Cohort study; Level of evidence, 3.

A national health network was queried for patients with an index visit between June 1, 2021, and January 1, 2023, and a body mass index (BMI) ≥30. Patients were stratified into groups without (n = 1,092,225) and with(n = 237,043) preexisting hip and/or knee OA. One-to-one propensity score matching was used to balance GLP-1-RA use based on age, sex, race, BMI, and comorbid type 2 diabetes mellitus. Primary outcomes were incidence of hip OA, knee OA, major joint injections, total hip arthroplasty (THA), and total knee arthroplasty (TKA) within 1 year. Cox proportional hazards models were used to estimate hazard ratios (HRs) between cohorts prescribed and not prescribed GLP-1-RAs.

In patients with preexisting OA, GLP-1-RA use correlated with reduced odds of conversion to THA (1.1% vs 2.2%; HR, 0.6; 95% CI, 0.5 to 0.8) and TKA (1.4% vs 2.1%; HR, 0.8; 95% CI, 0.6 to 0.9) within 1 year. In patients without preexisting OA, GLP-1-RA use was associated with an increased incidence of hip OA (0.9% vs 0.7%; HR, 1.4; 95% CI, 1.2 to 1.6), knee OA (2.1% vs 1.9%; HR, 1.3; 95% CI, 1.2 to 3.1), major joint injections (2.2% vs 1.8%; HR, 1.4; 95% CI, 1.3 to 1.5), and TKA (0.09% vs 0.04%; HR, 2.6; 95% CI, 1.6 to 4.3). Comparing cohorts without prior OA, patients who were prescribed a GLP-1-RA demonstrated slightly greater decreases in BMI (-1.00; 95% CI, -1.06 to -0.96) at 1-year after the index visit compared with patients not prescribed a GLP-1-RA (-0.90; 95% CI, -0.94 to -0.84). However, in patients with a prior diagnosis of hip or knee OA, there was no difference noted in BMI change.

GLP-1-RAs may provide direct disease-modifying behaviors in patients with preexisting OA diagnosis, per a reduced risk of conversion to TJA not attributable to weight loss. Further investigation is also needed to elucidate the association between GLP-1-RA use and the increased incidence of OA diagnosis and conversion to TKA in patients with no preexisting OA diagnosis.

The aim was to investigate the effects of lotiglipron, a once-daily, oral small-molecule glucagon-like peptide-1 (GLP-1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity.

A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study.

In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to -1.44% (90% confidence interval [CI]: -1.63, -1.26) (lotiglipron 80 mg), versus placebo, -0.07% (90% CI: -0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to -7.47% (90% CI: -8.50, -6.43) (lotiglipron 200 mg, five-step titration), versus placebo, -1.84% (90% CI: -2.85, -0.83). Across cohorts, the most frequently reported treatment-emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four-step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort).

The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at-risk population unsuccessful and therefore clinical development of lotiglipron terminated.

GOV: NCT05579977.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now widely used for treating type 2 diabetes mellitus (T2DM) and obesity. We examined their association with acetonemic vomiting, especially when given to patients with low body weight, in hopes of achieving early recognition of this complication which is potentially life-threatening if not dealt with appropriately.

Cases identified incidentally are described and discussed referring to prior reports.

We managed two episodes of acetonemic vomiting, associated with GLP-1 RA use, affecting type 2 diabetes patients with low body weight. The absence of significant abnormalities in regularly tested laboratory data or imaging workup findings in these patients made it difficult to diagnose and recognize the emergent nature of the problem.

GLP1-RAs have the potential to induce acetonemic vomiting when prescribed to patients with diabetes, especially those with low body weight. Although it is a potentially life-threatening disorder, acetonemic vomiting is not common in adults, making accurate diagnosis challenging. It is important that clinicians not hesitate to administer a dextrose-containing intravenous bolus, with insulin if necessary, to maintain normal glucose levels and thereby prevent progression to severe outcomes including death.

Prediabetes is the first stage of a continuum that extends through the diagnosis of clinical type 2 diabetes towards long-standing diabetes with multiple comorbidities. The diagnosis of prediabetes provides an opportunity to interrupt the diabetes continuum at an early stage to ensure long-term optimization of clinical outcomes. All people with prediabetes should receive intervention to improve their lifestyles (quality of diet and level of physical activity), as this has been proven beyond doubt to reduce substantially the risk of conversion to diabetes. Additionally, a large base of clinical evidence supports the use of metformin in preventing or delaying the transition from prediabetes to clinical type 2 diabetes, for some people with prediabetes. For many years, guidelines for the management of type 2 diabetes focused on lowering blood glucose, with metformin prescribed first for those without contraindications. More recently, guidelines have shifted towards prevention of diabetes complications as the primary goal, with increased use of GLP-1 receptor agonists (or multi-agonist incretin peptides) or SGLT-2 inhibitors for patients with existing atherosclerotic cardiovascular disease, heart failure or chronic kidney disease. Access to these medications often remains challenging. Metformin remains a suitable option for initial pharmacologic intervention to manage glycemia for many people with prediabetes or type 2 diabetes along with other therapy to maintain control of blood glucose or to address specific comorbidities as the patient progresses along the diabetes continuum.

From the pioneering moment in 1987 when the insulinotropic effect of glucagon-like peptide 1 (GLP-1) was first demonstrated in humans, to today's pharmaceutical gold rush for GLP-1-based treatments of obesity, the journey of GLP-1 pharmacology has been nothing short of extraordinary. The sequential conceptual developments of long-acting GLP-1 receptor (GLP-1R) mono-agonists, GLP-1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonists, and GLP-1R/GIPR/glucagon receptor (GcgR) triple agonists, have led to profound body weight-lowering capacities, with benefits that extend past obesity and towards obesity-associated diseases. The GLP-1R/GIPR dual-agonist tirzepatide has demonstrated a remarkable 23% body weight reduction in individuals with obesity over 72 weeks, eclipsing the average result achieved by certain types of bariatric surgery. Meanwhile, the GLP-1R/GIPR/GcgR triple-agonist retatrutide achieves similar body weight loss (∼25%) in just two-thirds of the time, potentially surpassing the efficacy of Roux-en-Y gastric bypass. These remarkable achievements rightfully raise the question whether and why there is still need for novel anti-obesity medications (AOMs) in the future.

To assess the level of adherence to glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment using real-world data and to investigate the sociodemographic and clinical factors associated with discontinuation of GLP-1RAs.

First-time users of GLP-1RAs with type 2 diabetes mellitus (T2DM), aged ≥18 years, in the period 2007 to 2020, were identified using Danish registries, allowing all participants a minimum of 18 months' follow-up. Adherence to GLP-1RA therapy (medication possession ratio >0.80) and discontinuation of GLP-1RA therapy was estimated at 6- and 12-month follow-ups. Multivariable cause-specific Cox regression was used to identify sociodemographic and clinical factors associated with risk of discontinuation.

In total, 44 343 first-time users of GLP-1RAs with T2DM were identified (mean age 58.6 years, 42.7% female, median duration of T2DM 6.8 years, median glycated haemoglobin level 65 mmol/mol). The absolute risk of discontinuing GLP-1RA treatment within 6 months was 14.2% (95% confidence interval [CI] 13.9-14.6) and 21.2% (95% CI 20.8-21.5) within 12 months. At 6 months, 50.4% were adherent to GLP-1RA therapy and at 12 months, 48.6% remained adherent. In the multivariable model, younger (<40 years) and older age (>75 years), higher Charlson Comorbidity Index score, lower household income, high school and longer university degree as educational attainment level, and longer diabetes duration were associated with a higher risk of discontinuing GLP-1RA treatment.

Approximately one in five patients discontinued GLP-1RA therapy within the first 12 months and only half were adherent. Overall, lower socioeconomic status and higher comorbidity burden were associated with higher risk of discontinuing GLP-1RA treatment.

Glucagon-like peptide-1 (GLP-1) agonists and GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) co-agonists are major treatment options for subjects with obesity and patients with type 2 diabetes mellitus (T2DM). They counter without addressing the mechanistic cause of the impaired incretin effect associated with obesity and T2DM. Incretin effect impairment is characterized by decreased secretion of incretins from enteroendocrine cells and incretin resistance of pancreatic β-cells. It is linked to hyperglycemia. We present evidence that subversion of the gating of glucose entry into glycolysis, mainly by glucokinase (hexokinase-4), during persistent hyperglycemia in enteroendocrine cells, pancreatic β- and α-cells and appetite-regulating neurons contributes to the biochemical mechanism of the impaired incretin effect. Unscheduled glycolysis and glycolytic overload thereby produced decreases cell signalling of incretin secretion to glucose and other secretion stimuli and incretin receptor responses. This mechanism provides a guide for development of alternative therapies targeting recovery of the impaired incretin effect.

Chronic liver disease is a major cause of mortality, with approximately 2 million deaths worldwide each year, and it poses a significant economic burden. The most common cause of chronic liver disease in the United States and Europe is steatotic liver disease (SLD), which includes metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, and alcohol-associated liver disease (ALD). Effective treatment of these conditions is essential to reduce the liver disease burden, with promising approaches including treating cardiometabolic risk factors and excessive alcohol intake. Glucagon-like peptide 1 receptor agonists, both as monotherapy and in combination with other drugs, are gaining attention for their beneficial impact on cardiometabolic risk factors and excessive alcohol intake. In this review, we examine the molecular and clinical effects of glucagon-like peptide 1 receptor agonists, focusing on their direct hepatic steatohepatitis and liver fibrosis but also the indirect influence on cardiometabolic risk factors and excessive alcohol intake as key features of SLD. We also explore the future implications of glucagon-like peptide 1 receptor agonists for treating metabolic dysfunction-associated SLD, metabolic dysfunction and alcohol-associated SLD, alcohol-associated liver disease, and the potential challenges.

Diabetes is the most common cause of kidney disease in individuals that receive a kidney transplant, and those without pre-existing diabetes are at greater risk of developing diabetes following kidney transplant. A class of diabetes treatment medications called glucagon-like peptide-1 receptor agonists (GLP-1RA) has seen recent widespread use for people with diabetes or obesity, with efficacy for improved glycemic control, weight loss, and reduced risk of cardiovascular events. Given these benefits, and indications for use that often co-occur in kidney transplant recipients, use of GLP-1RAs warrants consideration in this population. Therefore, we sought to review the current literature to better understand the mechanisms of action, clinical application, and person-centred considerations of GLP-1RAs in kidney transplant recipients.

Original articles were identified between December 2023 and July 2024 from electronic databases including the Ovid MEDLINE database, PubMed, and Google Scholar using terms "kidney transplant," "GLP-1," "glucagon-like peptide-1 receptor agonist," and "diabetes."

A comprehensive review of the literature was conducted to explore the relationship between GLP-1RAs and kidney transplant recipients. We reviewed the current state of evidence across the research disciplines of basic or fundamental science, clinical and health services research, and person-centred equity science, and highlighted important knowledge gaps that offer opportunities for future research.

Numerous clinical studies have demonstrated the benefit of GLP-1RAs in people with and without diabetic kidney disease, including decreased risk of cardiovascular events. However, there is a paucity of high-quality randomized controlled trials and observational studies analyzing use of GLP-1RAs in kidney transplant recipients. Evidence of benefit in this population is therefore limited to small studies or inferred from research conducted in nontransplant populations. Growing evidence from preclinical and clinical studies may elucidate renoprotective mechanisms of GLP-1RAs and remove barriers to application of these drugs in the transplant recipient population. Individuals who are female, non-white, have lower socioeconomic status, and live in rural communities are at greater risk of diabetes and have lower uptake of GLP-1RAs. There is a need for clinical trials across diverse kidney transplant populations to estimate the efficacy of GLP-1RAs on important health outcomes.

The search strategy for this narrative review may not have been sensitive to identify all relevant articles. Our search was limited to English language articles.

Research has suggested that glucagon-like peptide-1 receptor agonists (GLP-1-RAs) may have therapeutic effects on osteoarthritis of the hip and knee, in addition to managing diabetes and obesity. However, there is a lack of understanding regarding the association between GLP-1-RA use and the diagnosis of osteoarthritis (OA) of the hip and knee.

A collaborative network analytics platform was queried for obese diabetic (n = 1,094,198), obese nondiabetic (n = 916,235), and nonobese diabetic (n = 157,305) patients who had an index visit between 2015 and 2017. Patients who had pre-existing hip and/or knee OA were excluded. A 1:1 propensity score matching was used to balance GLP-1-RA use in stratified cohorts for age, sex, race, body mass index, and hemoglobin A1c. The primary outcomes were rates of progression to hip OA, knee OA, major joint injections, total hip arthroplasty, and total knee arthroplasty. Cox proportional hazards models determined hazard ratios (HRs) between cohorts prescribed and not prescribed GLP-1-RAs.

All patients had a five-year follow-up. Rates of progression to hip and knee OA were higher among the GLP-1-RA users in both obese diabetic (hip HR: 1.63, 95% confidence interval [CI]: 1.46 to 1.82; knee HR: 1.52, CI: 1.41 to 1.64) and nonobese diabetic (hip HR: 1.78, CI: 1.50 to 2.10; knee HR: 1.58, CI: 1.39 to 1.80) cohorts. These diabetic cohorts received higher rates of major joint injections, though there was no difference in rates of total hip arthroplasty or total knee arthroplasty. No differences in five-year outcomes were seen when comparing obese, nondiabetic patients who were prescribed GLP-1-RAs with obese, nondiabetic patients not exposed to GLP-1-RAs.

This five-year analysis found a greater risk of progression to hip and knee OA among obese and non-obese diabetic GLP-1-RA users. Further studies should explore GLP-1-RA effects upon glucose management, weight loss, and lower extremity arthritis development.

III, retrospective cohort study.

Background and Aim: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy provides glycemic benefits to individuals with type 2 diabetes (T2D). However, the effects of GLP-1 RA therapy in combination with FreeStyle Libre systems (FSL) are unknown. This study aimed to compare changes in hemoglobin A1c (HbA1c) between people acquiring GLP-1 with FSL (GLP-1+FSL) versus GLP-1 without FSL (GLP-1). Methods: This real-world study used Optum's de-identified Market Clarity Data, a linked electronic health records (EHR)-claims database, and included adults with T2D and HbA1c ≥8% who acquired their first GLP-1 RA medication between 2018 and 2022. GLP-1+FSL subjects acquired their first FSL within ±30 days of their first GLP-1 acquisition. Cohorts were matched 1:5 on baseline insulin therapy, age, sex, baseline HbA1c, and GLP-1 type. Paired changes in HbA1c were compared between unmatched and matched groups at 6 months. Results: The study included 24,724 adults in the unmatched cohort (GLP-1+FSL, n = 478; GLP-1, n = 24,246). The matched cohort included 478 GLP-1+FSL users and 2,390 GLP-1 users: mean age 53.5 ± 11.8 and 53.5 ± 11.3 years, HbA1c 10.25 ± 1.68% and 10.22 ± 1.69%, respectively. HbA1c reduction was greater in the GLP-1+FSL group compared with the GLP-1 group in the unmatched cohort (-2.43% vs. -1.73%, difference 0.70%, P < 0.001, respectively) and in the matched cohort (-2.43% vs. -2.06%, difference 0.37%, P < 0.001). GLP-1+FSL vs. GLP-1 treatment was associated with greater HbA1c reduction in the intensive insulin (-2.32% vs. -1.50%), nonintensive insulin (-2.50% vs. -1.74%), and noninsulin group (-2.46% vs. -1.78%), as well as in patients using semaglutide (-2.73% vs. -1.92%) and dulaglutide (-2.45% vs. -1.71%) GLP-1 RA, all P < 0.001. Conclusions: Adults with suboptimally controlled T2D, initiating GLP-1 RA with FreeStyle Libre, had greater improvement in HbA1c compared with those treated with GLP-1 RA only. These results suggest an additional glycemic benefit of FSL when used with a GLP-1 RA in T2D treatment.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of injectable antidiabetic drugs, have shown significant efficacies in improving glycemic and weight control in patients with type 2 diabetes (T2D). However, the long-term safety of GLP-1 RAs remains insufficiently studied. This study aimed to provide real-world evidence on potential adverse outcomes associated with GLP-1 RAs use in T2D patients without major chronic diseases including impaired cardiac or renal function.

We conducted a retrospective cohort study involving 7746 T2D patients on GLP-1 RAs in Shenzhen, China. They were compared with 124 371 metformin-only users and 36 146 insulin-only users, forming two therapy control groups. GLP-1 RAs users were also further 1:2 paired with the control groups. Competing risk survival analyses were conducted to assess the incidence risks, presenting subdistributional hazard ratios (sHRs) with 95% confidence intervals (CIs) for various adverse outcomes associated with GLP-1 RAs use.

Compared with metformin-only users, GLP-1 RAs use was associated with increased risks of various adverse outcomes (sHRs with 95% CIs), including pancreatitis (2.01, 1.24-3.24), acute nephritis (3.20, 2.17-4.70), kidney failure (3.73, 2.74-5.08), thyroid cancer (2.25, 1.23-4.10), and thyroid dysfunction (1.27, 1.00-1.63), respectively; Similar results were also found when compared with insulin-only users. Importantly, long-term (≥12 months) GLP-1 RAs use may further elevate the incidence risks of pancreatitis, acute nephritis, thyroid cancer, and thyroid dysfunction.

Compared with traditional T2D treatments, GLP-1 RAs use may be associated with increased risks of various adverse outcomes in a Chinese population. Cautions were strongly warranted in the use of GLP-1 RAs. Further validation is crucial across diverse populations.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are incretin-based therapies commonly used in the management of type 2 diabetes. Public interest in GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes. Objective: To examine recent trends in usage of GLP-1RA and DPP-4i in the Veterans Health Administration (VHA). Methods: We extracted GLP-1RA and DPP-4i use from the national VHA Corporate Data Workhouse (CDW) between fiscal years (FYs) 2011 to 2021, which encompass medication class, name, dosage, date of filled prescription, and patients' characteristics. Results: A total of 3 037 006 prescriptions for DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. More patients were prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) from FY 2011 to 2021. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001). The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over the years 2011 to 2021 (mean proportion = 19%). However, the proportion of patients who were 75 years of age or older prescribed GLP-1RA increased from 4.2% in 2011 to 16.9% in 2021. Conclusions: Incretin-based therapies have become a well-established class of drugs within the VHA. Even though DPP-4i usage in older adults has remained stable over the past 10 years, prescriptions for GLP-1RA in older adults have increased multifold over the last few years, which might be attributed to recent trial evidence showing benefit in cardiovascular outcomes and weight reduction.

Limited data are available on long-term weight loss achieved with semaglutide or liraglutide for type 2 diabetes (T2D) or obesity in clinical practice.

To document weight loss achieved with injectable forms of semaglutide or liraglutide and identify factors associated with weight reduction of 10% or greater at 1 year.

This retrospective cohort study used electronic health records from a large, integrated health system in Ohio and Florida. Participants included adults with a body mass index (calculated as the weight in kilograms divided by the height in meters squared) of at least 30.0 who initiated treatment with semaglutide or liraglutide between July 1, 2015, and June 30, 2022. Follow-up was completed July 28, 2023.

Injectable forms of semaglutide or liraglutide approved for T2D or obesity.

Percentage weight change and categorical weight reduction of 10% or greater at 1 year.

A total of 3389 patients (mean [SD] age, 50.4 [12.2] years; 1835 [54.7%] female) were identified. Of these, 1341 patients received semaglutide for T2D; 1444, liraglutide for T2D; 227, liraglutide for obesity; and 377, semaglutide for obesity. Mean (SD) percentage weight change at 1 year was -5.1% (7.8%) with semaglutide vs -2.2% (6.4%) with liraglutide (P < .001); -3.2% (6.8%) for T2D as a treatment indication vs -5.9% (9.0%) for obesity (P < .001); and -5.5% (7.5%) with persistent medication coverage (ie, a cumulative gap of less than 90 days) at 1 year vs -2.8% (7.0%) with 90 to 275 medication coverage days and -1.8% (6.7%) with fewer than 90 medication coverage days (P < .001). In the multivariable model, semaglutide vs liraglutide (adjusted odds ratio [AOR], 2.19 [95% CI, 1.77-2.72]), obesity as a treatment indication vs T2D (AOR, 2.46 [95% CI, 1.83-3.30]), persistent medication coverage vs 90 medication coverage days (AOR, 3.36 [95% CI, 2.52-4.54]) or 90 to 275 medication coverage days within the first year (AOR, 1.50 [95% CI, 1.10-2.06]), high dosage of the medication vs low (AOR, 1.58 [95% CI, 1.11-2.25]), and female sex (AOR, 1.57 [95% CI, 1.27-1.94]) were associated with achieving a 10% or greater weight reduction at year 1.

In this retrospective cohort study of 3389 patients with obesity, weight reduction at 1 year was associated with the medication's active agent, its dosage, treatment indication, persistent medication coverage, and patient sex. Future research should focus on identifying the reasons for discontinuation of medication use and interventions aimed at improving long-term persistent coverage.

This article summarizes the medical management of obesity with an emphasis on incretin-based therapeutics that target the neuro-hormonal basis of obesity.

Medications that mimic the effect of incretins, a group of peptide hormones released in response to nutrient intake that regulate appetite, result in potent and durable weight loss. Glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide (GIP) agonists such as semaglutide and tirzepatide are approved by the United States Food and Drug Administration (FDA) for the management of obesity. The SELECT trial demonstrated that semaglutide led to a reduction in major adverse cardiovascular events in patients without diabetes who were either overweight and had preexisting cardiovascular disease or obese.

The treatment of obesity is critical to prevent the progression of cardiovascular-kidney-metabolic syndrome. Incretin-based therapies offer remarkable weight loss and reduce major cardiovascular adverse events.

Diabetes mellitus is a chronic disease that significantly influences the patient's quality of life. This serious disease is approaching an epidemic, and the Arab countries are in the diabetes super region. Improving the patient's quality of life is vital for good glycemic control. However, the Diabetes Therapy-Related Quality of Life Questionnaire (DTR-QOL) is not available in Arabic. Thus, we aimed to validate the questionnaire among patients with diabetes in Saudi Arabia.

This pilot study was conducted among randomly selected 30 patients with diabetes who came for regular follow-up in the Diabetes Center in King Fahd Specialist Hospital in Tabuk City, Saudi Arabia, during March and April 2023. A structured questionnaire based on sociodemographic data and the DTR-QOL was used. The information collected were age, gender, diabetes medications, glycemic indices, lipid profile, fasting insulin, homeostatic model assessment for insulin resistance, and body mass index. Forward/backward translation, expert assessment, and Cronbach's alpha were used to assess the validity and reliability.

Out of the 30 patients with diabetes piloted for the questionnaire validation, 60% were females, the mean age was 51.1 ± 14.056 years, and 94% had type 2 diabetes. The internal consistency varied from 0.80 for hypoglycemia to 0.94 for anxiety and dissatisfaction with treatment. The Arabic version of the DTR-QOL is valid and reliable for use among patients with diabetes, with a content validity of 0.938 and Cronbach's alpha of 0.93.

The Arabic version of the DTR-QOL is valid and reliable for use among patients with diabetes in Arab countries and has good sensitivity and consistency.

Obesity is a chronic multi-system disease and major driver of type 2 diabetes and cardiometabolic disease. Nutritional interventions form the cornerstone of obesity and type 2 diabetes management. Some interventions such as Mediterranean diet can reduce incident cardiovascular disease, probably independently of weight loss. Weight loss of 5% or greater can improve many adiposity-related comorbidities. Although this can be achieved with lifestyle intervention, it is often difficult to sustain in the longer term due to adaptive endocrine changes. In recent years glucagon-like-peptide-1 receptor agonists (GLP-1RAs) have emerged as effective treatments for both type 2 diabetes and obesity. Newer GLP-1RAs can achieve average weight loss of 15% or greater and improve cardiometabolic health. There is heterogeneity in the weight loss response to GLP-1RAs, with a substantial number of patients unable to achieve 5% or greater weight. Weight loss, on average, is lower in older adults, male patients and people with type 2 diabetes. Mechanistic studies are needed to understand the aetiology of this variable response. Gastrointestinal side effects leading to medication discontinuation are a concern with GLP-1RA treatment, based on real-world data. With weight loss of 20% or higher with newer GLP-1RAs, nutritional deficiency and sarcopenia are also potential concerns. Lifestyle interventions that may potentially mitigate the side effects of GLP-1RA treatment and enhance weight loss are discussed here. The efficacy of such interventions awaits confirmation with well-designed randomized controlled trials.

The approval of the glucagon-like peptide 1 (GLP-1) mimetics semaglutide and liraglutide for management of obesity, independent of type 2 diabetes (T2DM), has initiated a resurgence of interest in gut-hormone derived peptide therapies for the management of metabolic diseases, but side-effect profile is a concern for these medicines. However, the recent approval of tirzepatide for obesity and T2DM, a glucose-dependent insulinotropic polypeptide (GIP), GLP-1 receptor co-agonist peptide therapy, may provide a somewhat more tolerable option. Despite this, an increasing number of non-incretin alternative peptides are in development for obesity, and it stands to reason that other hormones will take to the limelight in the coming years, such as peptides from the neuropeptide Y family. This narrative review outlines the therapeutic promise of the neuropeptide Y family of peptides, comprising of the 36 amino acid polypeptides neuropeptide Y (NPY), peptide tyrosine-tyrosine (PYY) and pancreatic polypeptide (PP), as well as their derivatives. This family of peptides exerts a number of metabolically relevant effects such as appetite regulation and can influence pancreatic beta-cell survival. Although some of these actions still require full translation to the human setting, potential therapeutic application in obesity and type 2 diabetes is conceivable. However, like GLP-1 and GIP, the endogenous NPY, PYY and PP peptide forms are subject to rapid in vivo degradation and inactivation by the serine peptidase, dipeptidyl-peptidase 4 (DPP-4), and hence require structural modification to prolong circulating half-life. Numerous protective modification strategies are discussed in this regard herein, alongside related impact on biological activity profile and therapeutic promise.

To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity.

Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron.

Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing.

The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses.

gov identifier: NCT04305587, NCT05158244.

The growing prevalence of type 2 diabetes (T2D) remains a leading health concern in the US. Despite new medications and technologies, glycemic control in this population remains suboptimal, which increases the risk of poor outcomes, increased healthcare resource utilization, and associated costs. This article reviews the clinical and economic impacts of suboptimal glycemic control in patients on basal-bolus insulin or multiple daily injections (MDI) and discusses how new technologies, such as tubeless insulin delivery devices, referred to as "patch pumps", have the potential to improve outcomes in patients with T2D.

Patients with type 2 diabetes (T2DM) are at high risk of atherosclerotic cardiovascular disease (ASCVD) and cardiovascular death. Cardiovascular protection is a key objective in T2DM.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM in placebo-controlled trials, a finding confirmed in observational studies compared with other glucose-lowering agents. Overall, GLP-1RAs have a good safety profile associated with a favorable benefit/risk ratio for the management of T2DM, even if their cost-effectiveness might be questionable. International guidelines recommend GLP-1RAs as preferred glucose-lowering agents in patients with ASCVD and as a valuable alternative in overweight/obese patients with T2DM. However, real-life studies worldwide revealed that only a minority of patients receive a GLP-1RA, despite a positive trend for increased prescriptions in recent years. Surprisingly, however, fewer patients with established ASCVD are treated with these cardioprotective antihyperglycemic agents versus patients without ASCVD.

The reasons for GLP-1RA underuse in clinical practice are multiple. Multifaceted and coordinated interventions targeting all actors of the health-care system must be implemented to stimulate the adoption of GLP-1RAs as part of routine cardiovascular care among patients with T2DM, especially in those with ASCVD.

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate the reinstatement of cocaine-seeking behavior, an animal model of relapse. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA) decreased cocaine reinstatement. Single nuclei transcriptomics and FISH studies revealed GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a novel functional role of GABAergic GLP-1R-expressing midbrain neurons in drug seeking.

Early initiation of intensive insulin therapy has been demonstrated to be effective in controlling glycemia and possibly preserving beta-cell function. Innovations in insulin formulations and delivery systems continue. However, we have seen an acceleration in the development of new classes of diabetes medications for individuals with type 2 diabetes and obesity, such as, for example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These formulations have been shown to confer significant benefits in achieving good glycemic control with reduced hypoglycemia risk, weight loss, and cardiorenal protection. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of type 2 diabetes. However, there are clear limitations inherent to GLP-1 RA therapy, including high rates of suboptimal adherence and treatment discontinuation due to high cost and side effects, which diminish long-term efficacy, and supply issues. In addition, newer formulations have shown improvements in convenience and tolerability, and have been shown to be even more effective when used in conjunction with basal insulin. In this narrative review, we discuss current evidence that supports GLP-1 RA use in combination with insulin therapy and the potential pitfalls of reliance on GLP-1 RAs as a substitute for insulin therapy.

The prevalence of obesity continues to rise in both adolescents and adults, in parallel obesity is strongly associated with the increased incidence of type 2 diabetes, heart failure, certain types of cancer, and all-cause mortality. In relation to obesity, many pharmacological approaches of the past have tried and failed to combat the rising obesity epidemic, particularly due to insufficient efficacy or unacceptable side effects. However, while the history of antiobesity medication is plagued by failures and disappointments, we have witnessed over the last 10 years substantial progress, particularly in regard to biochemically optimized agonists at the receptor for glucagon-like peptide-1 (GLP-1R) and unimolecular coagonists at the receptors for GLP-1 and the glucose-dependent insulinotropic polypeptide (GIP). Although the GIP receptor:GLP-1R coagonists are being heralded as premier pharmacological tools for the treatment of obesity and diabetes, uncertainty remains as to why these drugs testify superiority over best-in-class GLP-1R monoagonists. Particularly with regard to GIP, there remains great uncertainty if and how GIP acts on systems metabolism and if the GIP system should be activated or inhibited to improve metabolic outcome in adjunct to GLP-1R agonism. In this review, we summarize recent advances in GLP-1- and GIP-based pharmacology and discuss recent findings and open questions related to how the GIP system affects systemic energy and glucose metabolism.

To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan-O-AP) or basal insulin ± oral antidiabetic drugs (LixiLan-L-CN).

In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan-O-AP) or 30 (LixiLan-L-CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed.

HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups.

iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease.

Use of innovative technologies such as continuous glucose monitoring (CGM) and insulin delivery systems have been shown to be safe and effective in helping patients with diabetes achieve significantly improved glycemic outcomes compared to their previous therapies. However, these technologies are underutilized in many primary care practices. This narrative review discusses some of the clinical and economic benefits of tubeless insulin delivery devices and discusses how this technology can overcome the main obstacles inherent to use of conventional insulin delivery devices.

Nausea and vomiting are primitive aspects of mammalian physiology and behavior that ensure survival. Unfortunately, both are ubiquitously present side effects of drug treatments for many chronic diseases with negative consequences on pharmacotherapy tolerance, quality of life, and prognosis. One of the most critical clinical examples is the profound emesis and nausea that occur in patients undergoing chemotherapy, which continue to be among the most distressing side effects, even with the use of modern antiemetic medications. Similarly, antiobesity/diabetes medications that target the glucagon-like peptide-1 system, despite their remarkable metabolic success, also cause nausea and vomiting in a significant number of patients. These side effects hinder the ability to administer higher dosages for optimal glycemic and weight management and represent the major reasons for treatment discontinuation. Our inability to effectively control these side effects highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that drive and inhibit nausea and emesis. Here, we discuss clinical and preclinical evidence that highlights the glucose-dependent insulinotropic peptide receptor system as a novel therapeutic central target for the management of nausea and emesis.

Since its first use just over a century ago, insulin treatment has evolved dramatically, such that the molecules are physiologic in nature, and treatment can now closely resemble the natural hormone response over 24 hours. Newer, longer-acting basal insulin analogs have provided insulin therapies with improved characteristics and, therefore, ease of use, and can readily be incorporated as part of routine treatment for type 2 diabetes (T2D), but evidence suggests that insulin remains underused in people with T2D. We review the barriers to initiation of basal insulin and the education needed to address these barriers, and we provide practical pointers, supported by evidence, for primary care physicians and advanced practice providers to facilitate timely initiation of basal insulin in the people with T2D who will benefit from such treatment.

'Globesity' is a foremost challenge to the healthcare system. The limited efficacy and adverse effects of available oral pharmacotherapies pose a significant obstacle in the fight against obesity. The biology of the leading incretin hormone glucagon-like-peptide-1 (GLP-1) has been highly captivated during the last decade owing to its multisystemic pleiotropic clinical outcomes beyond inherent glucoregulatory action. That fostered a pharmaceutical interest in synthetic GLP-1 analogues to tackle type-2 diabetes (T2D), obesity and related complications. Besides, mechanistic insights on metabolic surgeries allude to an incretin-based hormonal combination strategy for weight loss that emerged as a forerunner for the discovery of injectable 'unimolecular poly-incretin-agonist' therapies. Physiologically, intestinal enteroendocrine L-cells (EECs) are the prominent endogenous source of GLP-1 peptide. Despite comprehending the potential of various G protein-coupled receptors (GPCRs) to stimulate endogenous GLP-1 secretion, decades of translational GPCR research have failed to yield regulatory-approved endogenous GLP-1 secretagogue oral therapy. Lately, a dual/poly-GPCR agonism strategy has emerged as an alternative approach to the traditional mono-GPCR concept. This review aims to gain a comprehensive understanding by revisiting the pharmacology of a few potential GPCR-based complementary avenues that have drawn attention to the design of orally active poly-GPCR agonist therapy. The merits, challenges and recent developments that may aid future poly-GPCR drug discovery are critically discussed. Subsequently, we project the mechanism-based therapeutic potential and limitations of oral poly-GPCR agonism strategy to augment intestinal GLP-1 for weight loss. We further extend our discussion to compare the poly-GPCR agonism approach over invasive surgical and injectable GLP-1-based regimens currently in clinical practice for obesity.

To assess the impact of concomitant metformin use on gastrointestinal adverse events during the initiation and titration of a glucagon-like peptide 1 receptor agonist (GLP-1RA).

Using data from four clinical trials of liraglutide and semaglutide (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER], Semaglutide Treatment Effect in People with Obesity [STEP 2], Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6], and Peptide Innovation for Early Diabetes Treatment [PIONEER] 6), we compared the incidence of gastrointestinal adverse events during GLP-1RA initiation and titration in participants with and without concomitant metformin use.

Of 16,996 participants, 12,928 (76%) were treated with metformin. Concomitant metformin use did not increase the percentage of participants who developed gastrointestinal adverse events or their severity during the observation window. Among participants experiencing gastrointestinal adverse events, metformin use did not increase study product discontinuation. Within treatment arms (GLP-1RA and placebo), a numerically higher percentage of metformin nonusers experienced gastrointestinal adverse events and discontinued the study product compared with metformin users.

Concomitant metformin use does not increase occurrence of gastrointestinal symptoms during GLP-1RA initiation or impact GLP-1RA discontinuation.