Beyond weight loss: the potential of glucagon-like peptide-1 receptor agonists for treating heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with various phenotypes, and obesity is one of the most common and clinically relevant phenotypes of HFpEF. Obesity contributes to HFpEF through multiple mechanisms, including sodium retention, neurohormonal dysregulation, altered energy substrate metabolism, expansion of visceral adipose tissue, and low-grade systemic inflammation. Glucagon-like peptide-1 (GLP-1) is a hormone in the incretin family. It is produced by specialized cells called neuroendocrine L cells located in the distal ileum and colon. GLP-1 reduces blood glucose levels by promoting glucose-dependent insulin secretion from pancreatic ß cells, suppressing glucagon release from pancreatic α cells, and blocking hepatic gluconeogenesis. Recent evidence suggests that GLP-1 receptor agonists (GLP-1 RAs) can significantly improve physical activity limitations and exercise capacity in obese patients with HFpEF. The possible cardioprotective mechanisms of GLP-1 RAs include reducing epicardial fat tissue thickness, preventing activation of the renin-angiotensin-aldosterone system, improving myocardial energy metabolism, reducing systemic inflammation and cardiac oxidative stress, and delaying the progression of atherosclerosis. This review examines the impact of obesity on the underlying mechanisms of HFpEF, summarizes the trial data on cardiovascular outcomes of GLP-1 RAs in patients with type 2 diabetes mellitus, and highlights the potential cardioprotective mechanisms of GLP-1 RAs to give a pathophysiological and clinical rationale for using GLP-1 RAs in obese HFpEF patients.

Evaluation of glucose-lowering medications in older people: a comprehensive systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population. METHODS: A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool. RESULTS: A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], -3.87 kg; 95% CI, -5.54 to -2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, -1.85 kg; 95% CI, -2.42 to -1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases. CONCLUSIONS: Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes.

Repurposing antidiabetic drugs for Alzheimer's disease: A review of preclinical and clinical evidence and overcoming challenges.

Repurposing antidiabetic drugs for the treatment of Alzheimer's disease (AD) has emerged as a promising therapeutic strategy. This review examines the potential of repurposing antidiabetic drugs for AD treatment, focusing on preclinical evidence, clinical trials, and observational studies. In addition, the review aims to explore challenges and opportunities in repurposing antidiabetic drugs for AD, emphasizing the importance of well-designed clinical trials that consider patient selection criteria, refined outcome measures, adverse effects, and combination therapies to enhance therapeutic efficacy. Preclinical evidence suggests that glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, metformin, thiazolidinediones, and sodium-glucose co-transporter-2 (SGLT2) inhibitors exhibit neuroprotective effects in AD preclinical models. In preclinical studies, antidiabetic drugs have demonstrated neuroprotective effects by reducing amyloid beta (Aß) plaques, tau hyperphosphorylation, neuroinflammation, and cognitive impairment. Antidiabetic drug classes, notably GLP-1 analogs and SGLT2 inhibitors, and a reduced risk of dementia in patients with diabetes mellitus. While the evidence for DPP4 inhibitors is mixed, some studies suggest a potential protective effect. On the other hand, alpha-glucosidase inhibitors (AGIs) and sulfonylureas may potentially increase the risk, especially in those experiencing recurrent hypoglycemic events. Repurposing antidiabetic drugs for AD is a promising therapeutic strategy, but challenges such as disease heterogeneity, limited biomarkers, and benefits versus risk evaluation need to be addressed. Ongoing clinical trials in mild cognitive impairment (MCI) and early AD patients without diabetes will be crucial in determining the clinical efficacy and safety of the antidiabetic drugs, paving the way for potential treatments for AD.

Efficacy and safety of glucagon-like peptide-1 receptor agonists in the elderly versus non-elderly patients with type 2 diabetes mellitus: insights from a systematic review.

This systematic review aimed to compare the influence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on the efficacy and safety of elderly patients with type 2 diabetes and younger individuals. A comprehensive search of PubMed, Embase, and Web of Science databases was conducted up to September 2022. The summary standard means difference and odds ratios were calculated. Thirteen articles were included in the analysis. The incidence of adverse events (AEs) leading to discontinuation was higher in elderly patients (OR = 0.67, 95% CI 0.47 to 0.96, p = 0.028). However, no significant differences were observed in weight loss (SMD = 0.03, 95% CI -0.12 to 0.19, p = 0.686), HbA1c% (SMD = -0.02, 95% CI -0.11 to 0.08, p = 0.715), FBG levels (SMD = -0.03, 95% CI -0.11 to 0.06, p = 0.537), and the incidence of overall AEs (OR = 0.85, 95% CI 0.71 to 1.01, p = 0.072), serious AEs (OR = 0.68, 95% CI 0.45 to 1.04, p = 0.077), nausea (OR = 0.91, 95% CI 0.81 to 1.03, p = 0.140), vomiting (OR = 0.95, 95% CI 0.79 to 1.13, p = 0.532), diarrhea (OR = 0.86, 95% CI 0.72 to 1.02, p = 0.081), and hypoglycemia (OR = 1.22, 95% CI 0.90 to 1.65, p = 0.193). In conclusion, while certain AEs leading to discontinuation may be more prevalent in older patients, GLP-1RAs are effective for weight loss and lead to decreased glucose concentrations with a low rate of complications in elderly patients.

Relationship between Glucagon-like Peptide-1 Receptor Agonists and Cardiovascular Disease in Chronic Respiratory Disease and Diabetes.

The purpose of this paper is to assess the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on stroke or heart disease in patients having chronic respiratory disease and diabetes (CD) with underlying diseases related to COVID-19. From 1998 to 2019, we adjusted competing risk by assessing the effect of GLP-1RAs on stroke or heart disease in a CD cohort after propensity matching based on the Taiwan National Health Insurance Research Database. We also used the time-dependent method to examine the results. GLP-1 RA and non-GLP-1 RA user groups included 15,801 patients (53% women and 46% men with a mean age of 52.6 ± 12.8 years). The time between the diagnoses of DM and the initial use of the GLP-1 RA among the stroke subcohort (<2000 days) was shorter than that of the heart disease subcohort (>2000 days) (all p-values < 0.05). The overall risks of stroke, ischemic, and hemorrhagic stroke were significantly lower in GLP-1 RA users than nonusers. The adjusted subhazard ratio (aSHR) was 0.76 [95% CI 0.65-0.90], 0.77 [95% CI 0.64-0.92], and 0.69 [95% CI 0.54-0.88] (p < 0.05 for all). Furthermore, a ≥351-day use had a significantly lower stroke risk than GLP-1 RA nonusers (aSHR 0.35 [95% CI 0.26-0.49]). The time-dependent method revealed the same result, such as lower stroke, and ischemic or hemorrhagic stroke risk. In contrast, the cardiac arrhythmia incidence was higher in GLP-1 RA users with an aSHR of 1.36 [95% CI 1.16-1.59]. However, this risk disappeared after the ≥351-day use with 1.21 (0.98, 1.68) aSHR. Longer GLP-1 RA use was associated with a decreased risk of ischemic or hemorrhagic stroke and the risk of cardiac arrhythmia disappears in a CD cohort. Both a shorter lag time use of the GLP-1 RA and a longer time use of GLP-1 RA were associated with a decreased risk of ischemic or hemorrhagic stroke in the CD cohort. The GLP-1 RA use in the early stage and optimal time use in the CD cohort may avoid the stroke risk.

GLP-1 receptor agonists alleviate colonic inflammation by modulating intestinal microbiota and the function of group 3 innate lymphoid cells.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are drugs used for treating type 2 diabetes, have been reported to exert anti-inflammatory effects on inflammatory bowel disease (IBD), the mechanism of which remains elusive. Here, we report that GLP-1RAs ameliorate dextran sulfate sodium (DSS)-induced colitis in both wild-type and T/B-cell-deficient mice through modulating group 3 innate lymphoid cells (ILC3s), a subset of innate lymphoid cells that regulate intestinal immunity. GLP-1RAs promote IL-22 production by ILC3, and the protective effect of GLP-1RAs on DSS-induced colitis was abrogated in ILC3-deficient RORgtgfp/gfp mice. Furthermore, the treatment effect of GLP-RAs on colitis, as well as the generation of IL-22-producing ILC3s by GLP-RAs, is dependent on the gut microbiota. GLP-1RAs increase the abundance of Firmicutes and Proteobacteria in the gut, particularly beneficial bacteria such as Lactobacillus reuteri, and decrease the abundance of enteropathogenic Staphylococcus bacteria. The untargeted gas chromatography (GC)/liquid chromatography (LC)-mass spectrometry (MS) of faecal metabolites further revealed enrichment of N,N-dimethylsphingosine (DMS), an endogenous metabolite derived from sphingosine, in the GLP-1RA-treated group. Strikingly, DMS ameliorates colitis while promoting intestinal IL-22-producing ILC3s. Taken together, our findings show that GLP-1RAs exert a therapeutic effect on colitis possibly by regulating the microbiota-DMS-IL-22+ILC3 axis, highlighting the potential beneficial role of GLP-RAs in inflammatory intestinal disorders with diabetes complications.

A diabetic patient increased premature ventricular contractions after using liraglutide: a case report.

The common adverse reactions of liraglutide are hypoglycemia and gastrointestinal reactions. This case reports a patient with type 2 diabetes mellitus who had an increase in ventricular premature beats after using liraglutide and a decrease in ventricular premature beats after stopping liraglutide, suggesting that clinicians should rule out the possibility of drug-related adverse reactions when using liraglutide in the treatment of diabetes mellitus complicated with coronary heart disease and arrhythmia.

Adipose tissue as a cause of endocrine dysfunction.

Adipose tissue is a large hormonally active organ that secretes several substances (adipokines), and an important site for the synthesis and metabolism of steroid hormones. With energy balance, the secretory and metabolic activity of adipose tissue determines the normal function of many organs, including the endocrine glands. However, in the course of overweight and obesity, adverse changes occur in the structure and function of adipocytes. Obesity-related adipose tissue dysfunction translates into a change in the profile of secreted adipokines, and it impairs steroidogenesis. These phenomena contribute to the development of obesity-related complications, which also affect the major tropic axes regulating the endocrine glands. However, there is increasing evidence that weight reduction is an effective treatment for obesity-related adipose tissue dysfunction, thereby restoring endocrine function. This narrative review presents the impact of adipose tissue on endocrine gland activity both in the physiological state and in obesity-related dysfunction. It also discusses how functional (related to excess adiposity) changes in the endocrine system can be restored with effective treatment of obesity.

The Weight-loss Effect of GLP-1RAs Glucagon-Like Peptide-1 Receptor Agonists in Non-diabetic Individuals with Overweight or Obesity: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are new drugs for the treatment of obesity. OBJECTIVE: To assess the weight-loss effects of GLP-1RAs in the treatment of patients with overweight or obesity without diabetes. METHODS: This is a systematic review with meta-analysis and trial sequential analysis. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from their inception to January 1, 2022. Eligible trials report on outcomes including body weight (BW), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), or total body fat (TBF). Mean differences (MDs) and standardized mean differences (SMDs) were summarized using random-effects models. RESULTS: Forty-one trials involving 15,135 participants were included. Compared with controls, GLP-1RAs significantly reduced BW (MD -5.319 kg, 95% CI: -6.465, -4.174), BMI (MD -2.373 kg/m2, 95% CI: -2.821, -1.924), WC (MD -4.302 cm, CI:-5.185 to -3.419), WHR (MD -0.011, CI -0.015 to -0.007), but not TBF (MD -0.320%, CI -1.420 to -0.780). Trial sequential analysis (TSA) supported conclusive evidence of the effects of GLP-1RAs on BW, BMI, and WC for weight loss. GLP-1RAs had nonlinear dose-response relationships with weight loss. Extensive sensitivity analyses demonstrated the robustness of the results, though the GRADE certainty of the evidence ranged from high to very low. High to moderate GRADE certainty of evidence suggested semaglutide as the most effective GLP-1RA agent, with the best efficacy and low to moderate risk of adverse effects. CONCLUSIONS: The present study provides conclusive evidence for the effect of GLP-1RAs on weight loss in a nonlinear dose-response manner in patients with obesity or overweight without diabetes. In terms of changes in BW, BMI, and WC, there is firm evidence for the overall weight-loss effects of GLP-1RAs. Of the GLP-1RAs, semaglutide might be the most effective agent.

GLP-1 RAs in Spain: A Short Narrative Review of Their Use in Real Clinical Practice.

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs with potent glucose-lowering activity. Additionally, some GLP-1 RAs have demonstrated cardiovascular and renal benefits. Current guidelines recommend their use in patients with type 2 diabetes (T2D) at high risk of or with established cardiovascular disease (CVD), regardless of glycaemic control, with lifestyle modification and metformin. However, several studies have recently highlighted the limited number of patients with T2D benefiting from these medications worldwide. Given the huge burden of CVD among patients with T2D, efforts should be made to bring clinical practice closer to expert guidelines. This review describes the current situation of GLP-1 RA use in Spain and the reasons behind the gap between guidelines and real-world practice and suggests possible solutions. Administrative issues, lack of awareness of the cardiovascular benefits, clinical inertia, rejection of injectable medication and costs could be some of the reasons for the current situation. Possible strategies that could help to close the gap include encouraging a multidisciplinary approach to the treatment of diabetes which involves cardiologists, endocrinologists, nephrologists, primary care providers and pharmacists; improved awareness of comorbidities and earlier evaluation and treatment or risks; and better education of healthcare providers regarding the cardioprotective benefits of these drugs.

The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a class of drugs that can be beneficial for patients with type 2 diabetes who are at high risk of cardiovascular complications, such as heart attacks. For this reason, the current clinical guidelines strongly recommend their use in these patients. Unfortunately, many patients with type 2 diabetes and high cardiovascular risk still do not benefit from these drugs. This review analyses the reasons for this situation in Spain, and proposes some possible solutions. The reasons for the low use of GLP-1 RAs could be related to doctors not updating a patient's diabetes medicine as often as they should, lack of awareness about the cardiovascular benefits of these drugs, fear of medicines that involve needles, administrative issues, and costs. Some of the possible strategies to improve the use of GLP-1 RAs among patients with type 2 diabetes with high cardiovascular risk could be to foster greater cooperation among specialists, increase awareness of the need to treat cardiovascular risk in patients with diabetes, and better education of doctors regarding the benefits of these drugs.

Comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists versus sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes: A population-based cohort study.

AIMS: To examine the comparative effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors for select cardiovascular outcomes and to examine whether the relative risks varied across different patient subgroups in patients with type 2 diabetes. MATERIALS AND METHODS: We conducted a nationwide cohort study of patients with type 2 diabetes who initiated GLP-1RAs or SGLT2 inhibitors between 2012 and 2018 in Taiwan. The study outcomes included myocardial infarction and total stroke, further classified into ischaemic or haemorrhagic stroke. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, comparing GLP-1RAs with SGLT2 inhibitors using Cox proportional hazards models after 1:1 propensity-score (PS) matching. We also examined if there was effect modification by age, underlying chronic kidney disease, or coexisting cardiovascular disease in prespecified subgroup analyses. RESULTS: Among 26 032 PS-matched patients, GLP-1RA initiators and SGLT2 inhibitor initiators showed similar risks of myocardial infarction (HR 0.99, 95% CI 0.65-1.52), total stroke (HR 0.90, 95% CI 0.69-1.17), ischaemic stroke (HR 0.86, 95% CI 0.65-1.14) and haemorrhagic stroke (HR 0.88, 95% CI 0.63-1.25). However, GLP-1RA treatment was associated with an increased risk of total stroke (HR 1.76, 95% CI 1.06-2.94) and ischaemic stroke (HR 1.88, 95% CI 1.09-3.23) among patients with chronic kidney disease, but not among patients without chronic kidney disease. GLP-1RA therapy seemed to have a lower risk of haemorrhagic stroke among patients with cardiovascular disease (HR 0.64, 95% CI 0.43-0.97), but not in patients without cardiovascular disease. CONCLUSIONS: Glucagon-like peptide-1 receptor agonists and SGLT2 inhibitors appeared to have comparable effectiveness with regard to several cardiovascular outcomes overall, but their comparative effectiveness may vary in certain patient subgroups.

The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome.

Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.

Cost-effectiveness analysis of 4 GLP-1RAs in the treatment of obesity in a US setting.

Background: The number of obese people continues to increase worldwide, and obesity-related complications add to every country's health burden. Consequently, new weight-loss medications, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), are attracting increasing attention. This study sought to assess the cost effectiveness for weight loss of 4 GLP-1RAs in adult patients with obesity in the United States. Methods: Four GLP-1RA groups that received Liraglutide (1.8 mg QD), Semaglutide (1.0 mg QW), Dulaglutide (1.5 mg QW), or Exenatide (10 µg BID), and one no-treatment group were compared using a decision-tree model. All the estimated parameters were derived from published articles. Quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) were adopted as the study endpoints. We analyzed the results with the willingness-to-pay (WTP) threshold, and conducted deterministic and probabilistic sensitivity analyses. Results: The GLP-1RAs produced effective weight-loss results; however, not all the GLP-1RAs were cost effective compared to no treatment based on a WTP threshold of $195000/QALY. Among the 4 GLP-1RAs, Semaglutide provided a cost-effective strategy with an ICER of $135467/QALY. The sensitivity analyses showed that these results are reliable. Conclusions: Among the 4 GLP-1RAs, Semaglutide was the most cost-effective obesity medication.

Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis.

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).

The Enhanced Cardiac Outcome of Conjugated SGLT2 Inhibitors and GLP-1RA Therapy in Diabetic Patients.

PURPOSE OF REVIEW: Cardiovascular disease secondary to diabetes continues to threaten the survivability of many people all over the world. We assess the most recent findings of synergistic effects of combined glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in lowering cardiac complications in the diabetic population. We describe drug therapies' mechanism of action, postulated cardioprotective process, the additive value of conjugated therapy, and analyze recently reported study and its limitation. RECENT FINDINGS: SGLT2 inhibitors and GLP-1RAs have gained popularity due to their ability to reduce major adverse cardiovascular events in diabetic patients. There is emerging evidence of the additional cardiovascular benefit from the combined application of SGLT2 inhibitors and GLP-1RAs therapy demonstrated by a recent real-world cohort study. Reducing cardiac mortality in patients with diabetes by administering dual antihyperglycemic therapies (GLP-1Rs and SGLT2 inhibitors) might play a key role in the future treatment of the diabetic population.

Time and metabolic state-dependent effects of GLP-1R agonists on NPY/AgRP and POMC neuronal activity in vivo.

OBJECTIVE: Long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs), like liraglutide and semaglutide, are viable treatments for diabetes and obesity. Liraglutide directly activates hypothalamic proopiomelanocortin (POMC) neurons while indirectly inhibiting Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons ex vivo. While temporal control of GLP-1R agonist concentration as well as accessibility to tissues/cells can be achieved with relative ease ex vivo, in vivo this is dependent upon the pharmacokinetics of these agonists and relative penetration into structures of interest. Thus, whether liraglutide or semaglutide modifies the activity of POMC and NPY/AgRP neurons in vivo as well as mechanisms required for any changes in cellular activity remains undefined. METHODS: In order to resolve this issue, we utilized neuron-specific transgenic mouse models to examine changes in the activity of POMC and NPY/AgRP neurons after injection of either liraglutide or semaglutide (intraperitoneal - I.P. and subcutaneous - S·C.). POMC and NPY/AgRP neurons were targeted for patch-clamp electrophysiology as well as in vivo fiber photometry. RESULTS: We found that liraglutide and semaglutide directly activate and increase excitatory tone to POMC neurons in a time-dependent manner. This increased activity of POMC neurons required GLP-1Rs in POMC neurons as well as a downstream mixed cation channel comprised of TRPC5 subunits. We also observed an indirect upregulation of excitatory input to POMC neurons originating from glutamatergic cells that also required TRPC5 subunits. Conversely, GLP-1Ra's decreased excitatory input to and indirectly inhibited NPY/AgRP neurons through activation of K-ATP and TRPC5 channels in GABAergic neurons. Notably, the temporal activation of POMC and inhibition of NPY/AgRP neuronal activity after liraglutide or semaglutide was injected [either intraperitoneal (I.P.) or subcutaneous (S·C.)] was dependent upon the nutritional state of the animals (fed vs food-deprived). CONCLUSIONS: Our results support a mechanism of liraglutide and semaglutide in vivo to activate POMC while inhibiting NPY/AgRP neurons, which depends upon metabolic state and mirrors the pharmacokinetic profile of these compounds in vivo.

New Antidiabetes Medications and Their Cardiovascular and Renal Benefits.

After 12 years of rigorous cardiovascular outcome trials (CVOTs), sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) emerged as new therapeutic options for patients with type 2 diabetes mellitus to reduce the risk of heart disease. SGLT2i additionally cause a reduction in heart failure and renal events in patients both with and without diabetes. This article reviews the major CVOTs that support the use of these agents, describes the mechanisms of action that lead to their broad cardiorenal benefits, explains current guidelines, and offers practical clinical advice to initiate and monitor treatment with these agents.

Glucagon-Like Peptide 1 Receptor Agonists in Type 2 Diabetes Mellitus: Data from a Real-World Study in Spain.

INTRODUCTION: This study aimed to describe utilization patterns, persistence, resource utilization and costs in patients with type 2 diabetes mellitus initiating treatment with glucagon-like peptide 1 receptor agonists in routine clinical practice in Spain. METHODS: This retrospective study of medical records in the Big-Pac database identified adults starting treatment with once-weekly (QW) dulaglutide, exenatide-QW or once-daily liraglutide between 1 November 2015 and 30 June 2017. Patients were followed for up to 18 months from treatment initiation. Data on clinical characteristics of patients, treatment patterns, average daily dose and costs were obtained for the three cohorts. Persistence over the 18-month period was evaluated using Kaplan-Meier curves. All analyses were descriptive. RESULTS: A total of 1402 patients were included in this study (dulaglutide [n = 492], exenatide-QW [n = 438] or liraglutide [n = 472]); 52.8% were men, and the mean (SD) age was 62 (11) years, glycated haemoglobin (HbA1c) was 8.1% (1.2) and body mass index was 35.5 (3.2) kg/m2 at treatment initiation. Persistence at 18 months was 59.1% (95% confidence interval [CI] 54.8-63.4) for dulaglutide, 45.7% (95% CI 41.0-50.4) for exenatide-QW and 46.6% (95% CI 42.1-51.1) for liraglutide. The average (SD) dose was 1.2 (0.4) mg/week for dulaglutide, 1.9 (0.3) mg/week for exenatide-QW and 1.1 (0.3) mg/day for liraglutide. The average reduction in HbA1c levels at 1 year was - 0.68% for patients who initiated dulaglutide, - 0.54% for patients who initiated exenatide-QW and - 0.50% for patients who initiated liraglutide. The mean (SD) total annual health care costs were €4072 (1946) for dulaglutide, €4418 (2382) for exenatide-QW and €4382 (2389) for liraglutide. CONCLUSION: Results suggest that patients who started treatment with dulaglutide had higher persistence over 18 months, presented lower HbA1c levels at 12 months and incurred lower annual total healthcare costs than patients who initiated exenatide-QW or liraglutide.

Type 2 diabetes has a major impact on patients psychologically and socially, as well as on healthcare costs. The glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are drugs that help maintain blood sugar at healthy levels. They are often used as the first injectable drugs if oral treatments are no longer effective. This study aimed to analyse the use of GLP-1 RAs, and the costs involved, among patients with type 2 diabetes who started treatment with once-weekly dulaglutide, once-weekly exenatide or liraglutide in routine clinical practice in Spain. An electronic database of medical records was used to obtain data from 1402 patients who started treatment with these drugs and were followed for a 1.5-year period. Results of this study suggest that patients who were prescribed dulaglutide stayed on their treatment longer and could reduce their blood sugar levels more efficiently, and at a lower cost, than those who received once-weekly exenatide or liraglutide. These findings could be helpful to physicians prescribing these drugs when considering how to improve the management of type 2 diabetes.

Comparison of the Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Patients With Metabolic Associated Fatty Liver Disease: Updated Systematic Review and Meta-Analysis.

Aims: Metabolic associated fatty liver disease (MAFLD) is the most common cause of chronic liver disease and is a major health and economic burden in society. New drugs are urgently needed to treat MAFLD. This systematic review and meta-analysis was conducted to evaluate the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with MAFLD. Method: We searched PubMed, Embase, Cochrane Library database, and Web of Science since 1977. We selected all randomized controlled trials which met the inclusion and exclusion criteria and evaluated the quality of evidence. A random-effects meta-analysis was performed to assess all the primary and second outcomes. Results: Eight randomized controlled trials, including 396 patients, of which 265 patients had type 2 diabetes mellitus, met the inclusion criteria. Compared with the placebo or active agents group, the GLP-RA group showed a significant reduction in the liver fat content [weight mean difference (WMD) -3.17%, 95%CI -5.30 to -1.03, P < 0.0001], body weight (WMD -4.58 kg, 95%CI -8.07 to -1.10, P = 0.010), waist circumference (WMD -3.74 cm, 95%CI -6.73 to -0.74, P = 0.010), alanine aminotransferase (WMD -10.73 U/L, 95%CI -20.94 to -0.52, P = 0.04), γ- glutamyl transferase (WMD -12.25 U/L,95% -18.85 to -5.66, P = 0.0003, with I²=23%), fasting blood glucose (MD, -0.36 mmol/L; 95%CI, -0.69 to -0.03, P = 0.030), and hemoglobin A1c (WMD -0.36%, 95%CI -0.52 to -0.19, P < 0.0001). The reported adverse events were gastrointestinal complications with no serious adverse events, and most symptoms were relieved within 1-2 weeks after dose titration. Conclusion: GLP-RAs may improve liver injury and metabolic disorder in patients with MAFLD, regardless of the presence of type 2 diabetes mellitus. The benefits of GLP-RAs treatment outweigh the adverse effects of drugs in patients with MAFLD.