Background: The objective was to evaluate the efficacy of the combination of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter 2 inhibitor (SGLT-2i) in the treatment of Type 2 diabetes with poor efficacy of basic insulin and metformin/sulfonylurea by umbrella review. Materials and Methods: Forming the data of publication of each database through 13 September 2022, PubMed, EMBASE, and Cochrane Library were surveyed. Results: A total of seven meta-analyses were included in the umbrella review. The combination of GLP-1 RA (WMD -3.41 [-5.61, -1.21], p = 0.002), SGLT-2i (WMD -5.34 [-9.56, -1.13], p = 0.013), and DPP-4i (WMD -5.56 [-7.39, -3.73], p ≤ 0.001) can significantly reduce HbA1c levels, respectively. The combination of GLP-1 RA (WMD -1.55 [-2.92, -0.18], p = 0.027), SGLT-2i (WMD -2.96 [-6.68, 0.77], p = 0.12), and DPP-4i (WMD -2.05 [-2.82, -1.28], p ≤ 0.001) can significantly reduce fasting plasma glucose (FPG) levels, respectively. The combination of GLP-1 RA (WMD -3.24 [-5.14, -1.34], p < 0.001) can significantly reduce body weight of Type 2 diabetes mellitus (T2DM). The dose of basic insulin in diabetes patients after combined use of GLP-1 RA (WMD -2.74 [-4.26, -1.22], p ≤ 0.001) was significantly reduced. The combination use of GLP-1 RAs (OR 1.28 [1.05, 1.56], p = 0.017) increases the risk of hypoglycemia. Conclusions: The combination of GLP-1 RAs, DPP-4i, and SGLT-2i can effectively lower HbA1c and FPG in T2DM patients who have poor therapeutic effects on basic insulin combined with metformin/sulfonylureas, respectively. Compared to placebo, GLP-1 RAs can significantly reduce body weight and basic insulin dosage, while DPP-4i and SGLT-2i have a lower risk of hypoglycemia. Trial Registration: CRD42023410345.

Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological and psychosocial interventions; however, currently available medications are limited in number and efficacy. The glucagon-like-peptide-1 (GLP-1) system is emerging as a potential novel pharmacotherapeutic target for alcohol and other substance use disorders (ASUDs). In this review, we summarize and discuss the wealth of available evidence from testing GLP-1 receptor (GLP-1R) agonist medications in preclinical models and humans with ASUDs, possible mechanisms underlying the impact of GLP-1R agonists on alcohol/substance use, gaps in knowledge, and future directions. Most of the research with GLP-1R agonists has been conducted in relation to alcohol use; psychostimulants, opioids, and nicotine have also been investigated. Preclinical evidence suggests that GLP-1R agonists reduce alcohol/substance use and other related outcomes. The main proposed mechanisms are related to reward processing, stress, and cognitive function, as well as broader mechanisms related to satiety, changes in gastric motility, and glucose homeostasis. More in-depth mechanistic studies are warranted. Clinical studies have been limited and their findings have been less conclusive; however, most support the safety and potential efficacy of GLP-1R agonists in ASUD treatment. Identifying preferred compounds, as well as possible subgroups who are most responsive to GLP-1R agonists are some of the key research questions to translate the promising preclinical data into clinical settings. Several clinical trials are underway to test GLP-1R agonists in people with ASUDs.

Chronic kidney disease (CKD) is a growing global public health challenge worldwide. In Mexico, CKD prevalence is alarmingly high and remains a leading cause of morbidity and mortality. Diabetic kidney disease (DKD), a severe complication of diabetes, is a leading determinant of CKD. The escalating diabetes prevalence and the complex regional landscape in Mexico underscore the pressing need for tailored strategies to reduce the burden of CKD. This narrative review, endorsed by the Mexican College of Nephrologists, aims to provide a brief overview and specific strategies for healthcare providers regarding preventing, screening, and treating CKD in patients living with diabetes in all care settings. The key topics covered in this review include the main cardiometabolic contributors of DKD (overweight/obesity, hyperglycemia, arterial hypertension, and dyslipidemia), the identification of kidney-related damage markers, and the benefit of novel pharmacological approaches based on Sodium-Glucose Co-Transporter-2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA). We also address the potential use of novel therapies based on Mineralocorticoid Receptor Antagonists (MRAs) and their future implications. Emphasizing the importance of multidisciplinary treatment, this narrative review aims to promote strategies that may be useful to alleviate the burden of DKD and its associated complications. It underscores the critical role of healthcare providers and advocates for collaborative efforts to enhance the quality of life for millions of patients affected by DKD.

Incretin hormones potentiate the glucose-induced insulin secretion following enteral nutrient intake. The best characterised incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are produced in and secreted from the gut in response to nutrient ingestion. The property of incretins to enhance endogenous insulin secretion only at elevated blood glucose levels makes them interesting therapeutics for type 2 diabetes mellitus with a better safety profile than exogenous insulin. While incretin therapeutics (especially GLP-1 agonists, and more recently also GLP-1 / GIP dual agonists and other drugs that influence the incretin metabolism (e.g., dipeptidyl peptidase-4 (DPP-4) inhibitors)) are already widely used treatment options for human type 2 diabetes, these drugs are not yet approved for the therapy of feline diabetes mellitus. This review provides an introduction to incretins and feline diabetes mellitus in general and summarises the current study situation on incretins as therapeutics for feline diabetes mellitus to assess their possible future potential in feline medicine. Studies to date on the use of GLP-1 receptor agonists (GLP-1RA) in healthy cats largely confirm their insulinotropic effect known from other species. In diabetic cats, GLP-1RAs appear to significantly reduce glycaemic variability (GV, an indicator for the quality of glycaemic control), which is important for the management of the disease and prevention of long-term complications. However, for widespread use in feline diabetes mellitus, further studies are required that include larger numbers of diabetic cats, and that consider and test a possible need for dose adjustments to overweight and diabetic cats. Also evaluation of the outcome of GLP-1RA monotherapy will be neceessary.

The aim of this narrative review is to synthesize the available data describing the efficacy and safety of medications approved for obesity management and to provide an overview of upcoming agents in development. A literature search of PubMed, Medline, and Embase databases identified relevant articles describing medications approved in the U.S., Australia, U.K., and/or Europe. Papers were selected based on relevance and originality, with phase 3 clinical trials and meta-analyses preferentially included. Six medications are widely approved for long-term weight management in conjunction with lifestyle interventions in people with body mass index (BMI) ≥30 ​kg/m2 or BMI ≥27 ​kg/m2 and at least one medical condition related to excess weight. Compared with lifestyle interventions alone, all medications approved for obesity management are more effective for long-term weight loss and improvements in cardiometabolic risk factors. Older obesity medications are associated with mean weight losses in the range of 5-10%. The new generation of agents, including the injectable incretin analogues semaglutide and tirzepatide are associated with sustained mean weight reductions of 15-20%, along with substantial benefits on a range of health outcomes. Several novel agents are under development, with multi-hormone receptor agonists and oral formulations likely to become available in the coming years. As effective treatment options expand, cost and availability will need to be addressed to enable equitable access to treatment. Other important challenges for clinical practice and research include the need for long-term strategies to prevent and manage weight regain and loss of lean muscle and bone mineral density.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of β-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce glucose levels in patients with type 2 diabetes mellitus since 2005. This meta-analysis discusses the mechanisms and potential benefits of several GLP-1 RAs. In particular, this meta-analysis focuses on the safety and associations with weight loss, glucose reduction, cardiovascular outcomes, heart failure, and renal outcomes of GLP-1 RAs to determine their benefits for patients with different conditions. In terms of glycemic control and weight loss, semaglutide was statistically superior to other GLP-1 RAs. In terms of cardiovascular outcomes, 14 mg of semaglutide taken orally once daily and 1.8 mg of liraglutide injected once daily reduced the incidence of cardiovascular death, whereas other GLP-1 RAs did not provide similar benefits. Moreover, semaglutide was associated with superior outcomes for heart failure and cardiovascular death in non-diabetic obesity patients, whereas liraglutide worsened heart failure outcomes in diabetic patients with a reduced ejection fraction. Additionally, semaglutide, dulaglutide, and liraglutide were beneficial in terms of composite renal outcomes: These GLP-1 RAs were significantly associated with less new or persistent macroalbuminuria, but not with improved eGFR deterioration or reduced requirement for renal replacement therapy. However, GLP-1 RAs may benefit patients with type 2 diabetes mellitus or obesity.

UNASSIGNED: Hypothalamic obesity represents a clinical condition within the broader spectrum of obesity that frequently eludes detection and appropriate diagnosis. This subset of obesity is characterized by a dearth of established predictive markers and a paucity of standardized therapeutic protocols. The advent and rising prominence of glucagon-like peptide-1 (GLP-1) receptor agonists in the obesity treatment landscape present novel therapeutic avenues for hypothalamic obesity management. Nonetheless, critical inquiries persist concerning the efficacy of GLP-1 receptor (GLP-1R) agonists in this context, particularly regarding their central mechanisms of action and specific impact on hypothalamic obesity.
UNASSIGNED: In this narrative review, we concentrate on analyzing research papers that delineate the detection and function of GLP-1 receptors across various hypothalamic and cerebral regions. Additionally, we examine clinical research papers and reports detailing the application of GLP-1 receptor agonists in treating hypothalamic obesity. Furthermore, we include a concise presentation of a clinical case from our unit for contextual understanding.
UNASSIGNED: Currently, the clinical evidence supporting the efficacy of GLP-1 receptor agonists in hypothalamic obesity, as well as the diverse characteristics of this obesity subtype, remains insufficient. Preliminary data suggest that GLP-1R agonists might offer an effective treatment option, albeit with variable outcomes, particularly in younger patient cohorts. From a mechanistic perspective, the presence of GLP-1 receptors in various hypothalamic and broader brain regions potentially underpins the efficacy of GLP-1R agonists, even in instances of hypothalamic damage. Nevertheless, additional research is imperative to establish the functional relevance of these receptors in said brain regions.
UNASSIGNED: GLP-1R agonists represent a potential therapeutic option for patients with hypothalamic obesity. However, further clinical and basic/translational research is essential to validate the efficacy of these drugs across different presentations of hypothalamic obesity and to understand the functionality of GLP-1R in the diverse brain regions where they are expressed.

Polycystic ovary syndrome is a common reproductive endocrine condition that affects women of fertile age and is characterized by three main features, including hyperandrogenism, chronic anovulation, and polycystic ovaries. In addition, half of women with polycystic ovary syndrome have insulin resistance, and obesity or overweight, type 2 diabetes, hypertension, and hyperlipidemia are the most common metabolic abnormalities affecting (30%) women with polycystic ovary syndrome. Weight loss is regarded as the first-line treatment as it can potentially improve polycystic ovary syndrome parameters (androgen levels, menstrual cyclicity, lipid and glucose metabolism). However, achieving and maintaining weight loss can be challenging, and pharmacological agents could be essential to achieve optimal glycemic control and improve the endocrine disturbance associated with polycystic ovary syndrome. Glucagon-like peptide-1 receptor agonist has been demonstrated as monotherapy or in combination with metformin for managing obesity and insulin resistance associated with polycystic ovary syndrome. Yet, its effect on endocrine and metabolic parameters remains elusive, and further research is needed to close the gap. The aim is to evaluate the efficacy of glucagon-like peptide-1 receptor agonist monotherapy and/or a combined treatment between glucagon-like peptide-1 receptor agonist and metformin for improving anthropometric measurements, endocrine and metabolic parameters in lean and obese women with polycystic ovary syndrome. A systematic review of longitudinal cohort studies was conducted across databases including Ovid Medline, PubMed Central, and Cochrane Library between 2015 and 2022. Eligible studies included participants with polycystic ovary syndrome diagnosed according to the 2003 Rotterdam or the 1990 National Institutes of Health criteria. A total of eight studies including 486 patients with polycystic ovary syndrome were analyzed. The mean age was between 18 and 45 years with mean follow-up period between 12 and 32 weeks. In all these studies, results were comparable for the reduction in body mass index, waist circumference, fat mass, and visceral fat mass; however, it was more in combination therapy versus comparator. In conclusion, glucagon-like peptide-1 receptor agonists effectively reduce body weight and improve some of the endocrine and metabolic parameters of polycystic ovary syndrome. A combined treatment with glucagon-like peptide-1 receptor agonist and metformin had significant effects on weight loss and favorable results on endocrine and metabolic parameters, yet further research is needed to discover the long-term safety of combined therapy in women diagnosed with polycystic ovary syndrome and obesity or overweight.

UNASSIGNED: Mounting evidence suggests that glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) attenuate cardiovascular-risk in type-2 diabetes (T2DM). Tirzepatide is the first-in-class, dual glucose-dependent-insulinotropic-polypeptide GIP/GLP-1 RA approved for T2DM.
UNASSIGNED: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate: (i) the incidence of major adverse cardiovascular events (MACE); and (ii) incidence of stroke, fatal, and nonfatal stroke in T2DM-patients treated with GLP-1 or GIP/GLP-1 RAs (vs placebo).
UNASSIGNED: Thirteen RCTs (9 and 4 on GLP-1 RAs and tirzepatide, respectively) comprising 65,878 T2DM patients were included. Compared to placebo, GLP-1RAs or GIP/GLP-1 RAs reduced MACE (OR: 0.87; 95% CI: 0.81-0.94; p < 0.01; I2 = 37%), all-cause mortality (OR: 0.88; 95% CI: 0.82-0.96; p < 0.01; I2 = 21%) and cardiovascular-mortality (OR: 0.88; 95% CI: 0.80-0.96; p < 0.01; I2 = 14%), without differences between GLP-1 versus GIP/GLP-1 RAs. Additionally, GLP-1 RAs reduced the odds of stroke (OR: 0.84; 95% CI: 0.76-0.93; p < 0.01; I2 = 0%) and nonfatal stroke (OR: 0.85; 95% CI: 0.76-0.94; p < 0.01; I2 = 0%), whereas no association between fatal stroke and GLP-1RAs was uncovered (OR: 0.80; 95% CI: 0.61-1.05; p = 0.105; I2 = 0%). In secondary analyses, GLP-1 RAs prevented ischemic stroke (OR: 0.74; 95% CI: 0.61-0.91; p < 0.01; I2 = 0%) and MACE-recurrence, but not hemorrhagic stroke (OR: 0.92; 95% CI: 0.51-1.66; p = 0.792; I2 = 0%). There was no association between GLP-1RAs or GIP/GLP-1 RAs and fatal or nonfatal myocardial infarction.
UNASSIGNED: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and mortality in T2DM. While there is solid evidence that GLP-1 RAs significantly attenuate the risk of ischemic stroke in T2DM, dedicated RCTs are needed to evaluate the efficacy of novel GIP/GLP-1 RAs for primary and secondary stroke prevention.