Incretin Mimetics Research Articles

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Heart failure and renal outcomes in patient treated with GLP1 agonists

Abstract Introduction Glucagon-like peptide-1 receptor (GLP1) agonists are emerging as a primordial treatment for diabetes and to reduce cardiovascular burden, both of them factors that play an important role in the developing of renal chronic disease and heart failure, and vice versa. The debut of renal chronic disease and the manifestation of acute renal injury/failure can lead to the discontinuation of treatment, which in patients suffering from heart failure who tend to be polymedicated could end up in lessening their survival. Methods A metanalysis of randomized clinical trials (RCT) comparing GLP1 agonists with placebo was performed. The endpoint of the study was to analyze all-cause mortality, hospitalization or urgent medical visit for heart failure, a kidney outcome composite, which is slightly heterogenic depending on the RCT, and the manifestation of acute renal injury/failure as an adverse effect or that lead to the discontinuation of treatment. The meta-analysis was performed using the inverse variance method, using the fixed effects model when there was no heterogeneity and the random effects model when heterogeneity is significant. Results A sum of 9 randomized controlled trial were included where a GLP1 agonists such as albiglutide, dulaglutide, exenatide, liraglutide, lixinatide or semaglutide compared with placebo. 77684 patients were incorporated, while 39497 were treated with a GLP1 agonists. The mean age was of 63.7 years (SD ± 1.97 years), 60080 (77.3%) suffered from diabetes, 60552 (77.9%) from cardiovascular disease and 14367 from chronic heart failure (18.4%). The mean eGFR was 77.3 mL/min (SD ± 3.3 mL/min). As showed in the forest plots, treatment with GLP1 agonists reduced all-cause mortality by 12% (RR: 0.88, 95% CI 0.83-0.92; p<0.001), hospitalization or urgent medical visit for heart failure by 10% (RR: 0.90, 95% CI 0.83-0.98; p<0.001), the kidney composite outcome by 22% (RR: 0.78, 95% CI 0.70-0.87; p<0.001), while it showed no statistical reduction in acute renal injury/failure (RR: 0.89, 95% CI 0.79-1.01; p=0.069). Conclusion Treatment with a GLP1 agonists reduced the incidence of all-cause mortality by 12%. In addition, hospitalization or urgent medical visit for heart failure was decreased by 10%. In terms of renal asessment, the composite of kidney function was reduced by 22%, while the manifestation of acute renal injury/failure, though no statistical signification was accomplished, showed some evidence of beneficial effect but more RCTs are needed to prove it. Hence, GLP1 analogues appear as a possible new pillar of treatment for heart failure and renal disease in determined patients.

Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

GLP-1 analog use is associated with improved disease course in inflammatory bowel disease: a report from the Epi-IIRN.

The growing use of GLP-1 analogs for type 2 diabetes mellitus (DM2) and obesity necessitates studies about their use in patients with inflammatory bowel diseases (IBD). Data on patients with DM2 were retrieved from an Israeli nationwide cohort of patients with IBD (epi-IIRN), recording GLP-1 analog exposure for at least 6 months. Primary outcome was poor disease outcomes (i.e. composite of steroid-dependence, initiation of advanced IBD therapy, hospitalization, surgery, or death). Cox proportional hazard models with time-varying covariables were used to assess the impact of GLP-1 use on outcomes during follow-up. We included 3,737 patients (24,338 patient-years) with IBD and DM2 [(50.4% ulcerative colitis (UC)], of whom 633 were treated with GLP-1 analogs. Accounting for demographics IBD/DM2 related variables, medication use, and laboratory measurements, GLP-1 analog use was associated with reduced composite outcome in the full cohort (adjusted Hazard Ratio (aHR) 0.74, 95%CI 0.62-0.89) and in each subtype [UC (aHR 0.71, 95%CI 0.52-0.96) and Crohn's disease (aHR 0.78, 95%CI 0.62-0.99)]. Similar trends were seen in multivariate analyses of each individual outcome, although only hospitalization was significant (aHR 0.74, 95%CI 0.61-0.91). The protective effect of GLP-1 analogs was seen in patients with obesity (aHR 0.61, 95%CI 0.50-0.77), but not in non-obese (aHR 0.94, 95%CI 0.67-1.31). GLP-1 analogs are associated with improved outcomes in IBD, specifically in patients with obesity. The mechanisms of these effects require further investigation as well as their role in patients without DM2.

Incretin Mimetics as Potential Disease Modifying Treatment for Alzheimer's Disease.

Alzheimer's disease is a devastating neurodegenerative condition that exerts a significant global burden. Despite recent efforts, disease modifying therapies remain extremely limited, with a tremendous proportion of patients having to rely on symptomatic treatment only. Epidemiological and pathological overlaps exist between Alzheimer's disease and diabetes mellitus type 2, with people with diabetes mellitus type 2 at a significantly increased risk of developing Alzheimer's disease in the future. Incretin mimetics, also known as GLP-1/GIP receptor agonists, are useful tools licensed for the treatment of diabetes mellitus type 2 which have recently been the subject of news coverage for their off-label use as weight loss medications. Emerging evidence highlights the possible neuroprotective function of incretin mimetics in models of Alzheimer's disease as well as in clinical studies. This review details the pre-clinical and clinical studies that have explored the effectiveness of incretin mimetics to alleviate Alzheimer's disease associated pathology and cognitive impairment, while also highlighting the progress made to examine the effectiveness of these molecules in Parkinson's disease. Should clinical trials prove effective, incretin mimetics may be able to be repurposed and become useful novel tools as disease-modifying treatments for Alzheimer's disease and other neurodegenerative diseases.

Conquering Insulin Network Dysfunctions in Alzheimer's Disease: Where Are We Today?

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver of the Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient and insulin-resistant states mimic those of diabetes mellitus and affect all cell types in the brain. Besides accounting for abundant amyloid-β and hyperphosphorylated tau lesions in AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss of synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte and microglial neuroinflammation and oxidative stress, deficits in energy metabolism, mitochondrial dysfunction, and microvascular disease. These same neuropathological processes have been linked to cognitive impairment in type 2 diabetes mellitus, Parkinson's disease, and vascular dementia. Strategies to address metabolic mediators of cognitive impairment have been borrowed from diabetes and other insulin-resistant diseases and leveraged on preclinical AD model data. The repurposing of diabetes drugs led to clinical trials with intranasal insulin, followed by insulin sensitizers including metformin and peroxisome-proliferator-activated receptor agonists, and then incretin mimetics primarily targeting GLP-1 receptors. In addition, other glucose-lowering agents have been tested for their efficacy in preventing cognitive declines. The strengths and limitations of these approaches are discussed. The main conclusion of this review is that we have now arrived at a stage in which it is time to address long-term deficits in trophic factor availability and receptor responsiveness, signaling abnormalities that extend beyond insulin and include IGFs and interconnected pathways, and the need for multi-pronged rather than single-pronged therapeutic targeting to remediate AD and other forms of neurodegeneration.

Liraglutide Therapy in Obese Patients Alters Macrophage Phenotype and Decreases Their Tumor Necrosis Factor Alpha Release and Oxidative Stress Markers-A Pilot Study.

Introduction: Obesity is one of the major healthcare challenges. It affects one in eight people around the world and leads to several comorbidities, including type 2 diabetes, hyperlipidemia, and arterial hypertension. GLP-1 analogs have become major players in the therapy of obesity, leading to significant weight loss in patients. However, benefits resulting from their usage seem to be greater than simple appetite reduction and glucose-lowering potential. Recent data show better cardiovascular outcomes, which are connected with the improvements in the course of atherosclerosis. Macrophages are crucial cells in the forming and progression of atherosclerotic lesions. Previously, it was shown that in vitro treatment with GLP-1 analogs can affect macrophage phenotype, but there is a paucity of in vivo data. Objective: To evaluate the influence of in vivo treatment with liraglutide on basic phenotypic and functional markers of macrophages. Methods: Basic phenotypic features were assessed (including inducible nitric oxide synthase, arginase 1 and mannose receptors), proinflammatory cytokine (IL-1β, TNFα) release, and oxidative stress markers (reactive oxygen species, malondialdehyde) in macrophages obtained prior and after 3-month therapy with liraglutide in patients with obesity. Results: Three-month treatment with subcutaneous liraglutide resulted in the alteration of macrophage phenotype toward alternative activation (M2) with accompanying reduction in the TNFα release and diminished oxidative stress markers. Conclusions: Our results show that macrophages in patients treated with GLP-1 can alter their phenotype and function. Those findings may at least partly explain the pleiotropic beneficial cardiovascular effects seen in subjects treated with GLP-1 analogs.

Therapies Using Anti-Diabetics to Prevent and Manage Progression of Parkinson's Disease

<p>Currently, a significant proportion of older individuals have demonstrated connections between Parkinson's disease (PD) and type 2 diabetes mellitus (T2DM). Emerging evidence from cohort studies, clinical data, and preclinical meta-analyses reveals that T2DM patients have an increased risk of developing PD, often accompanied by more severe disease progression. These two chronic conditions are believed to share common pathways. The pathways that likely connect the neurodegenerative process of PD include autophagy, mitochondrial dysfunction, dysregulated insulin signaling, inflammation, and insulin resistance. Preclinical PD models highlight the importance of cerebral insulin signaling, which confers numerous neuroprotective benefits. Several ongoing phase II and phase III trials are being conducted in PD-affected populations. These trials reflect the potential of existing anti-diabetic medications to improve PD motor symptoms and halt the progression of neurodegeneration. Brain insulin resistance plays a crucial role in the pathophysiology of PD. The insulin signaling pathway represents a promising novel target for disease modification in both diabetic and non-diabetic PD. Incretin receptors in the brain have emerged as the most promising targets for repurposing existing drugs in PD treatment. Targeting these receptors mitigates inflammation, apoptosis, toxic protein aggregation, long-term potentiation, autophagy, and insulin signaling failure. </p><p> Presently, various novel anti-diabetic targets are available that can regulate the insulin signaling pathway in dopaminergic neurons, suggesting improvements in cognitive function and significant neuroprotective effects in PD. Throughout neurodegenerative processes, insulin and incretins exert therapeutic effects in multiple manners. Preclinical studies have demonstrated that glucagon-- like peptide 1 (GLP-1) receptor agonists reduce neuroinflammation, tau phosphorylation, and amyloid deposition while increasing synaptic function and enhancing memory formation. Incretin mimetics may act through the restoration of insulin signaling pathways, inducing further neuroprotective effects. </p><p> This review examined the reported shared cellular and molecular pathologies between PD and T2DM, and explored the repurposing of anti-diabetic drugs for the prevention of PD progression through the regulation of insulin signaling pathways.</p>

8040 Precision-Engineered Activin and GDF Ligand Trap HS235: A Novel Lean Mass-Preserving Treatment for Obesity

Abstract Disclosure: G. Schang: Employee; Self; 35Pharma. M. De Molliens: Employee; Self; 35Pharma. E. Brule: Employee; Self; 35Pharma. C. Chauvet: Employee; Self; 35Pharma. J. Denis: Employee; Self; 35Pharma. A. Sours: Employee; Self; 35Pharma. V. Ganesh: Employee; Self; 35Pharma. G. Tremblay: Employee; Self; 35Pharma. J. Schoelermann: Employee; Self; 35Pharma. M. O'Connor: Employee; Self; 35Pharma. Introduction: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, incretins reduce body mass in a non-selective manner; both fat mass and lean mass are lost with incretin treatment. In obese patients treated with incretins, undesirable loss of lean body mass (LBM) can account for up to 40% of overall weight loss. Loss of LBM negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. Furthermore, individuals with sarcopenia, characterized by low muscle mass and strength, are at greater risk for heart failure. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and overall cardiometabolic health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. To validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, muscle weights, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic lead to a synergistic fat mass loss and prevented loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy orthogonal to incretin mimetics. Collectively, these data support the development of HS235 as a novel anti-obesity agent to complement currently approved incretin-based medications to improve quality of weight loss. Presentation: 6/3/2024

6866 Real-world implications and limitations of GLP-1 prescriptions in adolescents

Abstract Disclosure: G. Castano: None. S. Sisley: None. Background: Glucagon-like-peptide-1 agonists (GLP1), approved for adolescents ≥ 10 years in 2019 for type 2 diabetes (T2D) and ≥ 12 years in 2020 for obesity, require adequate dose titration and have known side effects. There is little information on insurance approval, adherence to titration regimens, or the side effects of liraglutide in clinical practice. Methodology: We performed a retrospective review of all patients <18 years old who were prescribed GLP-1 at a large children’s hospital. We collected demographic information, prescription orders, insurance approval, and drug initiation dates. For individuals who completed at least 26±8 weeks of treatment, we also collected dose titration, side effects, and insulin doses. Results:599 patients were prescribed GLP-1 from 2019 to 2023, with a mean age of 14.99±2.1 years, 58% female, 58% public insurance, and 74% (n=442) with T2D. The cohort was comprised of 63% White, 30% Black, and 2.3% Asian individuals, with 52% of Hispanic ethnicity. 90% of prescriptions were for liraglutide, and 10% for other GLP1 analogs, including exenatide, dulaglutide, and semaglutide. Insurance denied 41% (n=244) of prescriptions, with more denials in those without T2D, 64% vs 32% in patients with T2D.Whereas private insurance denied more prescriptions than Medicaid in patients with T2D (54% vs 27%), the reverse was true for patients without T2D ( 55% private vs 69% Medicaid). Patients lost to follow-up in the first 3 months accounted for 22% (n=135) of the cohort, even though 48% (n=66) of those patients had insurance approval.Those who had insurance approval and took liraglutide for at least 26 weeks accounted for 34% (n=204) of the cohort. Of the patients with T2D, 50% (n=95) titrated to 1.8mg by their first follow-up appointment (1-3 months after prescription start), 33% (n=62) by 6 months, and 17% (n=32) never reached 1.8mg. In patients prescribed a higher dose of liraglutide (3.0 mg daily), 42% (n=8) titrated to 3mg over 5 weeks as prescribed, and 52% (n=10) never reached 3mg, with only one of them not reaching 1.8 mg.Most patients (82%, n=169) had no side effects documented in their charts. From those with side effects reported, GI problems (nausea, vomiting, diarrhea) were noted in 12% (n=25), and 2% (n=4) reported injection site reactions. Side effects that required medication discontinuation included hypoglycemia (n=1), mild pancreatitis (n=1), and severe pancreatitis (n=2). Conclusion: In clinical practice, despite FDA approval, insurance coverage of liraglutide is limited. Almost half of the patients require extra time to reach full doses of liraglutide, with one-third never reaching full treatment doses. Severe pancreatitis may be a previously unpublished side effect. More research is needed to understand how real-world adherence and side effects of liraglutide affect clinical outcomes. Presentation: 6/1/2024

6486 Gastroparesis Exacerbation by a GLP-1 Agonist

Abstract Disclosure: J.M. Deirmenjian: None. C. Dagher: None. Gastroparesis is characterized by a delay in gastric emptying that may present with nausea, vomiting, satiety, abdominal pain, and anorexia. The most common cause of gastroparesis is diabetes mellitus due to vagal autonomic neuropathy which prevents coordinated gastric contractions. Medications may also induce gastroparesis. Glucagon-like peptide (GLP)- 1 agonists such as semaglutide are being prescribed for diabetes control but also due to benefits of cardiovascular disease and weight loss. Concerns of GLP-1 agonists causing gastroparesis are valid as the mechanism of action includes delaying gastric emptying, especially with newly developed analogs that are more potent with longer half-lives. Patient is a 43-year-old female with a history of hypertension, uncontrolled diabetes mellitus type 2, diabetic gastroparesis, diabetic neuropathy, hyperlipidemia, and obesity who presented with a one-month history of postprandial abdominal pain, nausea, vomiting, and a 40-pound unintentional weight loss with decreased oral intake. Her abdominal pain was sharp and was exacerbated with eating. While she had several gastroparesis flares in the past, she was in remission for almost two years until she was transitioned from dulaglutide to semaglutide after which she had a recurrent flare after two doses. On physical examination, her abdomen was diffusely tender to palpation.On admission, her hemoglobin A1c was 9.7%. She was made NPO, started on peripheral fluids, and initiated on scheduled metoclopramide given high suspicion of a gastroparesis flare. She underwent a gastric emptying study with the gastric amount retained as follows: 97% (at 1 hour), 88% (at 2 hours), and 79% (at 4 hours). Her hospital course was complicated by persistent symptoms of gastroparesis. Gastroenterology recommended scheduled metoclopramide and erythromycin for motility and dietary adjustments including small volume liquid calories. Her oral intake was insufficient and she opted for total peripheral nutrition until symptoms improved. She was advised to never take a GLP-1 agonist again and should her symptoms not improve the next step would be to pursue a gastric pacemaker. The etiology of the patient’s gastroparesis was uncontrolled diabetes. The proximity between starting semaglutide and symptom onset is compelling as an inciting factor in this flare. This admission’s gastric emptying study results showed higher gastric retention for a longer period of time, which may shed light to the potency of these new GLP-1 analogs. The patient tolerated maximum dose dulaglutide for months but not even two doses of semaglutide. With the race to invent more potent GLP-1 agonists for diabetes control and weight loss on the horizon, knowing their side effects and mechanism of action is crucial. While not listed as a contraindication, there should be hesitancy to offer these agents to anyone with significant gastroparesis. Presentation: 6/2/2024

6959 Variation of FIB-4 Classification In A 5-Year Follow-Up Cohort of Patients With Type 2 Diabetes Mellitus Managed By A Multi-Disciplinary Team In A Hospital In Northeastern Mexico

Abstract Disclosure: M. Romero Ibarguengoitia: None. D.P. Morales-Rodríguez: None. A. González-Cantú: None. A. Garza-Silva: None. A. Rivera-Cavazos: None. I. Fernández-Chau: None. A. Cepeda-Medina: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common pathology associated to type 2 diabetes mellitus (T2DM), however the change in its classification over time is unknown in patients with T2DM managed by a multidisciplinary team in a population of Northern Mexico. Therefore, we analyzed the change in the FIB-4 classification for MASLD before and during 3 years of SARS-CoV-2 pandemic. We conducted a retrospective observational cohort study on a population of steelworkers with T2DM from a hospital in Northeastern Mexico from 2018 to 2022 treated by a multidisciplinary team. This team was comprised by an internist or geriatrician based on patient’s age, an endocrinologist, a nutritionist, and other specialties related to T2DM. We analyzed levels of HbA1C, fasting serum glucose (FSG), attendance to various specialties consultations, trends in medication usage and changes in the classification of FIB-4 scale. A total of 999 subjects were studied, with 516 (51.7%) being male, average age (SD) of 60.1 (12.7) years. There was a significant difference in the proportion of patients with controlled HbA1C levels, being 55.5% in 2018 and rising to 64.3% in 2020 and to 70.7% in 2022 (p<0.001). An increase in the proportion of patients in control based on FSG was observed, from 13.8% in 2018 to 54.8% in 2020 and 56.1% in 2022 (p<0.001). Throughout the follow-up period, all patients had at least one annual consultation with an internist or geriatrician according to their age group. Additionally, there was an increase in assistance to endocrinology consultations from 8.5% in 2018 to 9.9% in 2020 and 12.1% in 2022 (p<0.001). There was a rise in the prescription of oral hypoglycemic agents in general from 4.9% in 2018 to 14.2% in 2020, with an increase of GLP-1 analogs from 3.3% in 2018 to 9.3% in 2020 (p<0.001). Regarding the categorization by FIB-4, in 2018, a proportion of 64.8% of patients were observed in the F0-F1 category, 30.2% in the F2 category, and 4.8% in the F3-F4 category (p<0.001). These levels remained similar for 2020, with 62.6% in the F0-F1 category, 32.4% in the F2 category, and 4.9% in the F3-F4 category (p<0.001). In 2022, there is an increase in the proportion of patients in the F0-F1 category, reaching 71.8% of our population, along with a decrease in those classified as F2 to 20.9%, and a slight increase in the proportion of patients in the F3-F4 category to 7.2% (p<0.001). MASLD is a condition that occurs frequently in our population; however, it is possible to stabilize and even decrease its classification through a multidisciplinary and specialized team capable of treating T2DM effectively by optimizing its management with GLP-1 prescription and a prompt referral to endocrinology consultation with the aim of providing a good quality of life for the patients. Presentation: 6/2/2024

From Glucose to Neuroprotection: Exploring Antidiabetic Medications as a Novel Approach to Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a major neurological disorder and a leading cause of dementia, which is characterized by progressive cognitive decline. Emerging research highlights the link between AD and type 2 diabetes mellitus (T2DM), suggesting that shared pathophysiological mechanisms, such as insulin resistance, inflammation, and oxidative stress, contribute to both conditions. This connection has led to the concept of type 3 diabetes.Given these overlaps, antidiabetic drugs are being explored for repurposing as potential AD treatments. Intranasal insulin, metformin, thiazolidinediones, and GLP-1 analogs like liraglutide have shown promise in reducing amyloid-beta levels and inflammation, and improving cognitive functions. Despite encouraging preclinical and early clinical results, challenges remain in translating these findings into safe and effective treatments. Continued research could lead to innovative therapies that address both AD and T2DM, offering improved patient outcomes.

Disorder of Glucose Metabolism and Therapy: Implications on the Natural History of Advanced Chronic Liver Disease

Introduction: Hepatogenous diabetes (HD) is a disorder of glucose metabolism (DGM) that develops as a complication of advanced chronic liver disease (ACLD) with an estimated prevalence of 20–70%. It appears to be associated with a larger number of decompensations, but its impact on the natural history of the disease is unclear. The treatment of DGM is hampered by the fact that some therapeutic agents are associated with a risk of complications in ACLD. The aim of this work was to study DGM in a population of patients with ACLD: prevalence, liver disease decompensation episodes, mortality analysis and study of the impact of antidiabetic therapies in patients with ACLD who developed DGM. Materials and Methods: A cohort of consecutive patients with ACLD without previous DGM, who attended a Hepatology clinic in the period of January to June 2015 was selected. Follow-up was carried out for 5 years. Data on age, gender, date of diagnosis and etiology of ACLD, Child-Pugh and MELD-Na classifications at enrollment, development of DGM, and antidiabetic therapy were collected. Logistic regression models for hospitalizations due to decompensated ACLD, ascites, hepatic encephalopathy (HE), upper gastrointestinal bleeding (UGB), hepatocellular carcinoma (HCC), portal vein thrombosis (PVT), infectious complications, acute-on-chronic liver failure (ACLF), and death were built. A survival analysis for patients with and without DGM was also performed. Treatment effectiveness for patients with DGM was assessed. Results: Initially, 221 patients were included, 154 (69.7%) of whom developed DGM after the diagnosis of ACLD. DGM patients presented a significantly higher number of hospitalizations. Odds ratio (OR) for death was not significantly related with DGM. At 5 years of follow-up, 68.9% of patients with DGM were alive, against 81.8% without DGM (p = 0.087). From the 154 patients who were diagnosed with DGM, 42.9% were not receiving pharmacological treatment for DGM. Treated patients were prescribed with either biguanides (34.8%), a SGLT2 inhibitor (8.6%), or insulin (7.7%). Only 1 patient was treated with a GLP-1 analogue. A tendency of OR favoring treatment was observed for biguanides and SGLT2 inhibitors in all outcomes except ascites. In the univariable analysis, the use of biguanides was associated with lower risk of death (OR: 0.84 [95% CI: 0.73–0.96]) and HE (OR: 0.85 [95% CI: 0.73–0.98]). Conclusion: DGM occurs with high prevalence in patients with ACLD and it seems to be related to more hospitalizations, which highlights the importance of its early identification and appropriate therapeutic approach. In the absence of contraindications, biguanides should be considered for treatment of patients with ACLD and DGM as they appear to be associated with a tendency to better outcomes and may present some advantage in terms of survival.

Hepatoprotective Benefits of SGLT-2 Inhibitors and GLP-1 Analogs

Hepatoprotective Benefits of SGLT-2 Inhibitors and GLP-1 Analogs

Objetivos del tratamiento de la diabetes mellitus tipo 1

There are three ways to assess blood glucose control in type 1 diabetes (DM1): glycated hemoglobin (HbA1c, general target less than or equal to 7%), time in the 70–180mg/dl range (general target 70% or higher), and capillary blood glucose. Diabetes education is a fundamental element in achieving self-management of the disease. It is based on three fundamental pillars: nutrition, insulin therapy, and management of diabetes technology (sensors, insulin pumps, smart insulin pens, and mobile applications). Drug treatment for DM1 consists of intensive insulin therapy using multiple dose injection (MDI) or continuous subcutaneous insulin infusion (CSII). The choice of treatment regimen should be based on patient characteristics and other clinical considerations (e.g., pregnancy, presence of undetected hypoglycemia, or variable insulin requirements). There are currently no other insulin adjuvant therapies approved for use in DM1, although DM2 drugs such as GLP-1 analogs or SGLT2 inhibitors that may provide benefits in blood glucose control or weight loss have been used. Kidney-pancreas or pancreatic islet transplantation is considered a final option in patients with end-stage chronic kidney disease together with or following renal transplantation or in individuals with undetected or severe recurrent hypoglycemia that does not respond to optimized management.

Effect of preoperative liraglutide 3.0mg on incidence of intraoperative adhesions in laparoscopic sleeve gastrectomy.

Liraglutide has shown promising results in the field of bariatric surgery, preparing patients for surgery. However, chronic therapy is often correlated with gastrointestinal disorders, such as subclinical pancreatitis. The aim of this study was to evaluate the incidence of intraoperative adhesions and post-operative complications in patients undergoing laparoscopic sleeve gastrectomy (LSG) with or without prior therapy with liraglutide. Clinical records of patients affected by obesity who underwent LSG between March 2017 and October 2022 were retrospectively reviewed using a prospectively maintained database. Patients were separated into two groups: those managed with preoperative liraglutide for 24weeks prior to LSG, and those without prior medical therapy. Demographic data, operative time, intraoperative adhesions, and postoperative complications were reported and compared between two groups. Ninety-three patients underwent LSG without prior medical therapy, while 87 were treated with liraglutide before surgery. There were no significant differences in terms of gender, age, and comorbidities. After treatment with liraglutide, weight (117 vs 109kg) and BMI (45 vs 42.2kg/m2) were statistically lower than the group with no prior treatment to surgery. Thirty-two (37%) patients of the group treated with liraglutide had intraoperative adhesion vs nine (10%) patients of the control group (p < 0.005). There were no differences recorded between the two groups concerning post-operative complications. Liraglutide has introduced a new way to treat obesity, improving weight loss and comorbidities. Gastrointestinal disorders, such as subclinical pancreatitis, associated with GLP-1 analogue could explain the elevated incidence of intraoperative adhesions during bariatric surgery.

GLP-1 and GIP analogues in the treatment of obesity

Obesity is a chronic disease and a significant public health problem. It is estimated that more than 650 million adults, 340 million adolescents, and 39 million children are obese. Obesity leads to organ complications including type 2 diabetes, hypertension and heart diseases. The management of obesity is based on nutritional therapy combined with lifestyle changes and increased physical activity. Pharmacotherapy is also crucial, and incretin analogues are a relatively new group of drugs. Glucose-independent insulinotropic peptide and glucagon-like peptide-1 are natural incretins. These short half-life hormones are degraded by the enzyme dipeptidyl peptidase-4. Glucose-independent insulinotropic peptide and glucagon-like peptide-1 receptor agonists increase blood glucose-dependent insulin secretion while inhibiting glucagon secretion and delaying gastric emptying, thus enabling the treatment of both type 2 diabetes and obesity. Glucagon-like peptide-1 also exhibits cardioprotective and neuroprotective effects. This study aimed to review the literature on the use of glucagon-like peptide-1 analogues and verify reports on the use of glucose-dependent insulinotropic polypeptide for weight reduction. An analysis of the available literature on the efficacy and safety of liraglutide, semaglutide and tirzepatide was conducted. The potential role of these drugs in weight reduction and possible adverse effects are discussed. Attention was also paid to the pharmacokinetics of the drugs and the mechanism of incretin action in the body.

GLP-1 analogue liraglutide attenuates CIH-induced cognitive deficits by inhibiting oxidative stress, neuroinflammation, and apoptosis via the Nrf2/HO-1 and MAPK/NF-κB signaling pathways

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer’s disease, and Parkinson’s disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1’s protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA.

The Influence of Non-Pharmacological and Pharmacological Interventions on the Course of Autosomal Dominant Polycystic Kidney Disease.

Polycystic kidney disease (PKD) includes autosomal dominant (ADPKD) and autosomal recessive (ARPKD) forms, both of which are primary genetic causes of kidney disease in adults and children. ADPKD is the most common hereditary kidney disease, with a prevalence of 329 cases per million in Europe. This condition accounts for 5-15% of end-stage chronic kidney disease (ESKD) cases, and in developed countries such as Poland, 8-10% of all dialysis patients have ESKD due to ADPKD. The disease is caused by mutations in the PKD1 and PKD2 genes, with PKD1 mutations responsible for 85% of cases, leading to a more aggressive disease course. Recent research suggests that ADPKD involves a metabolic defect contributing to cystic epithelial proliferation and cyst growth. Aim: This review explores the interplay between metabolism, obesity, and ADPKD, discussing dietary and pharmacological strategies that target these metabolic abnormalities to slow disease progression. Conclusion: Metabolic reprogramming therapies, including GLP-1 analogs and dual agonists of GIP/GLP-1 or glucagon/GLP-1 receptors, show promise, though further research is needed to understand their potential in ADPKD treatment fully.