Incretin Mimetics Research Articles

Non-Pharmacological and Pharmacological Approaches to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): An Update

Recently, based on an international consensus, the term The term “non-alcoholic fatty liver disease” (NAFLD) was replaced by “metabolic dysfunction-associated steatotic liver disease” (MASLD). Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with obesity and type 2 diabetes mellitus. Lifestyle interventions aiming at substantial weight loss and pharmacological intervention to achieve desired histological outcomes are cornerstones of management of MASLD. Among pharmacological interventions, originally developed as antidiabetic drugs, incretin mimetics and SGLT2 inhibitors were found to reduce steatosis and fibrosis. Certain incretin agonists effectively improve histological features of MASLD. On the other hand, despite mild weight gain, one PPARã agonist (pioglitazone) was found to improve MASLD with certain benefit on fibrosis. Furthermore, benefits of other drug options, which directly target hepatic lipid metabolism (e.g., lipogenesis inhibitors, FGF21 analogs) have also been highlighted. Some combination therapies were also proved beneficial. Our discussion is based on weight loss, glycemic control, reductions of liver enzymes and histological improvement. We have compared results from clinical trials of different drugs as well as systematic review and meta analysis. Mugda Med Coll J. 2024; 7(2): 119-126

Three decades of glucose-lowering therapy in patients at high cardiovascular risk - A real-world analysis.

Over recent years, therapy options and strategies for type 2 diabetes mellitus (T2DM) have developed substantially. This study investigated glucose-lowering treatment in patients with high cardiovascular risk over three decades. A total of 2158 patients undergoing elective coronary angiography at a tertiary care hospital in Europe were included in three sequential observational studies (OS): OS1 (1999-2000; n = 672), OS2 (2005-2008; n = 1005) and OS3 (2022-2023; n = 481). Sociodemographic data, patient-reported medication, medical histories and blood samples were analysed. A clear trend towards more complex glucose-lowering therapies was found. A wider array of glucose-lowering drugs was used over time (OS1: 11; OS2: 21; OS3: 25) and the number of different drugs used in combination therapy in a single patient increased to a maximum of five in OS3. Furthermore, substantial differences in applied medication regimens were observed: Sodium-glucose cotransporter-2 inhibitors were the most frequently reported substance class (34.0% of total reported glucose-lowering drugs) in OS3, whilst metformin remained a key component (OS1: 33.9%; OS2: 41.8%; OS3: 32.0%). Other drug classes like sulfonylureas were largely replaced. A total of 69.2% of patients in OS3 achieved an HbA1c level of < 7% (vs. OS1: 51.9%, OS2: 54.7%; ptrend < 0.001). Over 25% of patients with T2DM were newly diagnosed at admission (OS1: 43.8%, OS2: 29.7%, OS3: 27.2%; ptrend < 0.001) and had therefore no diabetes-related medication. These real-world data emphasize a marked shift in T2DM treatment towards novel substance classes. However, the use of incretin mimetics remained low. Significantly more patients reached HbA1c targets in the most recent cohort.

Combining SNAC and C10 in oral tablet formulations for gastric peptide delivery: A preclinical and clinical study.

Current oral formulations of macromolecules including peptides typically rely on single permeation enhancer (PE) to promote absorption and thus bioavailability. In this work, we combined two PEs, namely sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) and sodium caprate (C10), in one tablet formulation to potentially gain a synergistic effect for enhanced gastric absorption of a GLP-1 analogue and a PCSK9 inhibitor. Permeability tests on a gastric organoids-based cell model showed that the combination of SNAC and C10 can significantly improve peptide permeability compared to either SNAC or C10 alone. Tablet formulations were then designed, adjusting the total PE amount, relative ratio between SNAC and C10, and the peptide dose. To facilitate drug and PE release, a diluent was added. Upon oral administration in beagle dogs, the lead formulations made of SNAC/C10/diluent demonstrated higher bioavailability than either SNAC, SNAC/diluent and C10/diluent formulations for both peptides. Finally, the SNAC/C10/diluent formulation with PCSK9 inhibitor was tested in human, where it displayed similar bioavailability to the SNAC/diluent reference, thereby suggesting a low translatability between pre-clinical and clinical data when C10 was involved. This may be attributed to the difference in physiology, gastric pH environment as well as C10 concentration and colloidal form in the gastric lumen between dogs and humans. Hence, additional studies are needed for a better understanding of the clinical translation of C10-based peptide formulations.

Triazination/IEDDA Cascade Modular Strategy Installing Pyridines/Pyrimidines onto Tyrosine Enables Peptide Screening and Optimization.

Modular chemical postmodification of peptides is a promising strategy that supports the optimization and innovation of hit peptide therapeutics by enabling rapid derivatization. However, current methods are primarily limited to traditional bio-orthogonal strategies and chemical ligation techniques, which require the preintroduction of non-natural amino acids and impose fixed methods that limit peptide diversity. Here, we developed the Tyrosine-1,2,3-Triazine Ligation (YTL) strategy, which constructs novel linkages (pyridine and pyrimidine) through a "one-pot, two-step" process combining SNAr and IEDDA reactions, promoting modular post modification of Tyr-containing peptides. After optimizing the YTL strategy and establishing standard procedures, we successfully applied it to the solid-phase postmodification of various biorelated peptides, such as the synthesis of dual-mode imaging probes and long-acting GLP-1 analogs. As a proof of concept, a library of 384 amphipathic peptides was constructed using YTL based on 96-well microfiltration plates. Modular modifications were then performed on the screened template tripeptide RYR, leading to the generation of 20 derivatives. The antibacterial activity of these derivatives was systematically characterized, identifying Z8 as a potential antibacterial candidate.

Variability in the management of GLP-1 agonists and endoscopic procedures: an opportunity for standardization.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), also known as incretin mimetics, have significantly revolutionized the treatment of type 2 diabetes mellitus (T2DM) and obesity worldwide, far exceeding initial expectations regarding their global prescription. This class of medications has demonstrated weight losses of up to 20 % of baseline body weight. Beyond their proven benefits in T2DM and obesity, GLP-1RAs, as well as dual and triple agonists (GLP-1/GIP/glucagon), are being investigated for their effects on conditions such as metabolic-associated steatotic liver disease, various cardiovascular disorders, neurocognitive impairments, and certain addictions. These emerging effects appear to be linked not only to their metabolic action but also to their ability to modulate the chronic inflammatory state underlying these pathologies.

Effectiveness of Low Doses of Semaglutide on Weight Loss and Body Composition Among Women in Their Menopause.

Background and Aims: Menopause is a complex period in women's life, when weight gain and predisposition to obesity are frequent. Moreover, even during menopause transition, women begin to lose lean mass up to 0.5% and, therefore, an increase in the percentage of fat mass with central distribution and an increased risk of metabolic syndrome. Despite lifestyle habits remain the cornerstone in this period, their long-term effectiveness is a challenge. In this sense, GLP-1 analogs have shown their efficacy in improving weight loss and other cardiovascular risk factors. Methods: To assess the effectiveness of low doses of semaglutide on body weight and composition for 4 months during menopause compared with premenopausal women. Results: Baseline weight and body mass index were significantly greater among postmenopausal women (95 ± 23.4 vs. 86.4 ± 12.8 kg and 35.9 ± 7.3 vs. 32.9 ± 4.7 kg/m2; P = 0.02 and P = 0.03, respectively). Fat mass was higher among postmenopausal women (45.2 ± 17.1 vs. 38.2 ± 9.8 kg; P = 0.03). The percentage of fat mass and lean mass were comparable between the two groups (43.2 ± 8.1% vs. 40.9 ± 7.1% and 29.6 ± 5.5 vs. 32.4 ± 8.4 kg; P = 0.2 and P = 0.08, respectively). After 4 months of semaglutide 1 mg, either weight loss (5.9 ± 5.2 vs. 4.5 ± 3.5 kg; P = 0.1) or percentage of weight loss (5.8 ± 4.7% vs. 5.1 ± 3.2%; P = 0.4) were comparable. Furthermore, both fat mass loss in kilos (4.1 ± 4.5 vs. 3.1 ± 3.7 kg; P = 0.3) and lean mass loss (-0.4 ± 1.7 vs. -1.1 ± 3.7 kg; P = 0.1) were similar between the two groups. Conclusions: Despite a greater initial weight and fat mass among postmenopausal women, after 4 months of treatment with semaglutide 1 mg, either fat mass loss or weight loss were similar to premenopausal women.

Prevention of cardiovascular disease in women with type 2 diabetes: the role of incretin mimetics and sodium-glucose cotransporter-2 inhibitors.

Cardiovascular disease (CVD) is the leading cause of death among individuals with type 2 diabetes (T2D), with women experiencing a disproportionate risk of events compared with men. Women have an amplified burden of cardiovascular risk factors once T2D is diagnosed. Incretin mimetics now plays a central role in managing cardiovascular risk by improving glycemic control, promoting weight loss, and potentially exerting direct cardioprotective effects. Similarly, sodium-glucose cotransporter-2 inhibitors contribute to CVD prevention through various nonglucose-lowering mechanisms. Both classes of medications are integral to personalized treatment strategies aimed at addressing the heightened cardiovascular risk faced by women with diabetes. This mini-review addresses possible mechanisms underlying the increased cardiovascular risk and explores the role of incretin mimetics and SGLT2 inhibitors in mitigating CVD in women with T2D. Emphasizing personalized and sex-specific approaches in diabetes care is crucial for optimizing treatment outcomes and improving cardiovascular health.

Design, Structure-Activity Relationships, and Computational Modeling Studies of a Series of α-Helix Biased, Ultra-Short Glucagon-like Peptide-1 Receptor Agonists.

A systematic structure-activity and computational modeling analysis of a series of glucagon-like peptide-1 receptor (GLP-1R) agonists based upon an ultra-short GLP-1 peptide, H-His-Aib-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Bip-Bip-NH2, was conducted. This highly potent 11-mer peptide led to a deeper understanding of the α-helical bias of strategic α-methylation within the linear parent template as well as optimization of GLP-1R agonist potency by 1000-fold. These data were correlated with previously reported co-structures of both full-length GLP-1 analogs and progenitor N-terminal GLP-1 fragment analogs related to such ultra-short GLP-1R agonist peptides. Furthermore, the development of a quantitative structure-activity relationship (QSAR) model to analyze these findings is described in this study.

Activation of the Sympathoadrenal System under the Influence of Glucagon-Like Peptide-1 Mimetic in Rats

Glucagon-like peptide-1 (GLP-1) is the main incretin that ensures insulin secretion and normalization of postprandial glycemia. GLP-1 mimetics are used for treatment of type 2 diabetes mellitus and obesity. Besides the insulinotropic effect, GLP-1 and its mimetics have been shown to affect on the functions of the cardiovascular and endocrine systems, the central mechanisms of appetite and metabolism regulation, the ion-regulatory and osmoregulatory renal functions, and a paradoxical hyperglycemic effect of incretin mimetics was also discovered. In current work the mechanisms by which the sympathoadrenal system is involved in the development of hyperglycemic and natriuretic effects of the GLP-1 mimetic exenatide in rats were studied. Experiments with healthy rats revealed that GLP-1 and its mimetic exenatide augmented the renal sodium excretion. Exenatide at doses of 0.15-5 nmol/kg, but not GLP-1 (1.5 nmol/kg), showed a hyperglycemic effect (blood glucose increased to 7.2–9.1 mM during the first hour). It has been shown that the rise of blood glucose level in rats administrated with incretin mimetic was associated with increase in renal excretion of catecholamine metabolites, was delayed by preliminary injection of a ganglionic blocker (pentamine 30 mg/kg) and was considerably leveled by non-selective β- and selective β2-adrenergic blockers (propranolol 5 mg/kg, ICI-118551 1 mg/kg). A significant modulation of natriuresis was revealed in response to the administration of exenatide during blockade of various adrenergic receptors subtypes. α1- and α2-blockers appreciably reduced (by 80%), and β1- and β2-blockers increased (by 150%) exenatide-stimulated renal sodium excretion. Thus, the data obtained indicate on the exenatide-induced activation of the sympathoadrenal system, which modulates the direction and severity of the incretin mimetic effects on blood glucose level and renal sodium excretion in healthy animals. The potential action on the sympathoadrenal system is important to consider when assessing the risk of adverse side effects during incretin mimetic therapy.

Beyond Glycemic Control: The Expanding Role of GLP-1 Analogues in Type 2 Diabetes and Metabolic Health

Beyond Glycemic Control: The Expanding Role of GLP-1 Analogues in Type 2 Diabetes and Metabolic Health

Supaglutide alleviates hepatic steatosis in monkeys with spontaneous MASH

BackgroundGlucagon-like peptide 1 (GLP-1) is an incretin hormone and plays an important role in regulating glucose homeostasis. GLP-1 has a short half-life due to degrading enzyme dipeptidyl peptidase-IV and rapid kidney clearance, which limits its clinical application as a therapeutic agent. We demonstrated previously that supaglutide, a novel long-acting GLP-1 analog, exerted hypoglycemic, hypolipidemic, and weight loss effects in type 2 diabetic db/db mice, DIO mice, and diabetic monkeys. In the present study, we investigated supaglutide’s therapeutic efficacy in rhesus monkeys with spontaneous metabolic dysfunction-associated steatohepatitis (MASH).Methods15 rhesus monkeys with biopsy-confirmed MASH were divided into three groups, receiving supaglutide 50 µg/kg, supaglutide 150 µg/kg, and placebo, respectively, by weekly subcutaneous injection for 3 months. Liver fat content quantified by magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), liver pathology, and metabolic parameters were assessed.ResultsWe found that once-weekly subcutaneous injections of supaglutide for 3 months significantly reduced hepatic fat accumulation, with a 40% percentage decrease in MRI-PDFF from baseline (P < 0.001 vs. Placebo). Treatment with supaglutide alleviated hepatic histological steatosis (nonalcoholic fatty liver disease activity score P < 0.001 vs. Placebo) without worsening of fibrosis, as assessed by ultrasound-guided liver biopsy. Supaglutide concomitantly ameliorated liver injury exemplified by a lowering tendency of hepatic alanine aminotransferase levels. Supaglutide also decreased body weight in a dose-dependent fashion accompanied by decreased food intake, improved lipid profile and glycemic control.ConclusionsSupaglutide exerts beneficial effects on hepatic and metabolic outcomes in spontaneous MASH monkeys.

Polyethylene glycol loxenatide protects diabetic kidneys by inhibiting GRP78/PERK/eIF2α pathway, and improves cardiac injury by suppressing TLR4/NF-κB inflammatory pathway

BackgroundCardiovascular and renal complications of type 2 diabetes are the main causes of death in diabetic patients. Clinical studies have found that polyethylene glycol loxenatide (PEG-Loxe), a GLP-1 analog widely used to treat type 2 diabetes, boosts renal and cardiac functions in diabetic patients. However, its mechanism of action remains to be elucidated.MethodsUsing injury models of HK-2 human renal proximal tubular epithelial cells and H9C2 rat myocardial cells, as well as db/db mouse models of type 2 diabetes, this study assessed the protective effects of PEG-Loxe on T2DM mice kidneys and hearts and revealed their mechanisms of action.ResultsPEG-Loxe treatment significantly reduced the contents of serum creatinine, urea nitrogen, and 24 h urine protein, alleviated glomerular injury and inflammatory reaction, markedly elevated cardiac left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) levels, diminished pathological injuries in cardiac tissues, and improved renal and cardiac functions in db/db mice. In addition, PEG-Loxe considerably decreased the GRP78 mRNA and protein expressions of GRP78, p-eIF2α, ATF4, and CHOP in the kidneys of T2DM mice, inhibited GRP78/PERK/eIF2α pathway-related proteins in HK-2 cells cultured in high glucose concentrations, subdued renal endoplasmic reticulum stress, and eased renal injury in T2DM mice. PEG-Loxe also obstructed the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and mitigated cardiac trauma in T2DM by reducing TLR4, MyD88, and p-NF-κBp65 protein expressions in cardiac tissues. The H9C2 cell experiment further confirmed PEG-Loxe’s ability to protect the cardiovascular system of T2DM patients by inhibiting the TLR4/NF-κB inflammatory pathway and lessening LDH and CK-MB levels.ConclusionWe showed that PEG-Loxe could decrease renal stress response and improve renal injury in T2DM by inhibiting endoplasmic reticulum stress via the GRP78/PERK/eIF2α pathway. Additionally, PEG-Loxe could hinder the TLR4/NF-κB inflammatory pathway and myocardial apoptosis and boost cardiac function, thus exerting protective effects on the cardiovascular system in T2DM.

Are GLP-1 Analogues a New Solution for the Treatment of NAFLD?

ABSTRACT Introduction and purpose: There is currently a pandemic of overweight and obesity, which is closely associated with non-alcoholic fatty liver disease (NAFLD). It is the most common cause of chronic liver disease [1]. The global prevalence of this condition reaches 25% of the population and 65-70% of patients with type 2 diabetes [2]. There is no approved pharmacological treatment for NAFLD, and the current mainstay of NAFLD treatment is lifestyle modification and weight reduction, which is difficult to achieve and even more difficult to maintain. NAFLD represents a serious health and economic burden, which is why the search for an effective therapy is so important [1,2,3]. The purpose of this review was to assess the current knowledge of the efficacy of GLP-1 (Glucagon-like peptide-1) analogs in the treatment of NAFLD. Material and methods: Data bases such as Pubmed and GoogleScholar were used for research with the key words included: MAFLD, NAFLD, GLP‐1 receptor agonists, GLP‐1 analogues, incretin mimetics. The review included studies that evaluated the efficacy of GLP-1 receptor agonists in the adult population. Description of the state of knowledge: Glucagon-like peptide-1 (GLP-1) analogues are drugs approved for the treatment of type 2 diabetes and obesity with pleiotropic effects. They have a beneficial effect on the glycemic profile, reduce body weight and have an anti-inflammatory effect. They appear to be a promising therapy for the treatment of NAFLD, as these patients are usually overweight/obese and have insulin resistance and/or diabetes [1,3]. Conclusions: It is hoped that in the coming years the efficacy of these drugs in NAFLD will be confirmed and they will be approved for this indication [1].

Consideraciones Perioperatorias de los Análogos GLP-1.

GLP-1 agonists are novel medications. Its relationship with the decrease in gastric motility is clear; this presents a challenge when performing an induction under general anesthesia. Therefore, knowing its pharmacokinetics and the current recommendations described by the American Society Anesthesiologists (ASA) to evaluate perioperative risk during elective surgery are important. The objective is to review pharmacokinetics of GLP-1 analogues and evaluate current recommendations for perioperative management in patients undergoing elective surgery. We searched for articles using the keywords and medical topic titles: incretins; glucagon-like peptide-1; GLP-1; glucagon-like peptide 1 receptor agonists; GLP-1 RA; perioperative period; perioperative; perioperative; stomach emptying; gastric emptying; pulmonary aspiration; aspiration of gastric content; regurgitation of food; and regurgitation. The evidence was analyzed, synthesized and reported narratively. The elimination half-life of GLP-1 agonists determines the suspension time prior to the surgical procedure. Gastric ultrasound is a potentially quantitative tool to evaluate gastric contents prior to elective surgery.

The role of glucagon-like peptides in osteosarcopenia.

Various metabolic abnormalities, including obesity, insulin resistance, hypertension, dyslipidemia, hyperthyroidism and low vitamin D levels, have been linked to both osteopenia and sarcopenia. Osteosarcopenia is also commonly observed in older age groups, notably in postmenopausal women. Glucagon-like peptide-1 (GLP-1), a labile incretin secreted from the intestinal L-cells, stimulates insulin secretion and sensitivity, making it an effective anti-diabetic medication. GLP-1 binds to its receptor, the GLP-1 receptor, a G-protein-coupled receptor, and leads to the stimulation of adenylate cyclase, increasing the levels of cyclic AMP (cAMP). Elevated cAMP then activates protein kinase A and other downstream signaling pathways. These signaling cascades result in various cellular responses, such as enhanced insulin secretion from pancreatic beta cells, improved insulin sensitivity and modulation of appetite and gastric emptying. In addition, GLP-1 signaling can promote cell growth and survival, contributing to its effects on muscle and bone health. Its role as an anti-diabetic medication has been enhanced through various modifications to extend its half-life, thereby improving its effectiveness and druggability. GLP-1 analogs, initially developed for diabetes management, have also been harnessed for obesity treatment due to the effect of GLP-1 to induce satiety and slow gastric emptying. Beyond their well-known anti-diabetic and anti-obesity effects, GLP-1 agonists can enhance muscle mass and bone density, making them valuable in addressing conditions such as sarcopenia and osteoporosis. This review focuses on the effects of GLP-1 analogs on musculoskeletal health by critically assessing the underlying signaling mechanisms in order to understand their translational potential for the treatment of osteosarcopenia.

Therapeutic targets of antidiabetic drugs and kidney stones: A druggable mendelian randomization study and experimental study in rats.

Diabetes is known to increase the risk of kidney stones, but the influence of antidiabetic drugs on this risk remains uncertain. Genetic instruments for antidiabetic drugs were identified as variants, which were associated with both the expression of genes encoding target proteins of drugs and glycated hemoglobin level (HbA1c). Here, we investigated the effect of antidiabetic drugs on kidney stones in a mendelian randomization (MR) framework, and further explore the potential effect on CaOx stone rat models induced by glyoxylic acid. Genetically proxied thiazolidinediones (PPARG agonists) significantly reduced the risk of kidney stones (OR=0.42; P=0.004) per 1-SD decrement in HbA1c, while no significant association was noted in sulfonylureas, SGLT2 inhibitors, or GLP-1 analogs. Other antidiabetic drugs were not analyzed due to unclear pharmacological targets or no identified instruments. Additionally, PPARG agonists pioglitazone ameliorated CaOx nephrocalcinosis in glyoxylic acid-induced rats. The summary-data-based MR (SMR) results showed that PPARG mRNA expression in blood or kidney was not associated with kidney stone risk, and thus we performed mediation MR of PPARG agonists, circulating metabolites, and kidney stones. Among 249 circulating metabolites, we identified an indirect effect of PPARG agonists on kidney stones through increasing phospholipids to total lipids ratio in very large VLDL, with a mediated proportion of 6.87% (P=0.018). Our study provided evidence that PPARG agonists reduced the risk of kidney stones partially via regulating lipid metabolism, and PPARG agonists may be a promising study subject in clinical studies for the prevention of kidney stones.

Role of Incretin Mimetics in Cardiovascular Outcomes and Other Classical Cardiovascular Risk Factors beyond Obesity and Diabetes Mellitus in Nondiabetic Adults with Obesity: a Meta-analysis of Randomized Controlled Trials.

Emerging data on cardiovascular outcomes, specifically major adverse cardiovascular events (MACE), are being reported from various trials involving incretin mimetics, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and glucose-dependent insulinotropic polypeptide (GIP), especially among patients with obesity and diabetes. Our aim was to evaluate this matter, while also involving various traditional cardiovascular risk factors [e.g., several body weight (BW) parameters, blood pressure (BP), lipid profile]. A search of PubMed, Europe PMC, ScienceDirect, Cochrane, and ClinicalTrials.gov up to September 2024 was performed to identify GLP-1 RA and GIP trials in MACE risk reduction as a primary endpoint. Our secondary endpoints included a reduction in BW, waist circumference (WC), body mass index (BMI), BP changes, and lipid modifying effects, while also yielding safety concerns surrounding the use of these pharmaceutical agents. Mean differences (MD) and risk ratios (RR) were summarized using random-effects model. A total of 11 eligible randomized controlled trials (RCTs) comprising 8 GLP-1 RA trials and 3 dual GLP-1 RA/GIP (tirzepatide) trials were included. Compared with control groups, GLP-1 RA significantly reduced the MACE risk by 32% [RR 0.68 (95% CI 0.53-0.87); P = 0.002; I2 = 73%, P-heterogeneity < 0.001] and 59% for tirzepatide [RR 0.41 (95% CI 0.18-0.92); P = 0.03; I2 = 0%, P-heterogeneity = 0.96]. Incretin mimetics also substantially reduced BW, BP, and improved lipid panel measures. However, there was an increased risk of adverse events, specifically gastrointestinal disorders within the incretin mimetics subset. Incretin mimetics have shown promise in reducing MACE risk while also enhancing cardiovascular risk factors, including blood pressure and lipid profile, in adults with obesity without diabetes.

Genetic Variation in Targets of Antidiabetic Drugs and Amyotrophic Lateral Sclerosis Risk.

Previous studies have suggested that antidiabetic drug use may be associated with amyotrophic lateral sclerosis. However, these studies are limited by many confounding and reverse causality biases. We aimed to determine whether antidiabetic drug use has causal effects on ALS. Drug-target Mendelian randomization analysis was conducted to evaluate the association between genetic variation in the targets of antidiabetic drugs and ALS risk. The antidiabetic drugs included sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin/insulin analogues, metformin, and SGLT2 inhibitors. Summary statistics for ALS were retrieved from previous genome-wide association studies comprising 27,205 ALS patients and 55,058 controls. The instrumental variables for these drugs are from previous published articles. Genetic variation in SGLT2 inhibition targets was associated with lower risk of ALS (odds ratio [OR] = 0.32, 95% CI = 0.14-0.74; p = 0.008). We did not find that genetic variation in metformin targets was associated with ALS (OR = 1.61, 95% CI = 0.94-2.73; p = 0.081). Nevertheless, mitochondrial complex I, a target of metformin, was associated with a higher risk of ALS (OR = 1.83, 95% CI = 1.01-3.32; p = 0.047). The analysis showed that genetic variation in sulfonylureas, GLP-1 analogues, thiazolidinediones, insulin or insulin analogues targets was not associated with ALS (all p > 0.05). The complex interaction between hypoglycemic, antioxidation, and anti-inflammatory effects may account for the different results across antidiabetic drug types. These findings provide key evidence to guide the use of antidiabetic drugs and will help to identify novel therapeutic targets in ALS.

Incretin mimetics for the management of diabetes and associated comorbidities: An overview

Type 2 diabetes mellitus is commonly associated with various comorbidities that aggravate the disease&amp;rsquo;s overall impact on health. The most prevalent comorbidities of diabetes include obesity, dyslipidemia, hypertension, cardiovascular conditions, and kidney diseases. Incretin mimetics, also known as glucagon-like peptide-1 receptor agonists, mimic incretin hormones to stimulate insulin release in response to food intake. These medications help lower blood glucose by increasing insulin production, reducing glucagon secretion, slowing stomach emptying, and promoting satiety. A key advantage of incretin mimetics is their ability to reduce blood glucose levels without causing hypoglycemia, making them a safer option for many patients. They also promote weight loss, which is particularly beneficial for patients with both obesity and diabetes. Incretin mimetics are typically administered once or twice daily and are often used in combination with other treatments such as metformin or insulin. Evidence suggests that these drugs may reduce the risk of heart attack and stroke, an important consideration given the heightened cardiovascular risk in patients with diabetes. Additionally, incretin mimetics may help preserve pancreatic beta-cell function, potentially slowing the progression of diabetes. However, these drugs are costly and may be unaffordable for low-income individuals. Commonly reported side effects include nausea, vomiting, and diarrhea, which tend to decrease over time. While there have been reports of pancreatitis, current research indicates that incretin mimetics do not increase the risk of pancreatic cancer. Educating patients on proper use and potential side effects is crucial to ensure safe and effective treatment with incretin mimetics.

From the discovery of incretin hormones to GIP / GLP-1 / glucagon double and triple agonists

The concept of treating diabetes with gut hormones was proposed in the early days of endocrinology (1902), but was not put into practice until the early 2000s. The discovery of the incretin effect (potentiation of insulin secretion when glucose is taken orally compared to intravenously) led to the discovery of the two main gut hormones responsible for this effect: GIP and GLP-1. The reduction of the incretin effect is directly involved in the pathogenesis of type 2 diabetes, which has led to the development of a series of innovative therapies such as GLP-1 analogues, GLP-1 receptor agonists, GIP/GLP-1 co-agonists and GIP/GLP-1/glucagon tri-agonists. These therapies, with their potent hypoglycaemic and weight-lowering effects, promote optimal control of excess weight and hyperglycaemia, avoiding the escalation of treatment that was once considered inevitable.