Sex-specific Cardiovascular Risk Factors and Treatment in Females with T2DM and CVD: Developments and Knowledge Gaps.

PURPOSE: There are large disparities in the impact of diabetes on cardiovascular disease (CVD) risk and outcomes by sex and gender. Achieving health equity requires understanding risks and medication efficacy in female patients, especially now, as novel pharmacologic treatments are transforming the diabetes and CVD treatment landscape. This review examines two bodies of research that can inform sex differences in CVD in patients with diabetes: female-specific risk factors for CVD and sex-related limitations of clinical trial research in evaluating novel diabetes and CVD treatments. METHODS: Two literature searches were performed using Ovid Medline(R) All. The first retrieved manuscripts covering sex and gender differences related to CVD risk and therapies and diabetes. The second focused on randomized controlled trial data on sex/gender differences and GLP-1/SGLT-2/DPP-4 drugs. RESULTS: Female-specific risk factors for CVD include early menarche, premature or early menopause, irregular cycles and polycystic ovary syndrome (PCOS); pregnancy; adverse pregnancy outcomes; history of breast cancer; and autoimmune diseases. Clinical trials of novel pharmacological treatments for diabetes and CVD have undersampled female populations, and clinical characteristics of male and female participants have differed significantly. Thus, evidence to evaluate potential sex differences in treatment efficacy and side effects has been lacking. CONCLUSION: To improve health of female patients with diabetes, sex-specific cardiovascular risk factors should be taken into account in screening and treatment decisions. Further, studies of cardiovascular and diabetes medications must ensure adequate representation by sex and report participant characteristics and outcomes by sex.

Liraglutide innovations: a comprehensive review of patents (2014-2024).

Type-2 diabetes mellitus (T2DM) is a complicated long-term disorder associated with metabolism that is identified by insulin resistance, imbalance in glucose regulation and reduced secretion of insulin. GLP-1(Glucagon-like peptide-1) is an incretin mimetic that has excellent effects on the regulation of blood glucose levels and also the management of disorders associated with vital organs. GLP-1 agonist is an effective class of drug for the treatment of type-2 diabetes mellitus and associated complications. Liraglutide is one of the potent drugs of this class having similar effects as biological GLP-1. This review includes clinical trials and patents related to the pharmaceutical formulation, synthesis and biological action of liraglutide.

The Dispensing Error Rate in an App-Based, Semaglutide-Supported Weight-Loss Service: A Retrospective Cohort Study.

Digital weight-loss services (DWLSs) combining pharmacotherapy and health coaching have the potential to make a major contribution to the global struggle against obesity. However, the degree to which DWLSs compromise patient safety through the dispensation of Glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications is unknown. This study retrospectively analysed the rate at which patients reported GLP-1 RA dispensing errors from patient-selected and partner pharmacies of Australia's largest DWLS provider over a six-month period. The analysis found that 99 (0.35%) of the 28,165 dispensed semaglutide orders contained an error. Incorrect dose (58.6%) and unreasonable medication expiry window (21.2%) were the two most common error types. Most errors (84.9%) were deemed to have been of medium urgency, with 11.1% being considered high-urgency errors. Incorrect doses (45.5%) and supplies of the wrong medication (36.3%) comprised most errors reported in high-urgency cases. Female patients reported more dispensing errors than male patients (0.41% vs. 0.12%, p < 0.001). Similarly, reported dispensing error rates were highest among patients aged 18 to 29 years (0.6%) and 30 to 39 years (0.5%). This research provides preliminary evidence that GLP-1 RA dispensing errors within comprehensive Australian DWLSs are relatively low.

Cyclic adenosine monophosphate critically modulates cardiac GLP-1 receptor's anti-inflammatory effects.

BACKGROUND: Glucagon-like peptide (GLP)-1 receptor (GLP1R) agonists exert a multitude of beneficial cardiovascular effects beyond control of blood glucose levels and obesity reduction. They also have anti-inflammatory actions through both central and peripheral mechanisms. GLP1R is a G protein-coupled receptor (GPCR), coupling to adenylyl cyclase (AC)-stimulatory Gs proteins to raise cyclic 3`-5`-adenosine monophosphate (cAMP) levels in cells. cAMP exerts various anti-apoptotic and anti-inflammatory effects via its effectors protein kinase A (PKA) and Exchange protein directly activated by cAMP (Epac). However, the precise role and importance of cAMP in mediating GLP1R`s anti-inflammatory actions, at least in the heart, remains to be determined. To this end, we tested the effects of the GLP1R agonist liraglutide on lipopolysaccharide (LPS)-induced acute inflammatory injury in H9c2 cardiac cells, either in the absence of cAMP production (AC inhibition) or upon enhancement of cAMP levels via phosphodiesterase (PDE)-4 inhibition with roflumilast. METHODS & RESULTS: Liraglutide dose-dependently inhibited LPS-induced apoptosis and increased cAMP levels in H9c2 cells, with roflumilast but also PDE8 inhibition further enhancing cAMP production by liraglutide. GLP1R-stimulated cAMP markedly suppressed the LPS-dependent induction of pro-inflammatory tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6 cytokine expression, of inducible nitric oxide synthase (iNOS) expression and nuclear factor (NF)-kB activity, of matrix metalloproteinases (MMP)-2 and MMP-9 levels and activities, and of myocardial injury markers in H9c2 cardiac cells. The effects of liraglutide were mediated by the GLP1R since they were abolished by the GLP1R antagonist exendin(9-39). Importantly, AC inhibition completely abrogated liraglutide`s suppression of LPS-dependent inflammatory injury, whereas roflumilast significantly enhanced the protective effects of liraglutide against LPS-induced inflammation. Finally, PKA inhibition or Epac1/2 inhibition alone only partially blocked liraglutide`s suppression of LPS-induced inflammation in H9c2 cardiac cells, but, together, PKA and Epac1/2 inhibition fully prevented liraglutide from reducing LPS-dependent inflammation. CONCLUSIONS: cAMP, via activation of both PKA and Epac, is essential for GLP1R`s anti-inflammatory signaling in cardiac cells and that cAMP levels crucially regulate the anti-inflammatory efficacy of GLP1R agonists in the heart. Strategies that elevate cardiac cAMP levels, such as PDE4 inhibition, may potentiate the cardiovascular, including anti-inflammatory, benefits of GLP1R agonist drugs.

Exendin-4 exhibits cardioprotective effects against high glucose-induced mitochondrial abnormalities: Potential role of GLP-1 receptor and mTOR signaling.

Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stresses and mitochondrial damages resulted in an impairment of ATP production and oxidative defense markers such as catalase and SOD2 and a reduction of survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis (e.g., MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin). Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9-39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions.

Acute Pancreatitis Likely Due to Semaglutide.

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that has gained recent popularity in its effective management of type 2 diabetes mellitus (T2DM) and obesity. Minimal evidence has reported the link between Semaglutide use and acute pancreatitis. In this case report, we discuss the case of a 36-year-old female presenting to the Emergency Department with sudden-onset epigastric pain, subsequently diagnosed with acute pancreatitis. Moreover, she had recently started subcutaneous semaglutide injections for weight loss, which she had procured from one of her acquaintances without seeking medical advice. Semaglutide was thus stopped and her lipase levels normalized with significant improvement of her symptoms, making semaglutide the likely causative factor for her acute pancreatitis. Given the increased use of GLP-1RA, we aim to increase awareness among patients taking this medication whether prescribed or not and increase clinician awareness when prescribing this medication.

Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: a randomised, double-blind, placebo-controlled crossover study.

BACKGROUND: The reward-regulatory properties of GLP-1 are attracting increasing interest. Animal studies show that GLP-1 receptor agonists not only reduce consumption of addictive substances, but also influence sexual behaviour. We aimed to investigate the effect of dulaglutide versus placebo on sexual desire in humans. METHODS: In this randomised, double-blind, placebo-controlled crossover trial, healthy eugonadal men of normal weight, aged 18-50 years with active and satisfactory sex lifes were (1:1) randomly allocated to dulaglutide or placebo for four weeks. We assessed sexual desire (Massachusetts General Hospital-Sexual Functioning Questionnaire [MGH-SFQ]), hormones of the hypothalamic-pituitary-gonadal axis (total testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and sperm parameters. Changes in these parameters were compared under dulaglutide versus placebo using paired t-tests. FINDINGS: 24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI -0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI -1.5 to 3.3], FSH (IU/l) -0.2 [95% CI -0.3 to 0.0] and LH (IU/l) -0.8 [95% CI -1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred. INTERPRETATION: In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters. FUNDING: Swiss National Science Foundation (PZ00P3_193206), Gottfried and Julia Bangerter-Rhyner Foundation, Goldschmidt-Jacobson Foundation, Swiss Academy of Medical Sciences.

Lead-in calorie restriction enhances the weight-lowering efficacy of incretin hormone-based pharmacotherapies in mice.

OBJECTIVES: The potential benefits of combining lifestyle changes with weight loss pharmacotherapies for obesity treatment are underexplored. Building on recent clinical observations, this study aimed to determine whether "lead-in" calorie restriction before administering clinically approved weight loss medications enhances the maximum achievable weight loss in preclinical models. METHODS: Diet-induced obese mice (DIO) were exposed to 7 or 14 days of calorie restriction before initiating treatment with semaglutide (a glucagon-like peptide-1 receptor (GLP-1R) agonist), tirzepatide (a GLP-1R/glucose insulinotropic peptide receptor (GIPR) co-agonist), or setmelanotide (a melanocortin-4 receptor (MC4R) agonist). Follow-up assessments using indirect calorimetry determined the contributions of energy intake and expenditure linked to consecutive exposure to dieting followed by pharmacotherapy. RESULTS: Calorie restriction prior to treatment with semaglutide or tirzepatide enhanced the weight loss magnitude of both incretin-based therapies in DIO mice, reflected by a reduction in fat mass and linked to reduced energy intake and a less pronounced adaptive drop in energy expenditure. These benefits were not observed with the MC4R agonist, setmelanotide. CONCLUSIONS: Our findings provide compelling evidence that calorie restriction prior to incretin-based therapy enhances the achievable extent of weight loss, as reflected in a weight loss plateau at a lower level compared to that of treatment without prior calorie reduction. This work suggests that more intensive lifestyle interventions should be considered prior to pharmacological treatment, encouraging further exploration and discussion of the current standard of care.

Absorption, distribution, metabolism, and excretion of tirzepatide in humans, rats, and monkeys.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist used for treatment of type 2 diabetes (T2D) in adults and was recently approved for treatment of obesity. To determine the absorption, distribution, metabolism, and excretion (ADME) of tirzepatide, [14C]-radiolabeled tirzepatide was investigated in both humans and preclinical species. [14C]-Tirzepatide was prepared by incorporating four 14C's in the linker region between the amino acid backbone and the di-acid moiety. Healthy male participants received a single subcutaneous dose of approximately 2.9 mg tirzepatide containing approximately 100 µCi of [14C]-tirzepatide. Preclinical studies were conducted in male Sprague Dawley and Long Evans rats administered a single dose of 3 mg kg-1 (133 µCi/kg) of [14C]-tirzepatide, and male cynomolgus monkeys administered a single dose of 0.5 mg kg-1 (20 µCi/kg) of [14C]-tirzepatide. Following a single SC dose of [14C]-tirzepatide in humans, the majority of the excreted dose was recovered within 480 h. Renal excretion was identified as a principal route of elimination in all species with approximately 66 % of the administered radioactivity recovered in urine, while approximately 33 % was eliminated in feces in humans. Metabolite analysis of tirzepatide revealed the parent drug was the major circulating component in human, rat, and monkey plasma. Metabolites identified in human plasma were similar to circulating metabolites found in rats and monkeys with no circulating metabolites representing >10 % of the total radioactive drug-related exposure. Intact tirzepatide was not observed in urine or feces in any species. Tirzepatide was primarily metabolized via proteolytic cleavage of the amino acid backbone, ß-oxidation of the C20 diacid moiety, and amide hydrolysis. ClinicalTrials.gov identifier: NCT 04,311,424.

Intestinal stearoyl-CoA desaturase-1 regulates energy balance via alterations in bile acid homeostasis.

BACKGROUND AND AIMS: Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid assimilation and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance. METHODS: To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine- specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, metabolic phenotyping including body composition, indirect calorimetry, glucose tolerance analyses, quantification of the composition of the gut microbiome, and assessment of bile acid signaling pathways. RESULTS: IKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt. In addition, the alpha and beta diversity of the gut microbiome was reduced in iKO mice, with several alterations in microbe species being associated with the observed increases in plasma bile acids. These increases in plasma bile acids were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice. CONCLUSION: Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid homeostasis and whole-body energy balance, likely via activation of TGR5.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may reduce the risk of developing cancer-related lymphedema following axillary lymph node dissection (ALND).

Purpose: Patients undergoing axillary lymph node dissection (ALND) for breast cancer face a high risk of lymphedema, further increased by high body mass index (BMI) and insulin resistance. GLP-1 receptor agonists (GLP-1RAs) have the potential to reduce these risk factors, but their role in lymphedema has never been investigated. The purpose of this study was to determine if GLP-RAs can reduce the risk of lymphedema in patients undergoing ALND. Methods: All patients who underwent ALND at a tertiary cancer center between 2010 and 2023 were reviewed. Patients with less than 2 years of follow-up from the time of ALND were excluded. Race, BMI, radiation, chemotherapy history, pre-existing diagnosis of diabetes, lymphedema development after ALND, and the use of GLP-1RAs were analyzed. Multivariate logistic regression analysis was performed to assess if there was a significant reduction in the risk of developing lymphedema after ALND. A sub-group analysis of non-diabetic patients was also performed. Results: 3,830 patients who underwent ALND were included, 76 of which were treated with. GLP-1 RAs. The incidence of lymphedema in the GLP-1 RA cohort was 6.6% (5 patients). Compared to 28.5% (1,071 patients) in the non-GLP-1 RA cohort. On multivariate regression analysis, patients who were treated with GLP-1 RA were 86% less likely to develop lymphedema compared to the non-GLP-1 RA cohort (OR 0.14, 95% CI 0.04-0.32, p < 0.0001). A BMI of 25 kg/m 2 or greater was a statistically significant risk factor for developing lymphedema with an odds ratio of 1.34 (95% CI 1.16-1.56, p < 0.0001). Diabetes was associated with lymphedema development that closely approached statistical significance (OR 1.32, 95% CI 0.97-1.78, p = 0.06). A subgroup analysis solely on non-diabetic patients showed similar results. The odds of developing lymphedema were 84% lower for patients without diabetes treated with GLP1-RAs compared to those who did not receive GLP-1 RAs (OR 0.16, 95% CI 0.05-0.40, p < 0.0001). Conclusion: GLP1-RAs appear to significantly reduce the risk of lymphedema in patientsundergoing ALND. The mechanism of action may be multifactorial and not limited to weight reduction and insulin resistance. Future prospective analysis is warranted to clarify the role of GLP-1RAs in reducing lymphedema risk.

[A new era for incretins : from GLP-1 receptor agonists to co-agonists and poly-agonists]. / Une nouvelle ère pour les incrétines : des agonistes des récepteurs du GLP-1 aux co-agonistes et poly-agonistes.

Incretin gut hormones, especially glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), raise a huge interest in diabetology. GLP-1 receptor agonists have gained a privileged role in the management of type 2 diabetes (T2D). They improve glucose control without inducing hypoglycaemia, while promoting weight loss. Furthermore, they protect people with T2D against atherosclerotic cardiovascular disease and contribute to reduce the risk of heart failure and chronic kidney disease, two other common complications of T2D. A recent innovation consists in the development of co-agonists that target both GIP and GLP-1 receptors. Whereas the co-infusion of GIP and GLP-1 failed to further reduce hyperglycaemia of T2D compared to GLP-1 single infusion, tirzepatide, an original dual unimolecular biaised GIP/GLP-1 agonist, showed a remarkable improvement of glucose control in the SURPASS programme in patients with T2D. Consequently, it is now commercialized in many countries for the management of T2D. GLP-1/glucagon (GCG) co-agonists and GIP/GLP-1/GCG poly-agonists are currently in development, aiming to benefit from the favourable effects of GCG on energy expenditure and liver lipid metabolism, while mitigating the hyperglycaemic effects of this hormone thanks to balanced effects of GLP-1 and/or GIP. They might occupy in the future an interesting place in the management of obesity and its metabolic complications among which T2D and liver steatosis.

Les hormones digestives à effet incrétine, en particulier le «glucagon-like peptide-1¼ (GLP-1) et le «glucose-dependent insulinotropic polypeptide¼ (GIP) suscitent un intérêt considérable en diabétologie. Les agonistes des récepteurs du GLP-1 ont acquis une place de choix dans la prise en charge des patients avec un diabète de type 2 (DT2). Ils améliorent le contrôle glycémique, sans provoquer des hypoglycémies, tout en faisant perdre du poids. De plus, ils protègent contre les maladies cardiovasculaires athéromateuses. Enfin, ils contribuent à réduire le risque d'insuffisance cardiaque et de maladie rénale chronique, deux autres complications fréquentes du DT2. Une innovation récente consiste dans le développement de co-agonistes ciblant à la fois les récepteurs du GLP-1 et du GIP. Alors que la co-infusion de GIP et de GLP-1 ne réduit pas davantage l'hyperglycémie du DT2 qu'une perfusion isolée de GLP-1, le tirzépatide, un agoniste biaisé unimoléculaire original à effet double sur les récepteurs GIP/GLP-1, a montré une amélioration remarquable du contrôle glycémique, tout en favorisant l'amaigrissement, dans le programme SURPASS chez le patient avec DT2. Ce médicament est maintenant commercialisé dans de nombreux pays. Des co-agonistes GLP-1/glucagon (GCG) et des poly-agonistes GIP/GLP-1/GCG sont actuellement développés, profitant des effets favorables du glucagon sur les dépenses énergétiques et le métabolisme lipidique hépatique, tout en maîtrisant les effets hyperglycémiants de cette hormone grâce aux actions balancées du GLP-1 et/ou du GIP. Ils pourraient occuper à l'avenir une place intéressante dans le traitement de l'obésité et ses complications métaboliques dont le DT2 et la stéatopathie hépatique.

Risk of Suicide, Hair Loss, and Aspiration with GLP1-Receptor Agonists and Other Diabetic Agents: A Real-World Pharmacovigilance Study.

PURPOSE: With the increasing popularity of glucagon-like peptide 1 receptor agonists (GLP1-RAs), numerous safety concerns arose pertaining to suicide, hair loss, and aspiration risks. We attempted to validate these concerns. METHODS: We queried four pharmacovigilance databases to compare GLP1-RAs to sodium-glucose transporter 2 inhibitors (SGLT2is) with respect to these adverse events (AE): the FDA Adverse Event Reporting System (FAERS), the Australian Database of Adverse Event Notifications (DAEN), the European Medicines Agency's (EudraVigilance), and the World Health Organization-Vigibase. OpenVigil 2.1 was utilized to perform a disproportionality analysis for GLP1-RAs, SGLT2is, dipeptidyl peptidase 4 inhibitors (DPP4is), sulfonylureas, metformin, and insulin. The following indices were extracted from the FAERS database from Q4/2003 until Q3/2023: relative reporting ratio (RRR), proportional reporting ratio (PRR), reporting odds ratio (ROR), and chi-squared (χ2). A positive signal was detected if PRR > 2 and χ2 > 4 for any drug-event pair. RESULTS: No positive signals were observed between GLP1-RAs and either suicide, hair loss, or aspiration risks. Semaglutide [ROR = 0.60 (0.51-0.71)] and liraglutide [ROR = 0.28 (0.23-0.35)] had higher suicidal events than DPP4is and SGLT2is. GLP1-RAs were the most reported class with hair loss [ROR = 0.61 (0.60-0.64)], and semaglutide, liraglutide, and dulaglutide were the three leading medications. GLP1-RAs ranked lower with aspiration events, which were led by sitagliptin and DPP4is as a group. CONCLUSION: GLP1-RAs exhibit higher reporting of suicide, hair loss, and aspiration events when compared to several other antidiabetic medications despite not meeting the criteria for positive signals yet. This warrants intensive monitoring and reporting.

"Emerging clinical approaches in diabetic cardiomyopathy: insights from clinical trials and future directions".

AIM: We aim to explore the potential of diverse treatments, including perhexiline, calcium channel blockers, anti-hypertensives, PDE5 inhibitors, anti-anginal drugs, aldose reductase inhibitors, and SGLT-2 inhibitors, supported by clinical evidence. Additionally, this review seeks to identify novel therapeutic targets and future avenues for improving cardiovascular outcomes in diabetic populations. METHOD: We performed a comprehensive literature review of English-language studies across multiple electronic databases, such as PubMed, ScienceDirect, Scopus, and Google Scholar, focusing on clinical trials. The search utilized keywords including 'Anti-hyperglycaemic drug,' 'Diabetic cardiomyopathy,' 'DPP-4 inhibitors,' 'GLP-1 receptor agonists,' 'Heart failure,' and 'SGLT-2 inhibitors.' RESULT: We assessed clinical investigations in the treatment of cardiomyopathy and diabetes mellitus (DM) that are enhancing our understanding through trials evaluating the Polypill, Perhexiline, Eplerenone, IMB-1018972, AT-001, tadalafil, and dapagliflozin inhibitors. The development of new targeted interventions is of paramount importance due to the overlooked early symptoms, the complexity of the cellular and molecular pathways involved, and the absence of effective drug therapies. CONCLUSION: Pharmacological treatments like GLP-1 agonists, SGLT-2 inhibitors, NHE-1, NHE-3, and PPAR-γ agonists show promise for treating DCM. These treatments improve myocardial glucose absorption, address dysregulated glucose and lipid metabolism, and lower heart failure and cardiovascular events. Further research is needed to confirm effectiveness and safety.

Principal components analysis on genes related to inflammasome complex and microglial activation in the hypothalamus of obese mice treated with semaglutide (GLP-1 analog).

We studied the effect of semaglutide (glucagon-like peptide type 1 agonist) on hypothalamic pro-inflammatory genes in diet-induced obese mice. Male C57BL/6J mice were fed a control (C) or high-fat (HF) diet for 16 weeks, then divided into six groups and maintained for an additional four-week study: C, C+semaglutide (CS), C pair-feeding (CP), HF, HF+semaglutide (HFS), and HF pair-feeding (HFP).Weight gain (WG), food efficiency (FE), and plasmatic biochemistry were determined. The hypothalamus was removed and prepared for molecular analysis. Semaglutide reduced WG and FE in the HF group. High cytokines levels (tumor necrosis factor alpha, TNF alpha, monocyte chemoattractant protein 1, MCP1, and Resistin) in HF mice were reduced in HFS mice. High pro-inflammatory gene expressions were seen in HF (toll-like receptor 4, Tlr4; Mcp1; interleukin 6, Il6; Tnfa), inflammasome complex (Pirina domain-containing receptor 3, Nlrp3; Caspase 1, Il1b, Il18), and microglial activation (ionized calcium-binding adapter molecule 1, Iba1; cluster differentiation 68, Cd68; argirase 1, Arg1) but mitigated in HFS. The principal components analysis (PCA) based on these markers in a PC1 x PC2 scatterplot put HF and HFP together but far away from a cluster formed by C and HFS, indicating little significance of weight loss (HFP) but decisive action of semaglutide (HFS) in the results. In conclusion, semaglutide benefits hypothalamic pro-inflammatory genes, inflammasome complex, and microglial activation independent of the weight loss effect. Since GLP-1 receptor agonists such as semaglutide are already indicated to treat obesity and diabetes, the potential translational effects on neuroinflammation should be considered.

The impact of glucagon and exenatide on oxidative stress levels and antioxidative enzyme expression in in vitro induced steatosis in HepG2 cell culture.

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a healthcare issue of growing concern. Its development is multifactorial, and it is more commonly seen in obese patients. In those circumstances, intracellular lipid overload ensues, resulting in oxidative stress that might be responsible for progression toward steatohepatitis. Novel therapeutic approaches that are effective in weight management are expected to improve the course of MASLD. One of the potential mechanisms involved in such protective properties may relate to the reduction in oxidative stress. MATERIAL AND METHODS: The induction of steatosis and the assessment of oxidative stress level and expression of antioxidant enzymes (superoxide dismutase - SOD, glutathione peroxidase - GPx and catalase - Cat) in HepG2 hepatoma cell line subjected to glucagon and exenatide treatment. RESULTS: Exenatide monotherapy successfully reduced lipid accumulation by 25%. Significant reductions in markers of oxidative stress (reactive oxygen species and malondialdehyde) were obtained in cells subjected to combined treatment with glucagon and exenatide (by 24 and 21%, respectively). Reduced burden of oxidative stress was associated with elevated expression of SOD and GPx but not Cat. CONCLUSIONS: Combined activation of glucagon-like peptide-1 (GLP-1) and glucagon receptors reduces oxidative stress in HepG2 steatotic cell cultures. This observation may stem from increased antioxidative potential.