T2DM Disease Research Articles

Lygodium microphyllum Inhibits de Novo Lipogenesis Activity in the Hepatocytes of High-Fat High-Fructose-Induced Rats by Increasing the Levels of SIRT1 and AMPK.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is currently of great concern due to its risk of developing T2DM and cardiovascular disease. The development of NAFLD may be initiated by de novo lipogenesis in the hepatocytes. Sirtuin1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), are responsible for the lipogenesis mechanism. Interestingly, plant sterols, such as beta-sitosterol and stigmasterol, have the potential to lower the LDL-cholesterol in dyslipidemic patients. Beta-sitosterol was present in the ethanol extract of Lygodium microphyllum herbs at a concentration of 283.55µg/g extract. This sterol interacted with the active allosteric-binding site of SIRT1 and AMPK similarly to the proteins' activators. To investigate the anti-lipogenesis activity of the ethanol extract of L. microphyllum (ELM) in the liver tissue of rats through the SIRT1 and AMPK levels. Forty male Wistar rats were used in this study: (1) normal control group; (2) high-fat high-fructose diet (HFHFD) rats; (3) HFHFD rats treated with metformin; (4) HFHFD rats treated with resveratrol; (5) HFHFD rats treated with beta-sitosterol; (6-8) HFHFD rats treated with ELM doses of 200, 400, and 600 mg/kg BW. Rats in the normal control group were fed regular chow, while other groups of rats were given HFHFD for 35 days. All drugs were given orally on D15 till D35. On D35, the rats were sacrificed, and the liver organs were examined for the liver index, morphology, NAFLD activity score (NAS), and levels of SIRT1 and AMPK. ELM improves the morphology, the liver index, the steatosis condition, and the NAS of HFHFD-induced NAFLD rats. ELM increases the levels of SIRT1 and AMPK in the liver tissue of HFHFD-induced NAFLD rats. ELM may have the potential to inhibit de novo lipogenesis by increasing the levels of SIRT1 and AMPK.

Gamma-glutamyl transferase to high-density lipoprotein cholesterol ratio: A valuable predictor of coronary heart disease incidence

Background and AimExisting studies have found that serological markers for predicting coronary heart disease (CHD) have relatively low predictive value for the severity of coronary arteries and the types of CHD. GGT to HDL-C ratio (GHR) has been shown to be associated with T2DM and non-alcoholic fatty liver disease. Therefore, we explore the relationship among GHR, CHD and its subgroups. Methods and ResultsThe study retrospectively analyzed 2703 participants from August 2022 to August 2023. The patients were divided into CHD group (N=1911) and control group (N=792) according to the diagnostic criteria of CHD. Adjustments for all covariates found that the GHR was an independent risk factor for CHD (OR: 1.025, 95% CI 1.016-1.033) and had the highest AUC of 0.767 (95% CI 0.744-0.790) in identifying CHD. Additionally, GHR was significantly associated with multi-vessel CHD (OR: 1.018, 95% CI 1.012-1.023) and showed excellent diagnostic capability for patients with multi-vessel CHD (AUC: 0.638). Moreover, compared with chronic coronary syndromes (CCS) and unstable angina (UA) groups, the level of GHR was significantly increased in acute myocardial infarction (AMI) (ST elevation myocardial infarction and Non-ST elevation myocardial infarction) groups (P<0.05). GHR had the higher AUC in STMETI [0.819 (95% CI 0.796-0.854)] and NASTEMI [0.792 (95% CI 0.766-0.816)] than the CCS and UA groups. ConclusionsOur study analyses found that GHR is an independent risk factor for CHD and can predict the severity of coronary artery stenosis. Moreover, GHR has a high predictive value for AMI than CCS and UA in CHD patients.

Empagliflozin and left atrial function in patients with type 2 diabetes mellitus and coronary artery disease: insight from the EMPA-HEART CardioLink‐6 randomized clinical trial

BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated reduction in heart failure outcomes in patients with type 2 diabetes mellitus, although the exact mechanism of benefit remains unclear. Alteration in left atrial (LA) function due to chronic pressure or volume overload is a hallmark of heart failure.ObjectiveTo evaluate the effect of the SGLT2 inhibitor empagliflozin on LA volume and function.Methods90 patients with coronary artery disease and type 2 diabetes (T2DM) were randomized to empagliflozin (n = 44) or placebo (n = 46), and underwent cardiac magnetic resonance (CMR) imaging at baseline and after 6 months. The main outcome was change in LA volume; LA function, including active and passive components, was also measured by a blinded reader.ResultsAt baseline, there was no significant difference in LA volumes between the empagliflozin (indexed maximum LA volume 26.4 ± 8.4mL/m2, minimum LA volume 11.1 ± 5.7mL/m2) and placebo (indexed maximum LA volume 28.7 ± 8.2mL/m2, minimum LA volume 12.6 ± 5.0mL/m2) groups. After 6 months, changes in LA volumes did not differ with adjusted difference (empagliflozin minus placebo): 0.99 mL/m2 (95% CI: -1.7 to 3.7 mL/m2; p = 0.47) for indexed maximum LA volume, and 0.87 mL/m2 (95% CI: -0.9 to 2.6 mL/m2; p = 0.32) for indexed minimum LA volume. Changes in total LA emptying fraction were also similar, with between-group adjusted mean difference − 0.01 (95% CI: -0.05 to 0.03, p = 0.59).ConclusionSGLT2 inhibition with empagliflozin for 6 months did not have a significant impact on LA volume and function in patients with T2DM and coronary artery disease. (Effects of Empagliflozin on Cardiac Structure in Patients with Type 2 Diabetes [EMPA-HEART]; NCT02998970).

Mediterranean diet as a strategy for preserving kidney function in patients with coronary heart disease with type 2 diabetes and obesity: a secondary analysis of CORDIOPREV randomized controlled trial

BackgroundType 2 diabetes mellitus (T2DM) is recognized an independent risk factor for chronic kidney disease (CKD). The precise contribution and differential response to treatment strategies to reduce kidney dysfunction, depending on whether obesity is present alongside T2DM or not, remain to be fully clarified. Our objective was to improve our understanding of how obesity contributes to kidney function in patients with T2DM and coronary heart disease (CHD), who are highly predisposed to CKD, to assign the most effective dietary approach to preserve kidney function.Methods1002 patients with CHD and estimated glomerular filtration rate (eGFR)≥30 ml/min/1.73m2, were randomized to consume a Mediterranean diet (35% fat, 22% MUFA, < 50% carbohydrates) or a low-fat diet (28% fat, 12% MUFA, > 55% carbohydrates). Patients were classified into four groups according to the presence of T2DM and/or obesity at baseline: Non-Obesity/Non-T2DM, Obesity/Non-T2DM, Non-Obesity/T2DM and Obesity/T2DM. We evaluated kidney function using serum creatinine-based estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR) before and after 5-years of dietary intervention.ResultsPatients with Obesity/T2DM had the lowest baseline eGFR and the highest baseline uACR compared to non-diabetics (p < 0.05). After dietary intervention, the Mediterranean diet induced a lower eGFR decline in patients with Obesity/T2DM, compared to a low-fat diet but not in the other groups (p = 0.014). The Mediterranean diet, but not the low-fat diet, also reduced uACR only in patients with Obesity/T2DM (p = 0.024).ConclusionsObesity provided an additive effect to T2DM resulting in a more pronounced decline in kidney function compared to T2DM alone when compared to non-diabetics. In patients with concomitant presence of T2DM and obesity, with more metabolic complications, consumption of a Mediterranean diet seemed more beneficial than a low-fat diet in terms of preserving kidney function. These findings provide valuable insights for tailoring personalized lifestyle modifications in secondary prevention of cardiovascular disease.Trial registrationURL, http://www.cordioprev.es/index.php/en. Clinicaltrials.gov number, NCT00924937

HEART FAILURE WITH RELAPSING ATRIAL FIBRILLATION: BELOW THE SURFACE

Abstract Advances in pharmacologic and device therapy have greatly improved prognosis of patients with HFrEF. However, the typical clinical course is still characterized by recurring symptoms, worsening functional status and risk of frequent hospitalizations. A 72–years–old male patient with arterial hypertension, poorly controlled T2DM, TIA and chronic kidney disease presented to Cardiology service in 2018 with dyspnoea on effort and first evidence of EF 35% at echocardiography. He was admitted for elective coronary angiography, which demonstrated limited coronary heart disease of circumflex artery and its first marginal branch, treated by PTCA and stenting. CMR confirmed severe LV dysfunction, but also revealed extensive fibrotic areas with ischaemic and non–ischaemic patterns beyond revascularized regions. With such evidences, HF treatments were intensified, with titration of disease– modifying therapies and DOAC was added for asymptomatic paroxysmal AF. CRT–D was implanted for QRS of 160 msec, which was narrowed to 130 msec. Nevertheless, in one–year time the patient presented worsening of symptoms with several hospital admissions for acute HF and AF with fast rate. A switch to rhythm–control strategy was hence chosen. DCCV was performed, after an initial deferral for thrombosis of LAA due to poor adherence to DOAC. However, three–days after DCCV, the patient presented again to emergency services for dyspnoea, left upper flank pain and AF with fast rate. He was admitted to Acute Medicine Unit and treated with high flow O2, iv Furosemide and Digoxin, analgesics. CT chest and abdomen with contrast was performed in the suspicion of systemic venous thromboembolism for persistent type 1 respiratory failure, raised D–dimer and elevated liver function tests, despite appropriate anticoagulation. CT revealed an unexpected left superior pulmonary vein thrombosis, splenic and small left renal infarcts. The patient was discharged after recovery on subcutaneous heparin. At 15–day review, the patient was in stable conditions and awaiting completion of coagulation screening tests. This case study addresses some important aspects in the care of HF. An accurate assessment of HF aetiology and recurrent triggers, a timely planning of pharmacologic and device treatments, alongside with management of co–morbidities, therapeutic adherence and appropriate anticoagulation, can provide the clinician powerful tools to accomplish the difficult task of managing HF below the surface.

Impact of GLP-1 Receptor Agonist Use in Patients With Steatotic Liver Disease and Type 2 Diabetes: A Retrospective Cohort Study

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) help manage type 2 diabetes (T2DM) and may have efficacy in steatotic liver disease. Objective: To determine the prevalence and clinical impact of GLP-1 RA use in patients with T2DM and liver disease. Methods: This was a retrospective study of adult patients with T2DM and nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver (NAFL), or nonalcoholic steatohepatitis (NASH) between 1/1/21-12/31/21. Patients with hepatitis B or C, or on pioglitazone were excluded. Eligible patients treated with a GLP-1 RA were compared to controls. The primary outcome was change in Fibrosis-4 (FIB-4) score, with NAFLD Fibrosis Score (NFS) as a secondary outcome. Follow-up scores were calculated from labs within 3 to 15 months after baseline. Results: Of 242 eligible patients, 79 patients (32.6%) were treated with a GLP-1 RA. At baseline, FIB-4 score was lower and NFS was higher in the GLP-1 RA group vs controls (1.80 vs 2.33; P = .101, .36 vs −.47, P < .001; respectively). At follow up, FIB-4 score decreased to 1.77 in the GLP-1 RA group and increased to 2.71 in controls (P = .045). Follow up NFS was stable in the GLP-1 RA group and increased in the control group (.36 vs −.43; P = .308). Conclusion: Patients treated with GLP-1 RAs had less evidence of liver fibrosis progression compared to no treatment, although the differences were small. These results suggest that treatment with GLP-1 RAs may have clinical impact on slowing liver fibrosis, however results should be confirmed in a larger, more diverse sample.

Triglyceride-glucose index is capable of identifying metabolically obese, normal-weight older individuals

BackgroundThe concept of metabolically obese, normal weight (MONW) has emerged to describe individuals with a normal body mass index (BMI) who are at a relatively high risk of chronic diseases. However, BMI itself is a suboptimal index for the assessment of the health risks associated with visceral fat. The triglyceride-glucose (TyG) index is considered to be a reliable and cost-effective marker of insulin resistance. Therefore, in the present study, we aimed to determine the TyG index cut-off values that could be used to define MONW in older people and to determine the usefulness of these values for the prediction of chronic diseases.MethodsA total of 4,721 participants in the Korea National Health and Nutritional Examination Survey who were ≥ 60 years of age and did not have underweight or obesity were included. MONW was defined using the criteria for metabolic syndrome (MS), and the TyG index was calculated on the basis of the fasting plasma triglyceride and glucose concentrations. Chronic diseases, including T2DM, hypertension, and non-alcoholic fatty liver disease (NAFLD), were diagnosed.ResultsThe prevalence of MS increased from the lowest to the highest TyG index tertile. The cut-off values of the TyG index for MONW were calculated as 8.88 and 8.80 for males and females, respectively. MONW, defined using these cut-off values, was associated with high odds ratios for NAFLD, T2DM, and hypertension in both males and females.ConclusionsThe TyG index cut-off values calculated in the present study can be used to discriminate individuals with MONW from other older individuals without obesity and to predict the risk of chronic diseases. These findings show that the TyG index is an effective and cost-efficient method of assessing the risk of chronic diseases in people with MONW.

Association of T-wave electrocardiogram changes and type 2 diabetes: a cross-sectional sub-analysis of the MASHAD cohort population using the Minnesota coding system

BackgroundType 2 Diabetes Mellitus (T2DM) has become a major health concern with an increasing prevalence and is now one of the leading attributable causes of death globally. T2DM and cardiovascular disease are strongly associated and T2DM is an important independent risk factor for ischemic heart disease. T-wave abnormalities (TWA) on electrocardiogram (ECG) can indicate several pathologies including ischemia. In this study, we aimed to investigate the association between T2DM and T-wave changes using the Minnesota coding system.MethodsA cross-sectional study was conducted on the MASHAD cohort study population. All participants of the cohort population were enrolled in the study. 12-lead ECG and Minnesota coding system (codes 5–1 to 5–4) were utilized for T-wave observation and interpretation. Regression models were used for the final evaluation with a level of significance being considered at p < 0.05.ResultsA total of 9035 participants aged 35–65 years old were included in the study, of whom 1273 were diabetic. The prevalence of code 5–2, 5–3, major and minor TWA were significantly higher in diabetics (p < 0.05). However, following adjustment for age, gender, and hypertension, the presence of TWAs was not significantly associated with T2DM (p > 0.05). Hypertension, age, and body mass index were significantly associated with T2DM (p < 0.05).ConclusionsAlthough some T-wave abnormalities were more frequent in diabetics, they were not statistically associated with the presence of T2DM in our study.

Identification of active compounds as novel dipeptidyl peptidase-4 inhibitors through machine learning and structure-based molecular docking simulations

The enzyme dipeptidyl peptidase 4 (DPP4) is a potential therapeutic target for type 2 diabetes (T2DM). Many synthetic anti-DPP4 medications are available to treat T2DM. The need for secure and efficient medicines has been unmet due to the adverse side effects of existing DPP4 medications. The present study implemented a combined approach to machine learning and structure-based virtual screening to identify DPP4 inhibitors. Two ML models were trained based on DPP4 IC50 datasets. The ML models random forest (RF) and multilayer perceptron (MLP) neural network showed good accuracy, with the area under the curve being 0.93 and 0.91, respectively. The natural compound library was screened through ML models, and 1% (217) of compounds were selected for further screening. Structure-based virtual screening was performed along with positive control sitagliptin to obtain more specific and selective leads for DPP4. Based on binding affinity, drug-likeness properties, and interaction with DPP4, Z-614 and Z-997 compounds showed high binding affinity and specificity in the catalytic pocket of DPP4. Finally, the stability conformation of the DPP4 enzyme complex was checked by a molecular dynamics (MD) simulation. The MD simulation showed that both compounds bind better in the catalytic pocket, but the Z-614 compound altered the DPP4 native conformation. Therefore, Z-614 showed a high deviation in the backbone. This combined approach (ML and structure-based) study reported that Z-997 binds most stably to DPP4 in their catalytic pocket with a binding free energy of −70.3 kJ/mol, suggesting its therapeutic potential as a treatment option for T2DM disease. Communicated by Ramaswamy H. Sarma

THU334 Trends In GLP-1 Agonist Utilization In Diabetics With And Without Vascular Disease

Abstract Disclosure: P. Sargin: None. M. Barahona: None. H. Rubayet: None. G. Leef: None. GLP-1 agonists (GLP1) have emerged as a breakthrough class of drugs for the management of Type 2 Diabetes (T2DM). Data from cardiovascular outcomes trials has shown benefits in patients with known atherosclerotic vascular disease, including reduced cardiovascular mortality and stroke. These agents are now considered preferred therapy, however, prior studies have shown low rates of utilization. We hypothesized that recent guidelines and provider education may lead to increased prescribing of GLP1. We analyzed a large, multicenter database to investigate recent trends in GLP1 utilization in patients with T2DM and vascular disease. We extracted all patients from the database with T2DM and excluded patients with diagnoses of Type 1 Diabetes, thyroid cancer, pancreatitis, or MEN syndrome type 2, or age &amp;gt;90. We then stratified the cohort to compare patients with a diagnosis of ischemic heart disease, peripheral vascular disease, or cerebrovascular disease since January 1st, 2021 against diabetic patients without these diagnoses. Patients were compared for rates of prescription of diabetes medications and baseline characteristics including age, sex, race, BMI, HgA1c, and creatinine. Our search generated a total of 408553 patients with T2DM and vascular disease (defined as at least one of the following: ischemic heart disease, peripheral vascular disease, cerebrovascular disease), and 520383 with T2DM and no known vascular disease. The vascular disease cohort was 56% male, 68% white, mean age 70±13. Ischemic heart disease was present in 78%, cerebrovascular disease in 43%, and peripheral vascular disease in 22%. The non-vascular disease cohort was 54% female, 57% white, mean age 63±16. In the vascular disease cohort, 56% were prescribed insulin, 47% metformin, 17% SGLT2, and 14% GLP1. In the non-vascular disease cohort, 43% were prescribed metformin, 32% insulin, 11% GLP1, and 8% SGLT2. The P-value was less than 0.001 for all comparisons. Rates of the utilization of GLP1 agents in our database are still relatively low, but higher than has been reported before. This might suggest a favorable trend compared with prior studies on this topic, although they are not directly comparable due to different patient populations. With only 14% of the T2DM-vascular disease population receiving one of these agents (after excluding those with a documented contraindication), more work needs to be done to enable all patients who would benefit from these medications to access them. Presentation: Thursday, June 15, 2023

FRI652 Type 2 Diabetes Management: More GLP1 Agonists And Less Metformin?

Abstract Disclosure: F.J. Lopez Maldonado: None. R.A. Cota: None. Case presentation: A 41-year-old male patient with family history of T2DM in both parents and brother, personal history of mild alcohol consumption and a sedentary job (public accountant), and obesity since age 30 presented to the endocrinology clinic due to failure to lose weight after 1 year of treatment with a nutritionist. During his first visit, the was asymptomatic and had acanthosis nigricans, his blood pressure was measured at 142/92 mmHg, weight was 100.8 kg, waist circumference was 128 cm, and serum glucose was at 280 mg/dL with an HbA1c of 11.9%. Further laboratory tests showed elevated levels of triglycerides (310 mg/dL), LDL (139 mg/dL), AST (96 U/L), and ALT (65 U/L). Two days later, glucose and HbA1c were repeated with similar results. A liver ultrasound was ordered which revealed diffuse hyperechogenicity of the liver and severe fatty liver disease. The ASCVD risk score was 5.4%. The patient was diagnosed with T2DM, obesity, mixed dyslipidemia, and fatty liver disease. The patient received education, nutrition support, exercise, and pharmacotherapy management with stepped-dose oral semaglutide without metformin. The dose was increased monthly starting at 3 mg and reaching the target dose of 14 mg QD. After three months, the patient demonstrated significant improvements in various parameters such as blood pressure (−10/−8 mmHg), weight (−9.8 kg), waist circumference (−25 cm), serum glucose (−179 mg/dL), HbA1C (−5.7%), triglycerides (−154 mg/dL), LDL (−18 mg/dL), AST (−60 U/L), and ALT (−38 U/L), along with an increase in HDL (+6 mg/dL). After approximately 4 months on the target dose the patient showed further improvements in several parameters including ASCVD risk score (2.1%), blood pressure (−20/12 mmHg), weight (−14.8 kg), waist circumference (−30 cm), serum glucose (−183 mg/dL), HbA1C (−6%), LDL (−25 mg/dL), AST (−63 U/L), and ALT (−40 U/L), and HDL (+10 mg/dL), except for triglyceride levels (−130 mg/dL). Follow-up liver ultrasound showed significant improvement in fatty liver disease. Real-world experiences with newly introduced drugs should be reported, as they may have beneficial effects beyond the ones studied. Oral semaglutide, the first oral GLP-1 analog, has been shown to be non-inferior to other subcutaneous GLP-1 analogs. In this case, improvements were observed in glycemic control, weight loss, lipid levels, and a reduction in cardiovascular risk, as well as an improvement in fatty liver disease. Presentation: Friday, June 16, 2023

Changes in cardiac and vascular haemodynamics as potential mediators of improvements in cardiovascular and kidney outcomes with empagliflozin in type 2 diabetes

AimsEvaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin. MethodsPost-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure [HF], HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses. ResultsPulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown. ConclusionsImprovements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease.

Association of the Red Cell Distribution Width With the Glycemic Index and Lipid Profile in Patients With Type 2 Diabetes Mellitus.

Background The aim of this study was to assess the association between the red cell distribution width (RDW) and the hemoglobin A1C (HbA1c) and lipid profiles in patients with type 2 diabetes (T2DM). Materials and methods This case-control study included 130 individuals with T2DM disease who were admitted to the Diabetic Center in Taif, Saudi Arabia, between August and December 2022. The patients were divided into two groups: pre-diabetic (45 patients) and diabetic (85 patients). A total of 65 healthy people were included in the study as controls. The (HbA1c) level, lipid profile, and complete blood count (CBC) were determined for each participant, and differences in those parameters between the groups were evaluated using the one-way ANOVA test or Kruskal-Wallis test. The association between different parameters, including the RDW, was evaluated using the Pearson correlation coefficient. Results Both the pre-diabetic and diabetic patients were obese and had high concentrations of triglycerides, cholesterol, and low-density lipoprotein (LDL). None of the diabetic patients had anemia of any type. However, the RDW was higher in the diabetic group than in the healthy controls and a significant difference was detected. A positive correlation was detected between the RDW and the HbA1c levels and lipid profiles. Discussion The size of the red blood cells varied in patients with T2DM, as demonstrated by the high RDW values. The RDW showed a positive correlation with the glycemic index and with the lipid profile in patients with T2DM, suggesting that it is a useful prognostic marker for managing patients with T2DM.

1066-P: Gaps in Guideline-Indicated Prescribing of GLP1RA/SGLT2i in Patients with T2DM and Cardiorenal Disease according to ADA Standards of Care

We evaluated the treatment gap in prescribing guideline-directed therapies in patients with T2DM and cardiorenal disease using EHR data from a large academic medical center. Eligible patients had T2DM and an outpatient encounter after January 1, 2019 in either endocrinology, cardiology, nephrology, or primary care. Eligibility subgroups were defined using ADA 2022 Standards of Care: ASCVD (N=1,962) - ‘SGLT2i or GLP1RA’; HFrEF or HFpEF or CKD stage 3 (N=5,537) - ‘SGLT2i Only’; ASCVD and HF or CKD stage 3 (N=1,773) - ‘SGLT2i primary’; CKD stage 4/5 (N=1,547) - ‘GLP1RA Only’. We extracted prescriptions for any GLP1RA or SGLT2i since 2006 to characterize ever prescribed and currently prescribed. The treatment gap for patients (N=10,819) ever prescribed ranged from 45.5% for those who should have been prescribed either an SGLT2i or GLP1RA to 71.9% for those eligible for GLP1RA only (Panel A). The treatment gap was &amp;gt;20% higher for currently prescribed across all subgroups, ranging from 73.5% to 92.1% across the subgroups (Panel B). Large treatment gaps in prescribing of guideline-directed cardiorenal protective agents in high-risk patients with type 2 diabetes exist. While all subgroups were sub-optimally treated, those with CKD stage 4/5 had the largest gap. These findings will inform multi-faceted interventions geared to improve the care of such high-risk patients. Disclosure I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp &amp; Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. M.E.Bowen: Research Support; Boehringer-Ingelheim. C.Mai: None. K.Marble: None. J.Pak: None. M.A.Basit: Research Support; Boehringer Ingelheim Inc., Verily Life Sciences. Funding Boehringer Ingelheim

Arjunolic acid modulate pancreatic dysfunction by ameliorating pattern recognition receptor and canonical Wnt pathway activation in type 2 diabetic rats

BackgroundArjunolic acid (AA) is a potent phytochemical with multiple therapeutics effects. In this study, AA is evaluated on type 2 diabetic (T2DM) rats to understand the mechanism of β-cell linkage with Toll-like receptor 4 (TLR-4) and canonical Wnt signaling. However, its role in modulating TLR-4 and canonical Wnt/β-catenin crosstalk on insulin signaling remains unclear during T2DM.AimThe current study is aimed to examine the potential role of AA on insulin signaling and TLR-4-Wnt crosstalk in the pancreas of type 2 diabetic rats. MethodMultiple methods were used to determine molecular cognizance of AA in T2DM rats, when treated with different dosage levels. Histopathological and histomorphometry analysis was conducted using masson trichrome and H&E stains. While, protein and mRNA expressions of TLR-4/Wnt and insulin signaling were assessed using automated Western blotting (jess), immunohistochemistry, and RT-PCR. ResultsHistopathological findings revealed that AA had reversed back the T2DM-induced apoptosis and necrosis caused to rats pancreas. Molecular findings exhibited prominent effects of AA in downregulating the elevated level of TLR-4, MyD88, NF-κB, p-JNK, and Wnt/β-catenin by blocking TLR-4/MyD88 and canonical Wnt signaling in diabetic pancreas, while IRS-1, PI3K, and pAkt were all upregulated by altering the NF-κB and β-catenin crosstalk during T2DM. ConclusionOverall results, indicate that AA has potential to develop as an effective therapeutic in the treatment of T2DM associated meta-inflammation. However, future preclinical research at multiple dose level in a long-term chronic T2DM disease model is warranted to understand its clinical relevance in cardiometabolic disease.

Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db/db mice

IntroductionGut microbiome (GM) deregulation has been implicated in major conditions such as obesity and type 2 diabetes (T2DM). Our previous prospective study indicated that fecal microbiota transplantation (FMT) successfully improved...

Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Diabetes and Coronary Artery Disease: Translating the Benefits of the Molecular Mechanisms of Gliflozins into Clinical Practice.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed for the treatment of diabetes due to their antihyperglycemic activity. However, in the light of the most recent clinical studies, they are revolutionizing the approach to cardiovascular disease in patients with and without diabetes. We aimed to generate real-world data about the use of SGLT2i in patients with T2DM and coronary artery disease (CAD), focusing on their effectiveness in glycemic control, adherence, long-term efficacy, and safety outcomes. On the basis of the inclusion and exclusion criteria, 143 patients were enrolled. Patients were treated with canagliflozin (n = 33 patients; 23%), dapagliflozin (n = 52 patients, 36.4%), empagliflozin (n = 48 patients; 33.6%), or ertugliflozin (n = 10 patients; 7%) as monotherapy or in combination with other antidiabetic drugs. All patients performed a clinical visit, and their medical history, blood sampling, and anthropometric parameters were measured at discharge and at 1-year follow-up. The reduction in HbA1c % value at 12 months was significant (8.2 vs. 7.4; p < 0.001). Trends in body weight and body mass index also confirmed the positive effect of the treatment (p < 0.0001), as did the reduction in abdominal adiposity (expressed via waist circumference). At 1-year follow-up, 74.1% of patients were adherent to the treatment, and 81.1% were persistent to the treatment. A total of 27 patients (18.8%) had to discontinue treatment early due to drug intolerance caused by genitourinary infections (11.9%), the drub being permanently ineffective (HbA1c not at target or decreasing: 4.9%), or because of expressing. a desire not to continue (2%). No major drug-related adverse events (diabetic ketoacidosis, Fournier's gangrene, lower-limb amputations) occurred at follow-up, while MACE events occurred in 14 patients (9.8%). In real-world patients with T2DM and CAD, SGLT2i have been effective in long-term glycemic control and the improvement in anthropometric indices with good tolerance, high adherence, persistence to treatment, and no major adverse events at 1-year follow-up.

How Could Different Obesity Scenarios Alter the Burden of Type 2 Diabetes and Liver Disease in Saudi Arabia?

Introduction: Obesity is a major risk factor for type 2 diabetes (T2DM) and liver disease, and obesity-attributable liver disease is a common indication for liver transplant. Obesity prevalence in Saudi Arabia (SA) has increased in recent decades. SA has committed to the WHO “halt obesity” target to shift prevalence to 2010 levels by 2025. We estimated the future benefits of reducing obesity in SA on incidence and costs of T2DM and liver disease under two policy scenarios: (1) SA meets the “halt obesity” target; (2) population body mass index (BMI) is reduced by 1% annually from 2020 to 2040. Methods: We developed a dynamic microsimulation of working-age people (20–59 years) in SA between 2010 and 2040. Model inputs included population demographic, disease and healthcare cost data, and relative risks of diseases associated with obesity. In our two policy scenarios, we manipulated population BMI and compared predicted disease incidence and associated healthcare costs to a baseline “no change” scenario. Results: Adults <35 years are expected to meet the “halt obesity” target, but those ≥35 years are not. Obesity is set to decline for females, but to increase amongst males 35–59 years. If SA’s working-age population achieved either scenario, >1.15 million combined cases of T2DM, liver disease, and liver cancer could be avoided by 2040. Healthcare cost savings for the “halt obesity” and 1% reduction scenarios are 46.7 and 32.8 billion USD, respectively. Conclusion: SA’s younger working-age population is set to meet the “halt obesity” target, but those aged 35–59 are off track. Even a modest annual 1% BMI reduction could result in substantial future health and economic benefits. Our findings strongly support universal initiatives to reduce population-level obesity, with targeted initiatives for working-age people ≥35 years of age.

Does dulaglutide impact a composite outcome reflecting atherosclerosis? A post-hoc analysis of the REWIND trial

Abstract Background It has been postulated that the cardioprotective effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes (T2DM) may retard the progression of atherosclerosis. Purpose The aim of this post-hoc analysis of the REWIND trial was to test the hypothesis that treatment with dulaglutide impacts a clinical outcome that reflects atherosclerosis in patients with type 2 diabetes (T2DM). Methods In the double-blind, placebo-controlled REWIND trial recruiting 9901 patients (46.3% women, mean age 66 years) with T2DM and cardiovascular disease (CVD) or varying levels of CV risk, a weekly subcutaneous injection of dulaglutide 1.5 mg reduced the hazard of MACE by 12% versus placebo. This post hoc analysis assessed the impact of dulaglutide on atherosclerosis-related outcomes comprising a composite of the first of CV death, nonfatal myocardial infarction, nonfatal ischaemic stroke and any revascularization including coronary, peripheral or carotid. Cox proportional hazards models were used to estimate the effect of randomized treatment. The effect in selected subgroups (Table 1) was estimated by including each subgroup and an interaction term in the model for the primary outcome. The composite of any component of the primary endpoint and non-cardiovascular death was considered as a secondary outcome. Results The primary endpoint occurred in 799 (16.1%) patients in the dulaglutide group and 870 (17.6%) patients in the placebo group (incidence rates: 3.25/100 person-years vs 3.58/100 person-years; HR 0.91, 95% CI 0.83–1.00; p=0.05) during a median follow-up of 5.4 years. This finding was consistent regardless of sex, body mass index, previous CVD or not and diabetes duration. The incidence of the secondary outcome was also lower in the dulaglutide group (HR; 95% CI: 0.91; 0.83–0.99; p=0.03). Conclusion Dulaglutide was associated with a 9% reduced index of atherosclerosis in patients with T2DM and CVD or high CV risk. This finding supports the hypothesis that dulaglutide may retard progression of atherosclerosis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): EliLilly and Company

Study of pulsed electrostatic field (PESF) in the perfusion of peripheral tissues: Microangiopathy, nutrition and quality of perceiver life.

Microangiopathy compromises the structural and functional integrity of organs and tissues in patients with type II diabetes mellitus (T2DM) negatively affecting the perceived quality of life. Nitric oxide (NO) is a multifunctional signalling molecule, acting as a vasodilator, neurotransmitter, and modulator of inflammatory processes. Patients with type II diabetes mellitus and chronic kidney disease, controlled from glycaemic status, were treated or not with pulsed electrostatic field (PESF) cycles to evaluate effect on the perfusion of peripheral tissues. Everyone was monitored for the metabolic profile, and we tested circulating NO with a commercial enzyme immunoassay kit. In addition, we tested the perceived quality of life of patients before/after a PESF cycle using a questionnaire. Patients treated with PESF were improved circulating NO levels, significant changes in systolic and diastolic blood pressure, heart rate and were more homogeneous for their metabolic profile. The questionnaire showed also a marked improvement in the perceived quality of life. The use of pulsed electrostatic fields has allowed us to observe an improvement in the metabolic, psychological, and clinical profile in patients with T2DM and chronic kidney disease whose pathological profile is strongly compromised.