Glucose-lowering Efficacy Research Articles

Antioxidant effects of a novel pioglitazone analogue (PA9) in a rat model of diabetes: Modulation of redox homeostasis and preservation of tissue architecture

Oxygen-free radicals have been implicated in the initiation of diabetic complications. Thiazolidinediones (TZDs), known for their antidiabetic properties, also demonstrate notable antioxidant and anti-inflammatory effects. Although a recently developed imidazolyl analogue of pioglitazone (PA9) has exhibited superior glucose-lowering efficacy compared to pioglitazone, its antioxidant effects remain unexplored. Thus, the objective of this study is to evaluate the antioxidant properties of PA9 in animal models with diabetes.Rats were randomly separated into the following four groups: control, diabetic, and two groups treated orally with pioglitazone as a standard drug and PA9 for ten days. Upon completion of the experiment, tissues from the liver, heart, brain, pancreas, spleen, and kidneys were collected to assess oxidant/antioxidant markers and histological alterations. The administration of PA9 resulted in a noteworthy reduction in malondialdehyde (MDA) levels compared to the diabetic group (p < 0.05). The group receiving PA9 displayed elevated levels of three antioxidant markers, catalase (CAT), superoxide dismutase (SOD), and total thiol, in pancreatic tissue compared to diabetic rats (p < 0.05).Furthermore, increased content of CAT was evident in the heart (p < 0.05), spleen (p < 0.001), brain, and kidney tissues in the PA9-treated group, along with augmented thiol content in the spleen compared to the diabetic group. Remarkably, no significant histological changes were observed in the liver, pancreas, heart, brain, spleen, and kidneys of the PA9-treated groups relative to diabetic rats. PA9 effectively mitigates oxidative stress, modulates redox homeostasis, and shows promise in preventing diabetic complications. The proven safety profile of this analogue underscores its potential, warranting comprehensive clinical evaluation to thoroughly understand its therapeutic scope and efficacy in the management of diabetes.

Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants

Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.

Cardiovascular Protective Properties of GLP-1 Receptor Agonists: More than Just Diabetic and Weight Loss Drugs.

Owing to their potent glucose-lowering efficacy and substantial weight loss effects, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now considered part of the frontline therapeutic options to treat both type 2 diabetes mellitus and nondiabetic overweight/obesity. Stemming from successful demonstration of their cardiometabolic modulation and reduction of major adverse cardiovascular events in clinical outcome trials, GLP-1 RAs have since been validated as agents with compelling cardiovascular protective properties. Studies spanning from the bench to preclinical and large-scale randomised controlled trials have consistently corroborated the cardiovascular benefits of this pharmacological class. Most notably, there is converging evidence that they exert favourable effects on atherosclerotic ischaemic endpoints, with preclinical data indicating that they may do so by directly modifying the burden and composition of atherosclerotic plaques. This narrative review examines the underlying pharmacology and clinical evidence behind the cardiovascular benefits of GLP-1 RAs, with particular focus on atherosclerotic cardiovascular disease. It also delves into the mechanisms that underpin their putative plaque-modifying actions, addresses existing knowledge gaps and therapeutic challenges and looks to future developments in the field, including the use of combination incretin agents for diabetes and weight loss management.

Clinical efficacy and cost-effectiveness of metformin in different patient populations: A narrative review of real-world evidence.

Over the past two decades, diabetes pharmacopoeia has flourished, with new drugs that, on top of their glucose-lowering efficacy, have been shown to protect the heart and the kidney. Despite these new opportunities, metformin retains a pivotal role among glucose-lowering agents. As one of the few available insulin sensitizers, metformin is an effective, safe, and overall well-tolerated drug backed by over 60 years of clinical experience, including evidence for potential benefits beyond glucose reduction across different ages, sexes, genetic backgrounds, geographical areas, and stages of disease. Although there is some discussion of whether metformin offers the most effective front-line option in newly diagnosed type 2 diabetes (T2D), it remains a natural companion to all other glucose-lowering agents. Furthermore, metformin comes at a very low cost and, as such, it has extremely high cost-effectiveness, particularly given the serious economic burden associated with diabetes complications. This financial advantage is particularly relevant in resource-constrained healthcare systems, where the affordability of metformin may be instrumental in implementing an effective treatment in an evergrowing number of individuals. We present here compelling real-world evidence in support of the clinical efficacy and cost-effectiveness of metformin across different patient populations, highlighting areas where more population-based studies are needed to further incorporate and consolidate its use in the pharmacological management of T2D.

Network analysis combined with experimental assessment to explore the therapeutic mechanisms of New Shenqi Pills formula targeting mitochondria on senile diabetes mellitus.

The escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and chronic inflammatory cascades prevalent in individuals with senile diabetes significantly amplify disease progression and complication rates. Traditional Chinese Medicine (TCM) emerges as a pivotal player in enhancing blood sugar homeostasis and retarding complication onset in the clinical management of senile diabetes. Nonetheless, an evident research gap persists regarding the integration of TCM's renal tonification pharmacological mechanisms with experimental validation within the realm of senile diabetes therapeutics. The objective of this study was to investigate the mechanisms of action of New Shenqi Pills (SQP) in the treatment of SDM and make an experimental assessment. Network analysis is used to evaluate target pathways related to SQP and SDM. Mitochondrial-related genes were obtained from the MitoCarta3.0 database and intersected with the common target genes of the disease and drugs, then constructing a protein-protein interaction (PPI) network making use of the GeneMANIA database. Representative compounds in the SQP were quantitatively measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to ensure quality control and quantitative analysis of the compounds. A type 2 diabetes mice (C57BL/6) model was used to investigate the pharmacodynamics of SQP. The glucose lowering efficacy of SQP was assessed through various metrics including body weight and fasting blood glucose (FBG). To elucidate the modulatory effects of SQP on pancreatic beta cell function, we measured oral glucose tolerance test (OGTT), insulin histochemical staining and tunel apoptosis detection, then assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway in diabetic mice via Western blotting. Additionally, we observe the structural changes of the nucleus, cytoplasmic granules and mitochondria of pancreatic islet β cells. In this investigation, we identified a total of 1876 genes associated with senile diabetes, 278 targets of SQP, and 166 overlapping target genes, primarily enriched in pathways pertinent to oxidative stress response, peptide response, and oxygen level modulation. Moreover, an intersection analysis involving 1,136 human mitochondrial genes and comorbidity targets yielded 15 mitochondria-related therapeutic targets. Quality control assessments and quantitative analyses of SQP revealed the predominant presence of five compounds with elevated concentrations: Catalpol, Cinnamon Aldehyde, Rehmanthin D, Trigonelline, and Paeonol Phenol. Vivo experiments demonstrated notable findings. Relative to the control group, mice in the model group exhibited significant increases in body weight and fasting blood glucose levels, alongside decreased insulin secretion and heightened islet cell apoptosis. Moreover, β-cells nuclear condensation and mitochondrial cristae disappearance were observed, accompanied by reduced expression levels of p-GSK-3β protein in islet cells (p < 0.05 or p < 0.01). Conversely, treatment groups administered SQP and Rg displayed augmented expressions of the aforementioned protein markers (p < 0.05 or p < 0.01), alongside preserved mitochondrial cristae structure in islet β cells. Our findings suggest that SQP can ameliorate diabetes by reducing islet cell apoptosis and resist oxidative stress. These insulin-mediated PI3K/AKT/GSK-3β pathway plays an important regulatory role in this process.

Optimizing antidiabetic properties of Galega officinalis extract: Investigating the effects of foliar application of chitosan and salicylic acid.

Diabetes poses a significant global health burden, demanding safe and effective therapeutic interventions. Medicinal plants offer promising avenues for natural diabetic management. Galega officinalis (goat's rue) has long been recognized for its hypoglycemic potential, but optimizing its phytochemical content and antidiabetic activity remains a key challenge. This study aimed to address this aspect by investigating the impact of foliar application of chitosan and salicylic acid on the physiological and phytochemical properties of G. officinalis, and subsequently evaluating its antidiabetic efficacy compared to that of the established drug metformin. A randomized complete block design with three replications was employed. Laboratory mice were divided into treatment groups receiving G. officinalis extract from plants sprayed with four salicylic acid concentrations (0.5-3 mM/L) and four chitosan concentrations (0-0.8 g/L). Blood glucose levels and various physiological parameters were assessed. Chitosan at 0.4 g/L and salicylic acid at 2 mM significantly enhanced the growth, photosynthetic pigments, and antioxidant activity of G. officinalis. Notably, the extract from plants treated with 3 mM salicylic acid exhibited the highest total alkaloid content, a potential contributor to antidiabetic activity. In a separate study, diabetic mice treated with this optimized G. officinalis extract (50 mg/kg) exhibited significantly greater blood glucose reductions compared to those treated with metformin (500 mg). This study demonstrates the potential of chitosan and salicylic acid in optimizing the beneficial properties of G. officinalis. The extract derived from plants treated with 3 mM salicylic acid displayed superior blood glucose-lowering efficacy compared to metformin, suggesting its promising role as a potential natural antidiabetic therapy. Further research is warranted to elucidate the specific bioactive compounds responsible for this enhanced activity and translate these findings into clinical applications.

SGLT2 Inhibitors- The New Standard of Care for Cardiovascular, Renal and Metabolic Protection in Type 2 Diabetes: A Narrative Review.

A substantial evidence base supports the use of sodium-glucose cotransporter-2 inhibitors (SGLT2is) in the treatment of type 2 diabetes mellitus (T2DM). This class of medicines has demonstrated important benefits that extend beyond glucose-lowering efficacy to protective mechanisms capable of slowing or preventing the onset of long-term cardiovascular, renal and metabolic (CVRM) complications, making their use highly applicable for organ protection and the maintenance of long-term health outcomes. SGLT2is have shown cost-effectiveness in T2DM management and economic savings over other glucose-lowering therapies due to reduced incidence of cardiovascular and renal events. National and international guidelines advocate SGLT2i use early in the T2DM management pathway, based upon a plethora of supporting data from large-scale cardiovascular outcome trials, renal outcomes trials and real-world studies. While most people with T2DM would benefit from CVRM protection through SGLT2i use, prescribing hesitancy remains, potentially due to confusion concerning their place in the complex therapeutic paradigm, variation in licensed indications or safety perceptions/misunderstandings associated with historical data that have since been superseded by robust clinical evidence and long-term pharmacovigilance reporting. This latest narrative review developed by the Improving Diabetes Steering Committee (IDSC) outlines the place of SGLT2is within current evidence-informed guidelines, examines their potential as the standard of care for the majority of newly diagnosed people with T2DM and sets into context the perceived risks and proven advantages of SGLT2is in terms of sustained health outcomes. The authors discuss the cost-effectiveness case for SGLT2is and provide user-friendly tools to support healthcare professionals in the correct application of these medicines in T2DM management. The previously published IDSC SGLT2i Prescribing Tool for T2DM Management has undergone updates and reformatting and is now available as a Decision Tool in an interactive pdf format as well as an abbreviated printable A4 poster/wall chart.

The dual GCGR/GLP-1R agonist survodutide: Biomarkers and pharmacological profiling for clinical candidate selection.

To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP-1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in-depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15- to 17-fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight-lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%-0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.

The amelioration effect of antidiabetic agents on cytokine expression in patients with type 2 diabetes mellitus

Inflammation is a condition that is closely linked to diabetes mellitus type 2 (T2DM), short for T2DM several different antidiabetic medications have been produced to regulate hyperglycemia, with indications that these therapies may have anti-inflammatory effects along with their glucose-lowering efficacy. Thus, this research was planned to explore the impact of antidiabetic agents on the cytokine expression levels —interleukin (IL)-1β, IL-6, IL-17, and IL-37 when patients have T2DM.In this study, 168 eligible subject matter was split into two groups: 50 healthy individuals and 118 cases with T2DM, who were classified into two subgroups: 30 untreated patients and 88 patients treated with metformin-based therapy.The outcome exhibited a significant increase within HbA1c% and proinflammatory cytokines (i.e., IL-1β, IL- 6, and IL-17), whereas IL-37 decreased considerably in untreated cases with T2DM compared to those in subjects who are healthy. Furthermore, the results showed increased levels Regarding waist size, body mass index and assessment using that homeostasis model, cholesterol, triglycerides, low-density lipoprotein levels, and heart danger elements in untreated cases with T2DM in comparison with hygienic subjects. Notably, treated patients with T2DM revealed an ameliorative impact on HbA1c, IL-6, IL-17, IL-37, IL-1β levels and lipid profile compared with untreated patients with T2DM.Antidiabetic agents may have a beneficial activity on the inflammatory status by reducing blood glucose levels, hyperlipidemia, and proinflammatory cytokines. The anti-inflammatory activity of IL-37 can apply a potentially effective therapeutic goal in treating T2DM and its complications.

Approach to the Patient With Type 2 Diabetes Requiring Add-On Medication.

In the last 20 years, the number of approved agents and agent classes for management of type 2 diabetes has expanded significantly. This more robust armamentarium affords us the opportunity to utilize drugs with complementary modes of action to address progressive hyperglycemia as insulin secretion declines over time. Furthermore, some of these agents provide additional benefits, such as weight loss, prevention of major adverse cardiac events (MACE), and protection against declining renal function. This dramatic increase of treatment options has led to complex published treatment advice which may be challenging for the busy clinician. A critical element in medication selection is awareness of the hemoglobin A1c (HbA1c)-lowering potency of the agent being considered, and the distance of the patient's HbA1c level from the individualized goal. Other important factors in choosing medication as diabetes progresses include the recognition that there is a diminishing return of glucose-lowering efficacy as add-on agents are introduced, and that the extent of benefit for cardiac and renal protection is not fully understood. In addition, the availability of newer non-insulin agents may distract the clinician from utilizing insulin, the most potent agent available. The goal of this article is to provide a straightforward approach to add-on medication in the treatment of type 2 diabetes, recognizing the limits of polypharmacy and the importance of employing agents best suited to achieving treatment targets. Proposed is a practical tool which provides stepwise guidance, utilizing available data on medication efficacy, while allowing flexibility based on clinician and patient preference.

Efficacy and safety of enavogliflozin vs. dapagliflozin as add-on therapy in patients with type 2 diabetes mellitus based on renal function: a pooled analysis of two randomized controlled trials

BackgroundWe assessed the efficacy and safety of enavogliflozin (0.3 mg), a newly developed SGLT-2 inhibitor, in patients with type 2 diabetes mellitus based on kidney function via pooled analysis of two 24-week, randomized, double-blind phase III trials.MethodsData from 470 patients were included (enavogliflozin: 0.3 mg/day, n = 235; dapagliflozin: 10 mg/day, n = 235). The subjects were classified by mildly reduced (60 ≤ eGFR < 90 mL/min/1.73 m², n = 247) or normal eGFR (≥ 90 mL/min/1.73 m², n = 223).ResultsIn the mildly reduced eGFR group, enavogliflozin significantly reduced the adjusted mean change of HbA1c and fasting plasma glucose levels at week 24 compared to dapagliflozin (− 0.94% vs. −0.77%, P = 0.0196). Enavogliflozin exhibited a more pronounced glucose-lowering effect by HbA1c when combined with dipeptidyl peptidase-4 inhibitors than that observed in their absence. Enavogliflozin showed potent blood glucose-lowering effects regardless of renal function. Conversely, dapagliflozin showed a significant decrease in the glucose-lowering efficacy as the renal function decreased. Enavogliflozin showed a higher urinary glucose excretion rate in both groups. The homeostatic model assessment showed that enavogliflozin markedly decreased the insulin resistance. The blood pressure, weight loss, or homeostasis model assessment of beta-cell function values did not differ significantly between enavogliflozin and dapagliflozin. Adverse events were similar between both drugs.ConclusionsThe glucose-lowering efficacy of enavogliflozin is superior to that of dapagliflozin in patients with type 2 diabetes mellitus with mild renal function impairment; this is attributed to its potent urinary glucose excretion-promoting ability. The emergence of new and potent SGLT-2 inhibitors is considered an attractive option for patients with inadequate glycemic control and decreased renal function.Trial registrationNot applicable (pooled analysis).

Outcomes and Attributes Patients Value When Choosing Glucose-Lowering Medications: A Mixed-Methods Study.

This mixed-methods study sought to identify pharmacotherapy preferences among 40 noninsulin-treated adults with type 2 diabetes receiving care at two U.S. health care systems. Participants ranked by relative importance various health outcomes and medication attributes and then contextualized their rankings. Most participants ranked blindness (63%), death (60%), heart attack (48%), and heart failure (48%) as the most important health outcomes and glucose-lowering efficacy (68%) as the most important medication attribute, followed by oral administration (45%) and lack of gastrointestinal side effects (38%).

Role of Chia Seed (Salvia hispanica L.) Supplements in Managing Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis

Background: Chia seeds have been used traditionally for treating several diseases, including diabetes mellitus (DM). No meta-analysis has holistically analyzed and summarized the effect of chia seed supplementation on glycemic and metabolic parameters in patients with type 2 DM (T2DM); we conducted this meta-analysis to bridge this knowledge gap. Methods: Electronic databases were searched for clinical trials involving patients with T2DM receiving chia seeds in the intervention arm and control diet in the comparator arm. The primary outcome was the changes in glycated hemoglobin (HbA1c) from the baseline at the end of the trial. Results: From 60 initially screened articles, data from four randomized controlled trials involving 244 subjects were analyzed. Chia seed was not superior to control diets in HbA1c reduction (mean differences [MD] −0.09%, 95% confidence interval [CI] [−0.48, 0.29], P = 0.63, I 2 = 95%). It was inferior to control diets in fasting plasma glucose reduction (MD 0.27 mmol/L, 95% CI [0.17, 0.37], P &lt; 0.00001, I 2 = 0%). Chia seed was superior to the control diets regarding reductions in body weight (MD −1.58 mmol/L, 95% CI [−2.96,−0.20], P = 0.03, I 2 = 0%), systolic blood pressure (MD 13.15 mmHg, 95% CI [−22.18, −4.12], P = 0.004, I 2 = 0%) and diastolic blood pressure (MD −7.38 mmHg, 95% CI [−13.04, −1.72], P = 0.01, I 2 = 0%). Changes in C-reactive protein and lipid parameters were similar in the two groups. Conclusion: Current data do not support chia seeds’ glucose-lowering efficacy in patients with T2DM.

Blood glucose control in acute stroke patients under total energy restriction with different carbohydrate intake and SGLT2 inhibitors availability: a retrospective cohort study

Hyperglycemia in acute stroke patients worsens neurological outcomes. However, effective and safe management during the acute stage has not been established. Therefore, we aimed to compare the effect of medications and nutrition therapy on blood glucose control in three cohorts with different carbohydrate content and availability of sodium-glucose cotransporter 2 inhibitors (SGLT2is) to identify the current optimal treatment for acute-stage hyperglycemia. We retrospectively studied patients with acute stroke admitted to our hospital between 2011 and 2019. We divided the study period into three periods as follows: traditional (Td, 2011–2013), transition (Ts, 2013–2014), and novel (N, 2014–2019). To evaluate glucose-lowering efficacy and safety, we included conscious patients with glycated hemoglobin A1c ≥6.5%, blood glucose levels ≥11.1 mmol/L, normal renal function at admission, oral diet and medications, and fasting blood glucose (FBG) test on day 7. We performed total energy restriction (TER) in each period with different carbohydrate contents: 60% in Td, 40% in Ts, and N. The attending physicians chose glucose-lowering medications. SGLT2is were available in the N period only. Our target FBG was &lt;7 mmol/L by day 7. The 26, 22 and 36 patients were enrolled in the Td, Ts and N periods. The blood glucose levels significantly decreased by day 7 in all periods. The target FBG was achieved in 30.8% of Td patients, 31.8% of Ts patients, and 72.2% of N patients. The N period had the highest population of achieving the target FBG. The 40%-carbohydrate diet based on TER plus SGLT2is was the most effective way to lower blood glucose levels. The N period had the highest population of positive urine ketones. However, no symptomatic ketoacidosis occurred. A 40%-carbohydrate diet based on TER combined with SGLT2is might be a potentially effective and safe treatment for hyperglycemia in acute stroke-conscious patients.

Personalized glucose-lowering effect of chiglitazar in type 2 diabetes

Chiglitazar (carfloglitazar) is a peroxisome proliferator-activated receptor pan-agonist presenting non-inferior glucose-lowering efficacy with sitagliptin in patients with type 2 diabetes. To delineate the subgroup of patients with greater benefit from chiglitazar, we conducted a machine learning-based post-hoc analysis in two randomized controlled trials. We established a character phenomap based on 13 variables and estimated HbA1c decline to the effects of chiglitazar in reference to sitagliptin. Out of 1,069 patients, 63.3% were found to have greater reduction in HbA1c levels with chiglitazar, while 36.7% showed greater reduction with sitagliptin. This distinction in treatment response was statistically significant between groups (pinteraction<0.001). To identify patients who would gain the most glycemic control benefit from chiglitazar, we developed a machine learning model, ML-PANPPAR, which demonstrated robust performance using sex, BMI, HbA1c, HDL, and fasting insulin. The phenomapping-derived tool successfully identified chiglitazar responders and enabled personalized drug allocation in patients with drug-naïve diabetes.

THU244 Clinical Factors Affecting Dapagliflozin Response For Glycemic Control And Body Weight Reduction: Post-hoc Analysis Of BEYOND Study

Abstract Disclosure: K. Ahn: None. J. Ji Eun: None. J. In-Kyung: None. Background: Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, ameliorates hyperglycemia and obesity by inhibiting renal glucose reabsorption. However, significant heterogeneity exists in glucose-lowering efficacy and the magnitude of the weight loss among patients with type 2 diabetes. Herein, we aimed to evaluate the clinical factors affecting response to dapagliflozin treatment. Methods: We performed a post-hoc analysis of the BEYOND (Effects of Dapagliflozin Compared with Glimepiride on Body Composition in Patients with Type 2 Diabetes Inadequately Controlled with Metformin) randomized, double-blind, parallel-group trial. Patients were randomly assigned (1:1) to receive the addition of either dapagliflozin 10 mg per day or glimepiride 1∼2 mg per day to background metformin therapy for 52 weeks. Changes in HbA1c and body weight from baseline during the observation period were assessed for all patients. Responder to dapagliflozin was defined by &amp;gt;1% reduction in A1c and &amp;gt;3% reduction in body weight at week 52. Then, we classified the total subjects into 4 groups: non-responder of both A1c reduction and body weight reduction, responders of A1c reduction but non-responder of body weight reduction, non-responder of A1c reduction but responders of body weight reduction, and responders of both A1c reduction and body weight reduction. Results: Among 56 patients in a dapagliflozin arm, 55.4% (N = 31) and 57.1% (N = 32) experienced clinical responses as indicated by reductions in HbA1c and in body weight reduction, respectively. Younger age and higher HbA1c level at baseline were significantly associated with a greater HbA1c reduction, and a higher estimated glomerular filtration rate (eGFR) was significantly associated with a greater body weight reduction. However, there was no association between the change in HbA1c and the change in body weight (r = −0.133, P = 0.328). Responders of both A1c reduction and body weight reduction were most common (32.1%), non-responders of A1c reduction but responders of body weight reduction were second-most (25.0%), responders of A1c reduction but non-responders of body weight reduction were 23.2%, and non-responders of both A1c reduction and body weight reduction were 19.6%. Subjects with higher fasting plasma glucose (FPG) and HbA1c in addition to lower eGFR at baseline had a greater reduction in HbA1c, but less reduction in body weight. Conversely, those with lower FPG and HbA1c in addition to higher eGFR at baseline had a greater reduction in body weight, but less reduction in HbA1c level. Conclusion: Patients with type 2 diabetes actually exhibit a heterogeneous response to dapagliflozin treatment. Glucose-lowering efficacy of dapagliflozin was associated with worse baseline glycemic status, and body weight reduction was associated with baseline higher eGFR. Presentation: Thursday, June 15, 2023

Effect of Moringa oleifera Leaf Extract on Glycemic Parameters in Patients with Type 2 Diabetes Mellitus and Prediabetes: A Systematic Review and Meta-analysis

Background: Moringa oleifera leaf (MOL) extract has been used traditionally for treating several diseases, including diabetes mellitus (DM). This study aimed to holistically analyze and summarize the efficacy and safety of MOL extract on glycemic parameters in patients with type 2 DM (T2DM) and prediabetes. Materials and Methods: Electronic databases were searched for randomized controlled trials (RCTs) and nonrandomized trials involving patients with T2DM or prediabetes receiving MOL extract in the intervention arm and placebo (or no MOL extract) in the control arm. The primary outcome was the changes in glycemic parameters, for example, hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2-h postprandial plasma glucose (2-h PPG), from the baseline at the end of the trial. Results: From 86 initially screened articles, data from 5 studies (3 RCTs and 2 nonrandomized trials) involving 260 subjects were analyzed. Subjects in the MOL extract group had similar reductions in HbA1c (mean difference [MD] −0.11%, 95% confidence interval [CI] [ −0.37, 0.14], P = 0.39, I 2 = 24% [not important heterogeneity], very low certainty of evidence) and FPG (MD −0.63 mmol/L, 95% CI [−1.89, 0.64], P = 0.33, I 2 = 94% [high heterogeneity], very low certainty of evidence) than the control group although reductions in 2-h PPG were greater in the MOL extract group (MD −3.46 mmol/L, 95% CI [−4.96, −2.16], P &lt; 0.00001, I 2 = 0% [not important heterogeneity], very low certainty of evidence). Subjects in the MOL extract group achieved greater systolic and diastolic blood pressure reductions than the control group. No hypoglycemic events were reported in either group. Conclusion: Current preliminary data do not support MOL extract’s glucose-lowering efficacy in patients with T2DM and prediabetes.

Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study

AimsCompare the efficacy and safety of sitagliptin, dapagliflozin, and lobeglitazone in patients with uncontrolled type 2 diabetes, despite metformin and sulfonylurea therapy. MethodsThe study randomized patients into three groups, receiving sitagliptin 100 mg, dapagliflozin 10 mg, or lobeglitazone 0.5 mg daily (n = 26 each) and monitored changes in biochemical parameters and body composition for 24 months. The primary efficacy endpoint was changes in HbA1c at 24 months. ResultsThe mean change in HbA1c in the sitagliptin, dapagliflozin, and lobeglitazone groups was –0.81 ± 0.21%, –1.05 ± 0.70%, and –1.08 ± 0.98%, after 24 months. Dapagliflozin treatment significantly lowered systolic blood pressure by 5.5 mmHg and alanine aminotransferase levels. Dapagliflozin and lobeglitazone treatment significantly reduced proteinuria and insulin resistance. Dapagliflozin decreased whole body fat percentage by 1.2%, whereas sitagliptin and lobeglitazone increased it by 1.1% and 1.8%, respectively. Whole body muscle percentage increased in the dapagliflozin group and decreased in the lobeglitazone group. The safety profiles of the three treatments were comparable. ConclusionsAll three drugs displayed good glucose-lowering efficacy and comparable safety profiles. However, dapagliflozin therapy produced favorable changes in body composition. Dapagliflozin may be a suitable adjunct therapy for patients with type 2 diabetes seeking to improve their body composition.

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Metformin and sitagliptin fixed combination as the optimal choice in solving current problems in the type 2 diabetes mellitus treatment

The complex pathogenesis of type 2 diabetes mellitus (DM) is the basis for providing the therapeutic treatment for various disorders, which ensures a better glucose-lowering potential and maintenance of glycemic control as the disease progresses. A key reason for poor glycemic control is clinical inertia, which can be overcome by using antidiabetic fixed-dose combinations (FC). Their use improves glycemic control, as the multidirectional action of the combination components on the pathogenetic mechanisms of type 2 diabetes leads to increased pharmacological effects. The PK of metformin and sitagliptin is preferable in terms of glucose-lowering efficacy, safety and clinical benefits. The mechanism of action of metformin is not associated with the stimulation of insulin secretion by β-cells, but results from the drug’s effect on insulin sensitivity at the level of the liver, muscle and adipose tissue, although the effect on hepatic glucose production is the prevailing one. The mechanism of action of sitagliptin, a highly selective inhibitor of dipeptidyl peptidase-4, is additional to the basic pharmacological effects of metformin, which are caused by several mechanisms not associated with stimulation of insulin secretion by β-cells. The simultaneous use of sitagliptin and metformin has additive effects on the increase of glucagon-like peptide-1 levels. This action is implemented through various mechanisms, while metformin increases the release, and sitagliptin inhibits the active degradation of glucagon-like peptide-1. The article emphasizes the importance of rational combinations of glucose-lowering drugs, the need for a personalized approach to the choice of medicines. The current possibilities of sugar-reducing therapy, the issues of efficacy, safety and benefits of PK of metformin and sitagliptin are discussed using modern evidence-based data.