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In the present research work a sequence of substituted quinoline based thiazolidinedione moieties (12a–h) were designed and synthesized as potential antidiabetic agents. Pancreatic α‐amylase (PAA) and intestinal α‐glucosidase (IAG) enzymes were considered as potential targets for effective treatment of diabetes. The potential of all compounds (12a–h) was assessed in vitro against PAA and IAG using acarbose as standard. The results suggested that compound 12h has shown superior PAA and IAG inhibitory activity with respective to standard (IC50 = 4.683 ± 0.06 µM and 2.456 ± 0.07 µM). Furthermore, using computational (in silico) studies like AutoDock and Desmond, predicted the significant binding interactions responsible for the activity of all compounds (12a–h) at the active site of enzymes, while SwissADME and Osiris property explorer tools computed in silico drug likeliness and toxicity properties. The RMSD, RMSF, Rg and protein ligand contacts, confirmed the stable binding of compound 12h and 12g with the both PAA and IAG proteins. The in silico results confirmed the 12h molecule as a superior drug with high binding affinity and good drug likeness against PAA and IAG, confirming in vitro results. We also studied antioxidant activity (AOA) of all synthesized compounds and results confined that the compound 12h has good antioxidant potential (IC50 = 5.04 ± 0.054 µM) among all other compounds. In conclusion, in vitro, in silico and antioxidant studies revealed 12h compound was found to be potential compound. [ABSTRACT FROM AUTHOR]

Aims: While randomized controlled trials data on the long‐term effect of glucose‐lowering drugs (GLDs) on liver‐related outcomes are lacking, population‐based studies have evaluated the associations of GLDs with liver‐related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population‐based studies evaluating the effects of GLDs on liver‐related outcomes in people with T2D. Methods: PubMed, Web of Science, and Embase databases were systematically searched for population‐based studies testing the associations of GLDs with liver‐related outcomes in individuals with T2D and no liver disease other than non‐alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP‐1 RAs and dipeptidyl peptidase‐4 inhibitors (DPP4Is). Results: Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow‐up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver‐related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP‐1 RAs demonstrated a significant association with reduced liver‐related mortality. Conclusions: Observational data from population‐based studies suggest that GLDs such as SGLT2is are associated with beneficial long‐term liver‐related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long‐term follow‐up, are needed to confirm these findings. Registration Number: PROSPERO CRD442024536872. [ABSTRACT FROM AUTHOR]

AbstractObjectiveData SourcesStudy SelectionsResultsConclusionThis review aims to present existing evidence on the impact of pioglitazone, a thiazolidinedione class anti-diabetic drug, on asthma control and lung function, providing a comprehensive understanding of its potential as a treatment for asthma.The review draws upon data from preclinical animal studies and clinical trials investigating the effects of pioglitazone on asthma, focusing on its role in reducing airway inflammation, hyperreactivity, and remodeling, and its impact on pulmonary function.Relevant studies were selected based on their examination of pioglitazone’s therapeutic effects in asthma, including both animal models and clinical trials involving human asthma patients.Animal studies have suggested that pioglitazone could alleviate inflammation, airway hyperreactivity, and airway remodeling, thereby improving pulmonary function in asthma. However, clinical trials have not demonstrated significant therapeutic benefits, with minimal improvements observed in asthma control and lung function, and the presence of notable side effects.Despite promising preclinical data, the efficacy of pioglitazone in treating human asthma remains unproven, with safety concerns and limited clinical benefits observed in trials. Further research is needed to assess the safety and effectiveness of pioglitazone in asthma treatment and to explore its impact on other inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Background: This study assessed the efficacy and safety of triple therapy with pioglitazone 15 mg add-on versus placebo in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and dapagliflozin. Methods: In this multicenter, double-blind, randomized, phase 3 study, patients with T2DM with an inadequate response to treatment with metformin (≥1,000 mg/day) plus dapagliflozin (10 mg/day) were randomized to receive additional pioglitazone 15 mg/day (n=125) or placebo (n=125) for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin (HbA1c) levels from baseline to week 24 (ClinicalTrials.gov identifier: NCT05101135). Results: At week 24, the adjusted mean change from baseline in HbA1c level compared with placebo was significantly greater with pioglitazone treatment (--0.47%; 95% confidence interval, -0.61 to -0.33; P<0.0001). A greater proportion of patients achieved HbA1c <7% or <6.5% at week 24 with pioglitazone compared to placebo as add-on to 10 mg dapagliflozin and metformin (56.8% vs. 28% for HbA1c <7%, and 23.2% vs. 9.6% for HbA1c <6.5%; P<0.0001 for all). The addition of pioglitazone also significantly improved triglyceride, high-density lipoprotein cholesterol levels, and homeostatic model assessment of insulin resistance levels, while placebo did not. The incidence of treatment-emergent adverse events was similar between the groups, and the incidence of fluid retention-related side effects by pioglitazone was low (1.5%). Conclusion: Triple therapy with the addition of 15 mg/day of pioglitazone to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with T2DM inadequately controlled with dapagliflozin plus metformin. [ABSTRACT FROM AUTHOR]

The instrumental analytical methods that have been developed and utilized for the determination of thiazolidinedione in bulk medications, formulations and biological fluids have been reviewed after an in-depth analysis of the literature published in a variety of analytical and pharmaceutical chemistry-related journals. The approaches covered by this research, which covers the years 2001–2022, include complex methods for analysis, chromatographic techniques and spectrometric analytical procedures. The mobile phase, flow rate, sample matrix, wavelength and other factors identified in the literature were just a few of the parameters used to evaluate thiazolidinediones. The present review focuses on the published analytical techniques for thiazolidinedione analysis that have been previously identified in the literature. The specified outcomes followed extensive learning, and the most recent advances in analytical methods for the identification of pioglitazone, pioglitazone HCl, rosiglitazone, rosiglitazone maleate and lobeglitazone were reviewed. Additionally, this article briefly discusses features of analytical discovery on thiazolidinediones, which will enable readers to access all discoveries in one place with precise outcomes. [ABSTRACT FROM AUTHOR]

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed. [ABSTRACT FROM AUTHOR]

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 μg/ml) and 7a (38.15 μg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 μg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 μg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells. [ABSTRACT FROM AUTHOR]

Dementia risk is substantially elevated in patients with diabetes. However, evidence on dementia risk associated with various antidiabetic regimens is still limited. This study aims to comprehensively investigate the risk of dementia and Alzheimer's disease (AD) associated with various antidiabetic classes. Cochrane Central Register of Controlled Trials, Embase, MEDLINE (PubMed), and Scopus were searched from inception to March 2024 (PROSPERO CRD 42022365927). Observational studies investigating dementia and AD incidences after antidiabetic initiation were identified. Bayesian network meta-analysis was performed to determine dementia and AD risks associated with antidiabetics. Preferred Reporting Items for Systematic Reviews-Network Meta-Analyses (PRISMA-NMA) guidelines were followed. Statistical analysis was performed and updated in November 2023 and March 2024, respectively. A total of 1,565,245 patients from 16 studies were included. Dementia and AD risks were significantly lower with metformin and sodium glucose co-transporter-2 inhibitors (SGLT2i). Metformin displayed the lowest risk of dementia across diverse antidiabetics, whereas α-glucosidase inhibitors demonstrated the highest risk. SGLT2i exhibited the lowest dementia risk across second-line antidiabetics. Dementia risk was significantly higher with dipeptidyl peptidase-4 inhibitor (DPP4i), metformin, sulfonylureas, and thiazolidinediones (TZD) compared to SGLT2i in the elderly (≥75 years). Dementia risk associated with metformin was substantially lower, regardless of diabetic complication status or baseline A1C. Metformin and SGLT2i demonstrated lower dementia risk than other antidiabetic classes. Patient-specific factors may affect this relationship and cautious interpretation is warranted as metformin is typically initiated at an earlier stage with fewer complications. Hence, further large-scaled clinical trials are required. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is associated with an increased risk of fractures due to deterioration of bone quality, which can be referred to as "diabetic osteodystrophy." Furthermore, the risk of fracture is increased in DM, even if bone mineral density is normal or high and is associated with increased morbidity if a fracture develops. In addition to the pathophysiological mechanisms of DM, diabetesrelated complications and drugs used in the treatment of DM may also affect bone health. Moreover, the increased risk of falling due to microvascular complications, hypoglycemia, and postural hypotension also contributes to the development of fractures. Individuals with DM should be screened for osteoporosis with recommendations similar to those of the general population. When diagnosing osteoporosis and deciding on treatment, it should be kept in mind that DM may be an important risk factor, and lower threshold values of the T score should be used. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) or a sodium‐glucose cotransporter‐2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta‐analysis, and analysis of a large international real‐world database. Methods: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP‐1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane‐endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity‐score‐matched individuals who were treated for at least 1 year with pioglitazone and a GLP‐1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP‐1RA and SGLT2 inhibitor monotherapy. Outcomes were all‐cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. Results: The average follow‐up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP‐1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences −1% (95% confidence interval [CI] −1.27, −0.74) and −1.19 kg (95% CI −1.80, −0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference − 1.56 mmHg (95% CI −4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07–1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences −0.48% (95% CI −0.67, −0.28), −2.3 kg (95% CI −2.72, −1.88) and −2.4 mmHg (95% CI −4.1, −0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30–10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real‐world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38–0.65; p < 0.001). Conclusion: Both our systematic review/meta‐analysis and the real‐world dataset show that combination of pioglitazone with either GLP‐1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy. [ABSTRACT FROM AUTHOR]

Metformin, one of the most frequently used oral glucose-lowering drugs (GLDs), is associated with the occurrence of gastrointestinal (GI) adverse events in approximately 20% of users. These unwanted actions result in non-compliance or even discontinuation of metformin therapy. The aim of the presented meta-analysis was to determine whether adding a drug from the group of sulfonylureas, glitazones, DPP-IV inhibitors, or probiotics to metformin monotherapy may affect the risk of GI side effects. The material for this meta-analysis comprised data from 26 randomized controlled clinical trials (RCTs) published in English. This meta-analysis included 41,048 patients. The PubMed, Cochrane Library, and Clinical Trials databases were thoroughly searched to find relevant RCTs. The Population, Intervention, Comparison, Outcomes, and Study Type (PICOT) structure was used to formulate study selection criteria and the research question. Cochrane Review Manager Software 5.4 was used to carry out analysis of collected data. The results were presented as relative risk (RR) and 95% confidence interval (95% CI) for each group, and p < 0.05 was considered as statistically significant. As expected from clinical practice, metformin was associated with a markedly increased risk of abdominal pain, nausea, and vomiting compared to placebo. In comparison to other GLDs, taking metformin was related to an elevated risk of diarrhea and abdominal pain and to a lowered risk of vomiting and bloating. In turn, adding other GLDs to metformin treatment was associated with an elevated risk of nausea and vomiting than treatment with metformin in monotherapy. However, adding probiotics to metformin therapy was related to a decreased risk of diarrhea, bloating, and constipation. The obtained results demonstrate that the combination of metformin with other GLDs may elevate the risk of nausea and vomiting, whereas combination with probiotics decreases the risk of diarrhea, bloating, and constipation. Thus, the results of our meta-analysis suggest that probiotics may reduce the risk of some GI side effects in people with type 2 diabetes mellitus (T2DM) who started treatment with metformin. [ABSTRACT FROM AUTHOR]

Background: Due to increasing life expectancy, almost half of people with type 2 diabetes are aged 65 years or over worldwide. When metformin alone does not control blood sugar, the choice of which second-line therapy to prescribe next is not clear from currently available evidence. The existence of frailty and comorbidities in older adults further increases the complexity of medical decision-making. As only a relatively small proportion of trials report results separately for older adults, the relative efficacy and safety of second-line therapies in older adults with type 2 diabetes mellitus are unknown and require further investigation. This individual participant data (IPD) network meta-analysis evaluates the relative efficacy and safety of second-line therapies on their own or in combination in older adults with type 2 diabetes mellitus. Methods: All relevant published and unpublished trials will be identified. Studies published prior to 2015 will be identified from two previous comprehensive aggregate data network meta-analyses. Searches will be conducted in CENTRAL, MEDLINE, and EMBASE from 1st January 2015 onwards, and in clinicaltrials.gov from inception. Randomised controlled trials with at least 100 estimated older adults (≥ 65 years) receiving at least 24 weeks of intervention that assess the effects of glucose-lowering drugs on mortality, glycemia, vascular and other comorbidities outcomes, and quality of life will be eligible. The screening and data extraction process will be conducted independently by two researchers. The quality of studies will be assessed using the Cochrane risk of bias tool 2. Anonymised IPD of all eligible trials will be requested via clinical trial portals or by contacting the principal investigators or sponsors. Received data will be reanalysed where necessary to standardise outcome metrics. Network meta-analyses will be performed to determine the relative effectiveness of therapies. Discussion: With the increasing number of older adults with type 2 diabetes worldwide, an IPD network meta-analysis using data from all eligible trials will provide new insights into the optimal choices of second-line antidiabetic drugs to improve patient management and reduce unnecessary adverse events and the subsequent risk of comorbidities in older adults. Systematic review registration: PROSPERO CRD42021272686. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to assess the efficacy of incorporating a combination of SGLT2 inhibitors (SGLT2i) and thiazolidinediones (TZD) into the current triple therapy regimen (metformin+sulphonylurea+DPP4 inhibitors) for individuals with diabetes. The primary objective was to compare the outcomes of the active group, which received the supplementary treatment, with the control group, which followed the standard triple regimen without additional medications. Methods: Participants were allocated into two groups: the active group and the control group. The active group received SGLT2i and TZD in addition to their existing triple therapy, while the control group continued with the standard triple regimen. Various clinical parameters including blood pressure, glycemic control, and lipid profiles were assessed and compared between the two groups. Results: The active group demonstrated significant improvements in multiple clinical parameters. Notably, there were reductions in systolic blood pressure, diastolic blood pressure, HbA1c levels, and total cholesterol levels. In contrast, the control group showed more modest improvements in HbA1c levels and total cholesterol levels, but not as significant as those observed in the active group. The active group exhibited superior outcomes in terms of glycemic control, blood pressure control, and lipid profiles compared to the control group. Conclusion: The incorporation of SGLT2i and TZD into the preexisting triple therapy regimen resulted in notable enhancements in glycemic regulation, blood pressure, and lipid profiles in individuals with diabetes. These findings support the potential benefits of adding SGLT2i and TZD as adjunct therapies in diabetes management. However, further research with larger sample sizes and longer follow-up periods is needed to validate these findings and evaluate the long-term impacts and safety characteristics of this combined treatment approach. [ABSTRACT FROM AUTHOR]

Investigation pertaining to the design and synthesis of therapeutic drugs against lung cancer remains in high demand, considering the high fatality rate associated with this disease. Herein, a carboxyl and ester functionalization at the N3 position of the TZD (thiazolidine‐2,4‐dione) moiety in an indole‐TZD conjugate was envisaged and evaluated as a potential anticancer drug. Although TIA (thiazoindole acid) did not demonstrate significant effectiveness against the A549 human lung adenocarcinoma cell line, the ester analog TIE (thiazoindole ester) showed high cytotoxic potential against the A549 cell line in their monolayer and spheroid form. Further, preliminary mechanistic investigations, such as cell viability studies and nuclear staining, revealed typical apoptotic features, including chromatin condensation, cellular shrinkage, and the formation of horseshoe‐shaped nuclei. In addition, the TIE compound can disrupt the F‐actin protein, thereby decreasing cell migration. Moreover, the cell cycle analysis revealed a notable halt in the G2/M phase. Further docking studies elucidate the interaction between TIE and the (peroxisome proliferator‐activated receptor) PPAR‐γ receptor. In summary, the findings of our investigation suggest that TIE compounds possess considerable efficacy as an anti‐proliferative agent and hold promise for therapeutic applications in lung cancer treatment. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is known as the first non-communicable global epidemic. It is estimated that 537 million people have DM, but the condition has been properly diagnosed in less than half of these patients. Despite numerous preventive measures, the number of DM cases is steadily increasing. The state of chronic hyperglycaemia in the body leads to numerous complications, including diabetic cardiomyopathy (DCM). A number of pathophysiological mechanisms are behind the development and progression of cardiomyopathy, including increased oxidative stress, chronic inflammation, increased synthesis of advanced glycation products and overexpression of the biosynthetic pathway of certain compounds, such as hexosamine. There is extensive research on the treatment of DCM, and there are a number of therapies that can stop the development of this complication. Among the compounds used to treat DCM are antiglycaemic drugs, hypoglycaemic drugs and drugs used to treat myocardial failure. An important element in combating DCM that should be kept in mind is a healthy lifestyle—a well-balanced diet and physical activity. There is also a group of compounds—including coenzyme Q10, antioxidants and modulators of signalling pathways and inflammatory processes, among others—that are being researched continuously, and their introduction into routine therapies is likely to result in greater control and more effective treatment of DM in the future. This paper summarises the latest recommendations for lifestyle and pharmacological treatment of cardiomyopathy in patients with DM. [ABSTRACT FROM AUTHOR]

Background: The metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties can potentially be exploited for therapeutic intervention. In this context, we have developed troglitazone derivatives to treat hormone-sensitive and triple-negative breast cancers, which currently lack therapeutic targets, have an aggressive phenotype, and often have a worse prognosis than other subtypes. Here, we studied the metabolic impact of the EP13 compound, a desulfured derivative of Δ2-troglitazone that we synthetized and is more potent than its parent compounds. Methods: EP13 was tested on two triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T, and on the luminal cell line MCF-7. The oxygen consumption rate (OCR) of the treated cell lines, Hs578T mammospheres and isolated mitochondria was measured using the XFe24 Seahorse analyser. ROS production was quantified using the MitoSOX fluorescent probe. Glycolytic activity was evaluated through measurement of the extracellular acidification rate (ECAR), glucose consumption and lactate production in extracellular medium. The synergistic effect of EP13 with glycolysis inhibitors (oxamate and 2-deoxyglucose) on cell cytotoxicity was established using the Chou-Talalay method. Results: After exposure to EP13, we observed a decrease in the mitochondrial oxygen consumption rate in MCF7, MDA-MB-231 and Hs578T cells. EP13 also modified the maximal OCR of Hs578T spheroids. EP13 reduced the OCR through inhibition of respiratory chain complex I. After 24 h, ATP levels in EP13-treated cells were not altered compared with those in untreated cells, suggesting compensation by glycolysis activity, as shown by the increase in ECAR, the glucose consumption and lactate production. Finally, we performed co-treatments with EP13 and glycolysis inhibitors (oxamate and 2-DG) and observed that EP13 potentiated their cytotoxic effects. Conclusion: This study demonstrates that EP13 inhibits OXPHOS in breast cancer cells and potentiates the effect of glycolysis inhibitors. [ABSTRACT FROM AUTHOR]

Background and Aims: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. Methods: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. Results: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35–2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19–4.82) and silymarin (OR 4.54, 95% CI 1.18–17.43) in traditional meta-analysis. Conclusions: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo. [ABSTRACT FROM AUTHOR]

Introduction: Thiazolidinediones (TZDs), represented by pioglitazone and rosiglitazone, are a class of cost-effective oral antidiabetic agents posing a marginal hypoglycaemia risk. Nevertheless, observations of heart failure have hindered the clinical use of both therapies. Objective: Since the mechanism of TZD-induced heart failure remains largely uncharacterised, this study aimed to explore the as-yet-unidentified mechanisms underpinning TZD cardiotoxicity using a toxicometabolomics approach. Methods: The present investigation included an untargeted liquid chromatography–mass spectrometry-based toxicometabolomics pipeline, followed by multivariate statistics and pathway analyses to elucidate the mechanism(s)of TZD-induced cardiotoxicity using AC16 human cardiomyocytes as a model, and to identify the prognostic features associated with such effects. Results: Acute administration of either TZD agent resulted in a significant modulation in carnitine content, reflecting potential disruption of the mitochondrial carnitine shuttle. Furthermore, perturbations were noted in purine metabolism and amino acid fingerprints, strongly conveying aberrations in cardiac energetics associated with TZD usage. Analysis of our findings also highlighted alterations in polyamine (spermine and spermidine) and amino acid (L-tyrosine and valine) metabolism, known modulators of cardiac hypertrophy, suggesting a potential link to TZD cardiotoxicity that necessitates further research. In addition, this comprehensive study identified two groupings – (i) valine and creatine, and (ii) L-tryptophan and L-methionine – that were significantly enriched in the above-mentioned mechanisms, emerging as potential fingerprint biomarkers for pioglitazone and rosiglitazone cardiotoxicity, respectively. Conclusion: These findings demonstrate the utility of toxicometabolomics in elaborating on mechanisms of drug toxicity and identifying potential biomarkers, thus encouraging its application in the toxicological sciences. (245 words) [ABSTRACT FROM AUTHOR]

Background. Metformin is commonly prescribed to treat polycystic ovary syndrome (PCOS) patients, but in some cases, it may not be effective even at high doses or may cause intolerable side effects. Therefore, recent studies have examined the impact of combining metformin with other antidiabetic medications. Methods. A systematic search was performed in Scopus, PubMed, Web of Science, and Embase up to 30 June 2023. All interventional studies that assessed the efficacy of different antidiabetic agents were included. Results. Among the 3488 records found in the primary search, 16 papers were included. Our study showed that dipeptidyl peptidase-4 inhibitors (DPP4i) had the most significant impact on glycemic profile, while thiazolidinediones (TZDs) had the most influence on lipid levels. However, it was observed that patients taking only metformin experienced a greater increase in high-density lipoprotein cholesterol (HDL-C) levels. Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively modified various anthropometric measurements, such as weight, body mass index, waist circumference, and waist-to-hip ratio. The effects of different antidiabetic drugs on hormone levels were inconclusive, although testosterone levels were more affected by GLP1RA, sodium-glucose cotransporter-2 inhibitors (SGLT2i), and TZDs. None of the combined therapies showed a significant change in blood pressure. Conclusion. Since PCOS is a metabolic disorder, choosing the best combination of antidiabetic drugs in the clinical course of PCOS patients will be very important. Today, it seems that we need a new metabolic approach for better treatment of the metabolic aspects of these patients. [ABSTRACT FROM AUTHOR]

Summary: Visceral adiposity is a strong predictor of cardiometabolic risk. Thiazolidinediones (TZDs) are associated with a shift in fat redistribution from visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT). We aimed to compare the effects of TZD and other interventions on fat remodeling in adults in randomized controlled trials. Among the 1331 retrieved studies, 39 trials with 1765 participants were included in the meta‐analysis. The standardized mean difference in VAT change was not significantly different between TZD and comparators across the overall studies. Intriguingly, TZD treatment resulted in significant decreases in VAT compared with placebo and sulfonylureas (p < 0.05), although recombinant human growth hormone was superior to TZD regarding VAT reduction (p < 0.05). Data from 216 participants showed TZD leading to a greater reduction in liver fat percentage than comparators (p < 0.05). Compared with the controls, TZD significantly increased SAT, total body fat, weight, waist circumference, and body mass index (p < 0.05). However, TZD pronouncedly improved glucose control, insulin resistance, adiponectin, and lipid profile (p < 0.05). TZD provides a favorable effect on fat redistribution and benefits insulin sensitivity, suggesting a potentially valuable approach in cardiometabolic risk management. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a significant burden on the healthcare system with unique challenges in the value-based payment system. Although there are a variety of antidiabetic medications with clinical benefit, access to newer treatments are often limited in value-based settings due to cost, availability, and insurance coverage. Thiazolidinediones (TZDs) are glucose-lowering medications indicated for the management of type 2 diabetes that are often overlooked in therapy. These insulin sensitizing medications lower blood glucose and are less costly than other antidiabetic agents. Although concerns regarding safety issues and side effects of TZDs has limited their use in current practice, evidence-based guidelines still recommend pioglitazone in select patients and its use remains important. Pioglitazone should be prioritized in patients with a history of stroke or who have high risk of stroke and atherosclerotic cardiovascular disease (ASCVD), or patients on antidiabetic therapy who require additional A1c lowering. Pioglitazone should be avoided in patients with heart failure, edema, obesity, low bone mineral density, and a history of bladder cancer. This article discusses advantages and disadvantages of pioglitazone therapy, selecting patients who may be candidates for pioglitazone therapy, and considerations for prescribing in value-based settings. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) offer cardiovascular benefits, whereas thiazolidinediones (TZDs) and sulfonylureas (SUs) increase cardiovascular risk. The objective of this study was to describe the use of SGLT-2is, GLP-1RAs, TZDs, and SUs before and after a heart failure (HF)-related hospitalization in nursing home (NH) residents with type 2 diabetes (T2D). This was a cohort study using a 20% sample of Medicare claims linked with Minimum Data Set resident assessments. The study population was long-stay NH residents with T2D and an HF-related hospitalization between January 1, 2013, and August 31, 2018. For individuals with multiple HF hospitalizations, 1 hospitalization was randomly selected. We ascertained diabetes medications using Medicare Part D claims during the 120 days before and after hospital discharge (or skilled nursing facility discharge, where applicable). We calculated (1) the proportion of study participants who received a medication class of interest during pre- and posthospitalization periods; (2) the proportion of continuous users; and (3) the proportion of posthospitalization users who were new users. A total of 12,990 NH residents with T2D and an HF-related hospitalization were included (mean age 78 years, 66% female, 19% Black). Before hospitalization, 1.5% received TZDs, 14.1% received SUs, 1.2% received GLP-1RAs, and 0.3% received SGLT-2is. Among prehospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 49%, 62%, 60%, and 40% continued the medications, respectively. Among posthospitalization users of TZDs, SUs, GLP-1RAs, and SGLT-2is, 37%, 10%, 28%, and 11%, respectively, were new users. Among NH residents with hospitalized HF, GLP-1RAs and SGLT-2is were seldom used. TZDs and SUs were still used by many residents with T2D after HF hospitalizations. Barriers may exist in the use of newer diabetes medications to prevent heart failure in NH residents with T2D, which warrants further studies in older adults with multimorbidity. [ABSTRACT FROM AUTHOR]

Lipodystrophies involve the loss of subcutaneous adipose tissue, resulting in severe metabolic issues such as insulin resistance and challenging diabetes management. This case series aims to assess bromocriptine treatment response in lipodystrophy patients, offering insights into its antidiabetic effects. This retrospective analysis focused on four female lipodystrophy patients with poor glycemic control who were undergoing bromocriptine treatment. Statistical analysis used nonparametric tests. Metabolic parameters were assessed before and 3 months post-bromocriptine treatment, revealing a modest reduction in median daily insulin dose and decreased hemoglobin A1c and fasting glucose levels. Body weight remained constant, while triglyceride levels increased. Dopamine receptor expression in pancreatic ß-cells and adipocytes suggests a direct impact on glucose homeostasis. While this case series hints at bromocriptine's positive influence on glycemic control and insulin requirements in lipodystrophy patients, larger studies are essential for establishing efficacy and safety. [ABSTRACT FROM AUTHOR]

Aims: The objective of this umbrella review and meta‐analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. Materials and Methods: We conducted a systematic umbrella review on diabetes and its treatment, and a meta‐analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta‐analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random‐effects meta‐analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon‐like peptide‐1 receptor agonists (GLP1RAs) and sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) with risk of dementia from cohort/case‐control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle‐Ottawa Scale. Results: We included 100 reviews and 27 cohort/case‐control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase‐4 inhibitors, α‐glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. Conclusions: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, a metabolic disorder, arises from insufficient insulin levels or increased insulin resistance. An alternative approach to address this pathogenesis involves targeting PPAR- γ , which activates glucose homeostasis and improves peripheral glucose utilization. In this study, we aimed to investigate the designed 2-thioxothiazolidin-4-one derivatives (T1-25) and assess their potential as PPAR- γ regulators by an in silico approach. Physicochemical properties and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles were evaluated. Docking studies were performed using Schrödinger software, with the protein target being PPAR- γ (PDB ID: 2ZNO). Additionally, MD simulation studies were conducted, and the key interactions in the protein-ligand complexes were identified. The results demonstrate the drug-likeness of compounds T11, T24 and T25, with docking scores of –7.953 kcal/mol, –7.973 kcal/mol and –8.212 kcal/mol, respectively, and exhibit significant activity against PPAR- γ agonist and compared with the standard drug Pioglitazone (–7.367 kcal/mol). The density functional calculations were also performed to determine the geometrical properties, thermal parameters, chemical reactivity descriptors and molecular electrostatic potential of the compounds using the B3LYP functional and 6-31G++ basis sets. The energy difference between the highest occupied molecular orbitals and lowest unoccupied molecular orbitals for all the investigated compounds is in the range of 2.8–3.4 eV which allows for easy transfer of electrons and reactivity. Further research and development of these designed compounds could contribute to the advancement of effective antidiabetic treatments. Fifteen novel derivatives of 2-Thioxo-4-thiazolidinone were designed using computational techniques. These compounds were assessed for their interaction with Peroxisome Proliferator-Activated Receptor Gamma (PPAR- γ). The results demonstrated that these compounds exhibited notably strong binding affinities to PPAR- γ , suggesting their potential as effective ligands. Importantly, all of the designed molecules conformed to the established criteria commonly used to assess drug-likeness, enhancing their promise for further development in drug discovery efforts. [ABSTRACT FROM AUTHOR]

Thiazolidinediones (TZD) are synthetic molecules that have a range of biological effects, including antifibrotic and anti-inflammatory, and they may represent a promising therapeutic strategy for systemic sclerosis (SSc). The aim of this study was to investigate the immunomodulatory and antifibrotic properties of LPSF/GQ-16, a TZD derivative, in peripheral blood mononuclear cells (PBMC) from SSc patients and in a murine model of SSc HOCl-induced. The PBMC of 20 SSc patients were stimulated with phytohemagglutinin (PHA) and treated with LPSF/GQ-16 for 48 h, later cytokines in the culture supernatants were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA). Experimental SSc was induced by intradermal injections of hypochlorous acid (HOCl) for 6 weeks. HOCl-induced SSc mice received daily treatment with LPSF/GQ-16 (30 mg/kg) through intraperitoneal injections during the same period. Immunological parameters were evaluated by flow cytometry and ELISA, and dermal and pulmonary fibrosis were evaluated by RT-qPCR, hydroxyproline dosage and histopathological analysis. In PBMC cultures, it was possible to observe that LPSF/GQ-16 modulated the secretion of cytokines IL-2 (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.001), IL-17A (p = 0.006), TNF (p < 0.001) and IFN-γ (p < 0.001). In addition, treatment with LPSF/GQ-16 in HOCl-induced SSc mice promoted a significant reduction in dermal thickening (p < 0.001), in the accumulation of collagen in the skin (p < 0.001), down-regulated the expression of fibrosis markers in the skin (Col1a1, α-Sma and Tgfβ1, p < 0.001 for all) and lungs (Il4 and Il13, p < 0.001 for both), as well as reduced activation of CD4 + T cells (p < 0.001), B cells (p < 0.001) and M2 macrophages (p < 0.001). In conclusion, LPSF/GQ-16 showed immunomodulatory and antifibrotic properties, demonstrating the therapeutic potential of this molecule for SSc. [ABSTRACT FROM AUTHOR]

Objective: Characteristic features of polycystic ovary syndrome (PCOS) include insulin resistance and an increased risk for type 2 diabetes. To promote improved insulin sensitivity, insulin sensitisers have been used in PCOS. However, direct comparisons across these agents are limited. This study compared the effects of metformin, rosiglitazone and pioglitazone in the management of PCOS to inform the 2023 International Evidence‐based PCOS Guideline. Design: Systematic review and meta‐analysis of the literature. Patients: Women with PCOS and treatment with insulin sensitisers. Measurements: Hormonal and clinical outcomes, as well as side effects. Results: Of 1660 publications identified, 13 randomised controlled trials were included. Metformin was superior in lowering weight (mean difference [MD]: −4.39, 95% confidence interval [CI]: −7.69 to −1.08 kg), body mass index (MD: −0.95, 95% CI: −1.41 to −0.49 kg/m2) and testosterone (MD: −0.10, 95% CI: −0.18 to −0.03 nmol/L) versus rosiglitazone, whereas there was no difference when comparing metformin to pioglitazone. Adding rosiglitazone or pioglitazone to metformin did not improve metabolic outcomes. However, rosiglitazone seemed superior to metformin in lowering lipid concentrations. Conclusions: Metformin should remain the first‐line insulin sensitising treatment in adults with PCOS for the prevention and management of weight and metabolic features. The addition of thiazolidinediones appears to offer little benefit. [ABSTRACT FROM AUTHOR]

Simple Summary: Diabetes affects patients with breast cancer. Women with diabetes and the comorbidities related to diabetes tend to receive less aggressive breast cancer treatments primarily because of the potential side effects of the treatment. Managing proper antidiabetic treatment should affect the patient's breast cancer prognosis in patients with both conditions. This review explores the link between diabetes and an elevated risk of breast cancer, highlighting the global prevalence of these conditions. It delves into the impact of antihyperglycemic therapy, including insulin, metformin, and novel groups: incretins and SGLT-2 inhibitors, on the prognosis of breast cancer in diabetic patients. The review also underscores the increased incidence and mortality rates of breast cancer in individuals with diabetes, along with the role of obesity and its connection to the metastasis process in those undergoing antidiabetic treatment. The role of obesity as a confounding variable is confirmed, highlighting the importance of considering obesity during hypoglycemic therapy selection in breast cancer patients. Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs. [ABSTRACT FROM AUTHOR]

Objective: Using non-geriatric type 2 diabetic patients with and without diabetic foot ulcers (DFUs), this study investigated the frequency of poor handgrip strength and examined the association between handgrip strength and diabetic foot disorder. Methods: The study comprised a total of 525 patients with type 2 diabetes who visited the endocrinology outpatient clinic between August 2020 and June 2022; 242 of them had DFUs. Patients were selected according to inclusion and exclusion criteria. Data on medications used, as well as demographic and clinical information, were taken from hospital archives. The severity of ulcers was assessed using the Wagner score. Using a portable digital dynamometer, a test of handgrip strength was conducted. Low handgrip strength was defined as less than 16 kg for females and 27 kg for males. Results: Patients with DFUs exhibited lower handgrip strength, older age, a longer duration of diabetes diagnosis, a lower body mass index, and higher fasting plasma glucose and hemoglobin A1c levels. Comorbidities such as peripheral artery disease and ischemic heart disease were more frequent in patients with DFUs and low handgrip strength. Diabetic foot ulcer frequency was 3.149 times higher among those with poor hand grip strength than those with good strength (odds ratio = 3.149; 95% CI, 2.118-4.672; P < .001). Conclusion: Non-geriatric type 2 diabetes patients with DFUs had a higher frequency of low handgrip strength. Low handgrip strength was independently associated with the presence of DFUs. This study emphasizes the importance of addressing low handgrip strength as a potential risk factor in managing diabetic foot disease in non-geriatric type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

A simple and sensitive dual-emission ratiometric fluorescent probe was developed using zeolitic imidazolate framework 8 (ZIF8) and L-ascorbic acid Au-doped dopamine nanoparticles (ZIF8/L-ASC-AuNP/DA NP) for the determination of pioglitazone (Pio), an oral hypoglycemic agent and insulin sensitizer, in real samples. The prepared system was based on the Pio-enhanced dual-emission intensity of ZIF8/L-ASC-AuNP/DA NP. The potential impact of various parameters on the system's emission intensity was tested. According to the findings, there is a strong linear correlation between the system's turn-on fluorescence intensity and Pio concentrations in the range 0.3 nM to 30.0 μM. The obtained value for the limit of detection (LOD) was 0.14 nM. In addition, the intra- and inter-day accuracy of the nanoprobe was studied and the findings revealed satisfactory precision and accuracy of the system. The short-term and freeze-thaw stability of Pio in plasma samples was evaluated and the results indicated the high stability of the developed nanoprobe under the test conditions. Pio was accurately detected in human plasma samples under ideal conditions with analytical recoveries in the range 86.0 − 109.3%. The results showed that the devised probe may be employed as an easy, sensitive, and precise approach for detecting Pio in real samples. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients. [ABSTRACT FROM AUTHOR]

Sulfonylureas (SU) continue to be a vital therapeutic category of oral hypoglycemic agents (OHAs) for the management of type 2 diabetes mellitus (T2DM). Physicians consider modern SU (gliclazide and glimepiride) as "safe and smart" choices for T2DM management. The presence of multiple international guidelines and scarcity of a national guideline may contribute to the challenges faced by few physicians in choosing the right therapeutic strategy. The role of SU in diabetes management is explicit, and the present consensus aims to emphasize the benefits and reposition SU in India. This pragmatic, practical approach aims to define expert recommendations for the physicians to improve caregivers' knowledge of the management of T2DM, leading to superior patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is a known risk factor for Parkinson's disease (PD), but does this risk vary with antidiabetic medications is still unclear. This meta-analysis aims to compile evidence from the literature to assess the risk of idiopathic PD with various oral antidiabetic medications. Methods: Databases PubMed, CENTRAL, Scopus, Web of Science, and Embase were searched till 5th April 2023. Adjusted outcomes were pooled to generate a hazard ratio (HR) on the risk of PD with different antidiabetic medications. Results: Fifteen studies with 2,910,405 diabetic patients were eligible. Pooled analysis failed to show any significant difference in the risk of PD among users of metformin (HR: 1.05 95% CI: 0.91, 1.22 I2 = 81%), glitazones (HR: 0.84 95% CI: 0.68, 1.05 I2 = 91%), glucagon-like peptide-1 agonists (HR: 0.63 95% CI: 0.26, 1.55 I2 = 33%), and sulfonylureas (HR: 1.13 95% CI: 0.96, 1.32 I2 = 76%). However, a meta-analysis of four studies showed that dipeptidyl peptidase-4 inhibitor use was associated with reduced risk of PD in diabetics (HR: 0.69 95% CI: 0.56, 0.86 I2 = 46%). Insufficient data was available on sodium-glucose cotransporter-2 inhibitors, α-glucosidase inhibitors, and glinides. Conclusions: Limited retrospective evidence indicates that DPP4i may reduce the risk of idiopathic PD in diabetics. Metformin, sulfonylureas, glucagon-like peptide-1 agonists, and glitazones were not associated with any change in the risk of PD. Further studies taking into confounding factors and using a common comparator group are needed to strengthen present evidence. [ABSTRACT FROM AUTHOR]

Purpose: The association between non-alcoholic fatty liver disease (NAFLD) and metabolic disorders, especially type-2 diabetes (T2DM), has been proven to be bidirectional. Hypoglycemic agents may be promising treatments for those disorders. However, there is currently no approved hypoglycemic therapy for NAFLD. In this review, we aimed to compare the efficacy and safety of twelve different hypoglycemic treatments in patients with NAFLD and T2DM. Methods: We systematically screened randomized controlled trials (RCTs) published from March 2013 to March 2023 by searching PubMed, Embase, Medline, and Web of Science without any language restriction. We registered this project on the PROSPERO website: https://www.crd.york.ac.uk/PROSPERO/(ID: CRD42023429701). All subsequent analyses were performed under the registered protocol. The mean difference (MD) and 95% confidence interval (95% CI) were adapted to evaluate the effect size of the treatment. The surface under the cumulative sorting curve (SUCRA) was used to rank the efficacy of the included treatments. Results: We included 19 trials involving 1212 patients in total. Insulin plus glucagon-like peptide-1 receptor agonist (GLP1RA) combination therapy was probably the most effective treatment for reducing weight and body mass index (BMI) (SUCRA: 0.93 and 1.00). Thiazolidinediones (TZD) were probably the most effective treatment for reducing glycosylated hemoglobin (HbA1c) and γ-glutamyltranspeptidase (γ-GGT) levels (SUCRA: 0.78 and 0.97). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) had the highest probability of presenting good therapeutic efficacy in reducing triglyceride (TG) levels (SUCRA: 0.72). The most common adverse reactions were gastrointestinal disorders, mainly after the administration of GLP1RA, and mild hypoglycemia, which was closely related to the use of insulin. Conclusion: GLP1RA plus insulin combination therapy, GLP1RA, SGLT2i, and TZD may be the most effective therapeutic methods for patients with NAFLD and T2DM. [ABSTRACT FROM AUTHOR]

Simple Summary: The effects of thiazolidinedione (TZD) on multiple myeloma have not been investigated in humans. The reimbursement database of Taiwan's National Health Insurance was used to select a propensity score-matched 86,999 pairs of TZD users and non-users who had a new-onset type 2 diabetes mellitus from 1999 to 2005. They were followed up from 1 January 2006 until 31 December 2011. The findings suggest a 35% lower risk of multiple myeloma associated with TZD with borderline significance. Subgroup analyses suggest a null association in patients aged <65 years but a significantly 45% lower risk in patients aged ≥65 years. Patients who have been treated with TZD may have a survival advantage. Background: Thiazolidinedione (TZD) exerts anti-proliferative effects on multiple myeloma (MM) cells. However, there has not been any human study investigating the risk of MM associated with TZD use. Methods: We used Taiwan's National Health Insurance database to identify 423,949 patients who had been newly diagnosed with diabetes mellitus between 1999 and 2005. After excluding ineligible patients, 86,999 pairs of patients with and without the use of TZD (rosiglitazone or pioglitazone) that had been matched based on propensity score were selected for a follow-up for MM until 31 December 2011. The hazard ratios for MM were estimated using Cox regression and weighted using a propensity score. Results: After a median follow-up of 4.6 years and 4.7 years in ever users and never users of TZD, 32 and 47 cases were diagnosed with MM, respectively. A 35% lower risk (though not statistically significant) was observed among ever users (hazard ratio 0.652, 95% confidence interval: 0.416–1.023, p = 0.0625). When ever users were divided by the median (15 months) cumulative duration of TZD therapy, the hazard ratios (95% confidence interval) for the lower and upper medians were 0.706 (0.394–1.264) and 0.603 (0.346–1.051), respectively. When treated as a continuous variable, the hazard ratio for every 1-month increment of the cumulative duration was 0.980 (95% confidence interval: 0.963–0.997, p = 0.0185). In the age subgroup analysis, a significantly lower risk could be seen in the older age subgroup of ≥65 years (hazard ratio 0.550, 95% confidence interval: 0.305–0.992, p = 0.0468). Additional analyses suggested that there were no interactions between TZD and some medications and between TZD and some clinical diagnoses, and that the use of TZD as a preventive drug for MM might not be cost-effective because a number-needed-to-treat of 5800 was too large. Survival analyses suggested that ever users had a significantly lower risk of death when all patients were analyzed (hazard ratio: 0.84, 95% confidence interval: 0.81–0.87, p < 0.0001 via a log-rank test) or when patients who developed MM were analyzed (hazard ratio: 0.40, 95% confidence interval: 0.19–0.86, p = 0.0153 via a log-rank test). Conclusions: In Taiwanese patients with type 2 diabetes mellitus, TZD use is associated with a borderline lower risk of MM, which is more remarkable in patients aged ≥65 years. Because of the low incidence of MM, the use of TZD for the prevention of MM may not be cost-effective. Patients who have been treated with TZD may have a survival advantage. Future research is required to confirm the findings. [ABSTRACT FROM AUTHOR]

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development. [ABSTRACT FROM AUTHOR]

Introduction: The maturation faith of dendritic cells is restrained by the inflammatory environment and cytokines, such as interleukin-6 and its downstream component. Therefore, introducing the suitable antigen to dendritic cells is crucial. However, reducing the severity of the suppressive tumor microenvironment is indispensable. The present study examined the combination therapy of lymphocyte antigen 6 family member E (LY6E) pulsed mature dendritic cells (LPMDCs) and pioglitazone against colorectal cancer (CRC) to elevate the effectiveness of cancer treatment through probable role of pioglitazone on inhibiting IL-6/STAT3 pathway. Methods: Dendritic cells were generated from murine bone marrow and were pulsed with lymphocyte antigen 6 family member E peptide to assess antigen-specific T-cell proliferation and cytotoxicity assay with Annexin/PI. The effect of pioglitazone on interleukin (IL)-6/STAT3 was evaluated in vitro by real-time polymerase chain reaction (PCR). Afterward, the CRC model was established by subcutaneous injection of CT26, mouse colon carcinoma cell line, in female mice. After treatment, tumor, spleen, and lymph nodes samples were removed for histopathological, ELISA, and real-time PCR analysis. Results: In vitro results revealed the potential of lysate-pulsed dendritic cells in the proliferation of double-positive CD3-8 splenocytes and inducing immunogenic cell death responses, whereas pioglitazone declined the expression of IL-6/STAT3 in colorectal cell lines. In animal models, the recipient of LPMDCs combined with pioglitazone demonstrated high tumor-infiltrating lymphocytes. Elevating the IL-12 and interferon-gamma (IFN-γ) levels and prolonged survival in lysate-pulsed dendritic cell and combination groups were observed. Conclusion: Pioglitazone could efficiently ameliorate the immunosuppressive feature of the tumor microenvironment, mainly through IL-6. Accordingly, applying this drug combined with LPMDCs provoked substantial CD8 positive responses in tumor-challenged animal models. [ABSTRACT FROM AUTHOR]

Background: Thiazolidinediones (TZDs) are a type of oral drug that are utilized for the treatment of type 2 diabetes mellitus (T2DM). They function by acting as agonists for a nuclear transcription factor known as peroxisome proliferator-activated receptor-gamma (PPAR-γ). TZDs, such as pioglitazone and rosiglitazone, help enhance the regulation of metabolism in individuals with T2DM by improving their sensitivity to insulin. Previous studies have suggested a relationship between the therapeutic efficacy of TZDs and the PPARG Pro12Ala polymorphism (C > G, rs1801282). However, the small sample sizes of these studies may limit their applicability in clinical settings. To address this limitation, we conducted a meta-analysis assessing the influence of the PPARG Pro12Ala polymorphism on the responsiveness of TZDs. Method: We registered our study protocol with PROSPERO, number CRD42022354577. We conducted a comprehensive search of the PubMed, Web of Science, and Embase databases, including studies published up to August 2022. We examined studies investigating the association between the PPARG Pro12Ala polymorphism and metabolic parameters such as hemoglobin A1C (HbA1C), fasting plasma glucose (FPG), triglyceride (TG), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and total cholesterol (TC). The mean difference (MD) and 95% confidence intervals (CIs) between pre- and post-drug administration were evaluated. The quality of the studies included in the meta-analysis was assessed by using the Newcastle–Ottawa Scale (NOS) tool for cohort studies. Heterogeneity across studies was assessed by using the I2 value. An I2 value greater than 50% indicated substantial heterogeneity, and a random-effects model was used for meta-analysis. If the I2 value was below 50%, a fixed-effects model was employed instead. Both Begg's rank correlation test and Egger's regression test were performed to detect publication bias, using R Studio software. Results: Our meta-analysis incorporated 6 studies with 777 patients for blood glucose levels and 5 studies with 747 patients for lipid levels. The included studies were published between 2003 and 2016, with the majority involving Asian populations. Five of the six studies utilized pioglitazone, while the remaining study employed rosiglitazone. The quality scores, as assessed with the NOS, ranged from 8 to 9. Patients carrying the G allele exhibited a significantly greater reduction in HbA1C (MD = −0.3; 95% CI = −0.55 to −0.05; p = 0.02) and FPG (MD = −10.91; 95% CI = −19.82 to −2.01; p = 0.02) levels compared to those with the CC genotype. Furthermore, individuals with the G allele experienced a significantly larger decrease in TG levels than those with the CC genotype (MD = −26.88; 95% CI = −41.30 to −12.46; p = 0.0003). No statistically significant differences were observed in LDL (MD = 6.69; 95% CI = −0.90 to 14.29; p = 0.08), HDL (MD = 0.31; 95% CI = −1.62 to 2.23; p = 0.75), and TC (MD = 6.4; 95% CI = −0.05 to 12.84; p = 0.05) levels. No evidence of publication bias was detected based on Begg's test and Egger's test results. Conclusions: This meta-analysis reveals that patients with the Ala12 variant in the PPARG Pro12Ala polymorphism are more likely to exhibit positive responses to TZD treatment in terms of HbA1C, FPG, and TG levels compared to those with the Pro12/Pro12 genotype. These findings suggest that genotyping the PPARG Pro12Ala in diabetic patients may be advantageous for devising personalized treatment strategies, particularly for identifying individuals who are likely to respond favorably to TZDs. [ABSTRACT FROM AUTHOR]

A new cytotoxic alkaloid, named streptothiazolidine B (1), together with three known compounds (2-4), were isolated from Streptomyces violaceoruber. The structure of the undescribed compound was established using 1D and 2D NMR, and HRESIMS. Streptothiazolidine B was isolated and identified as an amide alkaloid with a unique thiazolidine side chain and its absolute configuration was determined by a combination of NOESY experiment and ECD analysis. Streptothiazolidine B exhibited significant cytotoxic activities against two human tumor cell lines, Li-7 and A2780, with IC50 values of 7.8, and 9.1 μM. Meanwhile, compound 4 showed obvious cytotoxic activities against four human tumor cell lines, THP-1, HT29, Li-7 and A2780, with IC50 values ranging from 3.1 to 10.2 μM. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite substantial progress and effort, the clinical efficacy of chemotherapy remains suboptimal due to chemoresistance, which is partly attributed to adipocytes in the tumor microenvironment. Adipocytes, major stromal cells in the bone marrow, are known to uptake lipophilic molecules. As many chemotherapeutics are hydrophobic, bone marrow adipocytes may contribute to the development of chemoresistance. However, detailed investigation has been challenging due to the limited accessibility and heterogeneity of the bone marrow microenvironment. To address these barriers, we have established 2D and 3D in vitro culture models of human bone marrow adipocytes. Our models provide compelling evidence that bone marrow adipocytes sequester doxorubicin in lipid droplets, resulting in a reduction in its cytotoxicity. These findings reveal an orthogonal mechanism for bone marrow tumor microenvironment-driven chemoresistance. Chemoresistance is a significant problem in the effective treatment of bone metastasis. Adipocytes are a major stromal cell type in the bone marrow and may play a crucial role in developing microenvironment-driven chemoresistance. However, detailed investigation remains challenging due to the anatomical inaccessibility and intrinsic tissue complexity of the bone marrow microenvironment. In this study, we developed 2D and 3D in vitro models of bone marrow adipocytes to examine the mechanisms underlying adipocyte-induced chemoresistance. We first established a protocol for the rapid and robust differentiation of human bone marrow stromal cells (hBMSCs) into mature adipocytes in 2D tissue culture plastic using rosiglitazone (10 μM), a PPARγ agonist. Next, we created a 3D adipocyte culture model by inducing aggregation of hBMSCs and adipogenesis to create adipocyte spheroids in porous hydrogel scaffolds that mimic bone marrow sinusoids. Simulated chemotherapy treatment with doxorubicin (2.5 μM) demonstrated that mature adipocytes sequester doxorubicin in lipid droplets, resulting in reduced cytotoxicity. Lastly, we performed direct coculture of human multiple myeloma cells (MM1.S) with the established 3D adipocyte model in the presence of doxorubicin. This resulted in significantly accelerated multiple myeloma proliferation following doxorubicin treatment. Our findings suggest that the sequestration of hydrophobic chemotherapeutics by mature adipocytes represents a potent mechanism of bone marrow microenvironment-driven chemoresistance. [ABSTRACT FROM AUTHOR]

Thiazolidinedione (TZD) is one of the privileged heterocyclic rings and has shown many biological applications in medicinal chemistry and drug discovery. This review covers the synthetic approaches of TZD and its derivatives, different synthetic techniques for affording the desired regioselectivity and stereoselectivity, and the techniques that would enhance reaction conditions such as microwave, one‐pot, or ultrasound synthesis. It focuses on synthetic challenges of glitazones and the transformation of other heterocycles to TZD. Moreover, the chemical and biological behavior of TZD through the substitution in the N3 position, modification of the C5 position, annealing in complex heterocyclic systems, and hybridization with other pharmacologically attractive moieties are discussed. All reactions mentioned are provided as possible with different reaction conditions, mechanisms, derivatives scope, yield and clarified by applications of such reactions in the construction of potential medicinal agents. The review also answers questions about rapid racemization of glitazones, their toxicity, considering TZD as pan‐assay interference compounds (PAINS) or not, and the influence of saturation of 5‐position of TZD in their biological activities. This review is a comprehensive guide to make informed decisions for construction of TZD derivatives with biological potentials. [ABSTRACT FROM AUTHOR]

Risk for asthma in the overweight/obese may be mediated by adiponectin and peroxisome proliferator activated receptor pathways and may be reduced by the use of oral drugs impacting these pathways, such as angiotensin converting enzyme inhibitors (ACE-I), thiazolidinediones (TZD), and angiotensin receptor blockers (ARB). Our study objective was to determine whether ACE-I, TZD, and/or ARB use in overweight/obese adults with diabetes mellitus and/or hypertension is associated with a lower risk for incident asthma. Using an existing cohort of American veterans, we performed a longitudinal data analysis over 15 years. Exposure was defined by the prescription pickup of ACE-I, TZD, and/or ARB for at least 4 weeks. The outcome, time until new-onset of clinician-diagnosed asthma, was studied using survival analysis. The propensity scoring method controlled for treatment selection bias. 2.83 million eligible veterans, including 77,278 with incident asthma, were studied. As compared to those unexposed, the use of ACE-I alone, TZD alone, or their combinations were each associated with decreased risk for incident asthma (hazard ratios of 0.88, 0.74, and 0.20, respectively; p < 0.001 for all analyses in the fully adjusted statistical models). TZD lowered the risk among racial/ethnic minority subjects more than among White participants (p < 0.001). On the other hand, ARB use alone or in combination with TZD was associated with a higher risk for incident asthma. Use of ACE-I and/or TZD was associated with a lower risk for incident asthma in overweight/obese patients with diabetes mellitus and/or hypertension. [ABSTRACT FROM AUTHOR]

Keywords: fatty liver; hepatic steatosis; insulin resistance; NAFLD; thiazolidinediones EN fatty liver hepatic steatosis insulin resistance NAFLD thiazolidinediones 1112 1116 5 03/08/23 20230401 NES 230401 INTRODUCTION Treatment with pioglitazone (PIO) has been shown to be effective, inducing resolution of nonalcoholic steatohepatitis (NASH) in patients with or without diabetes.[[1]] Moreover, there is evidence that long-term treatment with PIO can even improve liver fibrosis,[3] an accomplishment that most other drugs assessed for treatment of NASH have failed to reach in randomized controlled trials.[4] This places PIO high on the list when deciding treatment for patients with prediabetes or type 2 diabetes (T2D) and NASH.[5] Unfortunately, data regarding the optimal treatment duration and the effects of stopping PIO are scarce.[6] Therefore, the aim of this study was to assess the biochemical changes in patients with NASH discontinuing PIO treatment. Patients with lower adipose tissue insulin sensitivity and greater hyperinsulinaemia before starting PIO treatment are at a higher risk of plasma AST and ALT increases after stopping PIO, which may indicate liver disease recurrence. In the current work, we showed that interrupting PIO treatment in patients with NASH was associated with a significant plasma AST and ALT elevation back to pretreatment levels, suggesting that therapy gains are lost after drug discontinuation. [Extracted from the article]

Asymmetric catalytic transformations of N‐unprotected cyclic carboxyimides such as succinimides, hydantoins, oxazolidinediones, and glitazones, is a powerful way of directly accessing variety of biologically valuable chiral compounds. Herein, a bis(trichlorosilyl) nucleophilic intermediate formed from cyclic carboxyimides was reacted with aldehydes via (S)‐SEGPHOS dioxide (SEGPHOSO), proceeding the aldol reaction in highly enantioselective fashion through a cyclic transition state. Furthermore, N‐unprotected carboxyimides were chemoselectively activated, even in the presence of N‐alkylated carboxyimides, to undergo stereoselective and chemoselective aldol reactions via in situ silicon tetrachloride activation. The functionalized cyclic carboxyimides is readily derived to the several synthetic units derivatization to various chiral building blocks without unnecessary protection/deprotection steps. [ABSTRACT FROM AUTHOR]

Adults with obesity may develop asthma that is ineffectively controlled by inhaled corticosteroids and long-acting beta-adrenoceptor agonists. Mechanistic and translational studies suggest that metabolic dysregulation that occurs with obesity, particularly hyperglycemia and insulin resistance, contributes to altered immune cell function and low-grade systemic inflammation. Importantly, in these cases, the same proinflammatory cytokines believed to contribute to insulin resistance may also be responsible for airway remodeling and hyperresponsiveness. In the past decade, new research has emerged assessing whether hypoglycemic therapies impact comorbid asthma as reflected by the incidence of asthma, asthma-related emergency department visits, asthma-related hospitalizations, and asthma-related exacerbations. The purpose of this review article is to discuss the mechanism of action, preclinical data, and existing clinical studies regarding the efficacy and safety of hypoglycemic therapies for adults with obesity and comorbid asthma. [ABSTRACT FROM AUTHOR]

Concomitant administration of lobeglitazone, empagliflozin, and metformin is expected to enhance blood glucose-lowering effects and improve medication compliance in patients with diabetes mellitus. In this study, we investigated the pharmacokinetic (PK) interactions and safety of lobeglitazone and co-administered empagliflozin and metformin, which are approved agents used in clinical settings. Two randomized, open-label, multiple-dose, 2-treatment, 2-period, 2-sequence crossover clinical trials (parts 1 and 2) were conducted independently. In part 1, lobeglitazone monotherapy or lobeglitazone, empagliflozin, and metformin triple therapy was administered for 5 days. In part 2, empagliflozin and metformin dual therapy or the abovementioned triple therapy were administered for 5 days. Serial blood samples were collected up to 24 hours after the last dose in each period for PK evaluation. The primary PK parameters (AUCtau, ss, Cmax, ss) of treatment regimens in each study part were calculated and compared. For lobeglitazone, the geometric mean ratios (GMRs) with 90% confidence intervals (CI) for triple therapy over monotherapy were 1.08 (1.03-1.14) for Cmax, ss and 0.98 (0.90-1.07) for AUCtau, ss. For empagliflozin, the GMRs and 90% CIs for triple therapy over dual therapy were 0.87 (0.78-0.97) for Cmax,ss and 0.97 (0.93-1.00) for AUCtau,ss. For metformin, the GMRs and 90% CIs for triple therapy over dual therapy were 1.06 (0.95-1.17) for Cmax,ss and 1.04 (0.97-1.12) for AUCtau,ss. All reported adverse events were mild. The triple therapy consisting of lobeglitazone, empagliflozin, and metformin did not show any clinically relevant drug interactions in relation to the PKs and safety of each drug substance. [ABSTRACT FROM AUTHOR]

Oral cancer is increasing in prevalence and its treatment is associated with high degree of morbidity and mortality. Thus, prevention of oral cancer is of utmost importance. Chemoprevention is the use of natural, synthetic, or biologic compounds to halt, reverse, or prevent the initial phases of carcinogenesis or the progression of neoplastic cells to cancer. This modality has been extensively researched in the last two decades for the prevention of oral cancer with the emergence of new information. Retinoids were the first chemopreventive agents to be tested in clinical settings. Since then, a number of new agents such as COX2 inhibitors, EGFR inhibitors, p53 targeted agents, thiazolidinediones and several natural agents have shown promise in oral cancer prevention. Chemopreventive trials in oral cancer tend to be long term studies and are thus challenging. This review article looks into the clinical evidence for the application of chemopreventive agents in clinical settings and also highlights the recent trends in oral cancer chemopreventive trials. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes are more likely to suffer COVID‐19 complications. Using noninsulin antihyperglycemic medications (AGMs) during COVID‐19 infection has proved challenging. In this study, we evaluate different noninsulin AGMs in patients with COVID‐19. Methods: We searched Medline, Embase, Web of Science, and Cochrane on 24 January 2022. We used the following keywords (COVID‐19) AND (diabetes mellitus) AND (antihyperglycemic agent). The inclusion criteria were studies reporting one or more of the outcomes. We excluded non‐English articles, case reports, and literature reviews. Study outcomes were mortality, hospitalization, and intensive care unit (ICU) admission. Results: The use of metformin rather than other glucose‐lowering medications was associated with statistically significant lower mortality (risk ratio [RR]: 0.60, 95% confidence interval [CI]: 0.47, 0.77, p <.001). Dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use was associated with statistically significantly higher hospitalization risk (RR: 1.44, 95% CI: 1.23, 1.68, p <.001) and higher risk of ICU admissions and/or mechanical ventilation vs nonusers (RR: 1.24, 95% CI: 1.04, 1.48, p <.02). There was a statistically significant decrease in hospitalization for SGLT‐2i users vs nonusers (RR: 0.89, 95% CI: 0.84–0.95, p <.001). Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) use was associated with a statistically significant decrease in mortality (RR: 0.56, 95% CI: 0.42, 073, p < 0.001), ICU admission, and/or mechanical ventilation (RR: 0.79, 95% CI: 0.69–0.89, p <.001), and hospitalization (RR: 0.73, 95% CI: 0.54, 0.98, p =.04). Conclusions: AGM use was not associated with increased mortality. However, metformin and GLP‐1RA use reduced mortality risk statistically significantly. DPP‐4i use was associated with a statistically significant increase in the risk of hospitalization and admission to the ICU. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) and dementia cause heavy health burden in mainland China, where few studies have investigated the association between glucose‐lowering agents and dementia risk. We aimed to assess the association between use of thiazolidinediones (TZDs) and dementia incidence in a mainland Chinese population with T2DM. Methods: A retrospective cohort of T2DM patients who were new users of TZDs or alpha glucosidase inhibitors (AGIs) was assembled using the Yinzhou Regional Health Care Database. A Cox model with inverse probability of treatment weighting (IPTW) for controlling potential founding was applied to estimate the hazard ratio (HR) of the association between use of TZDs and dementia risk. Results: A total of 49 823 new users of AGIs and 12 752 new users of TZDs were included in the final cohort. In the primary analysis, the incidence of dementia was 195.7 and 78.2 per 100 000 person‐years in users of AGIs and TZDs respectively. TZD use was associated with a reduced risk of incident dementia after adjusting for potential confounding using IPTW, with a HR of 0.51 (95% CI, 0.38–0.67). The results in various subgroup analyses and sensitivity analyses were consistent with the findings of the primary analysis. Conclusions: Use of TZDs is associated with a decreased risk of dementia incidence in a mainland Chinese population with T2DM. [ABSTRACT FROM AUTHOR]