Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion: This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

AIM: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add-on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add-on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. MATERIALS AND METHODS: In this randomized, double-blind, double-dummy, active-controlled, parallel-group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. RESULTS: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were -1.34% with GEMI + DAPA, -0.90% with GEMI (difference between GEMI + DAPA vs. GEMI -0.44% [95% confidence interval {CI}: -0.58% to -0.31%], P < .01) and -0.78% with DAPA (difference between GEMI + DAPA vs. DAPA -0.56% [95% CI: -0.69% to -0.42%], P < .01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. CONCLUSIONS: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well-tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone.

A phase 4 randomized active-controlled clinical study to compare the efficacy and safety of sustained-release pregabalin with immediate-release pregabalin in type 2 diabetic patients with peripheral neuropathic pain.

AIMS: The objective of this study was to demonstrate that sustained-release (SR) pregabalin is non-inferior to immediate-release (IR) pregabalin in attenuating diabetic peripheral neuropathic (DPN) pain along with patient satisfaction and compliance. METHODS: This was an 8-week, randomized, active-controlled, open-label, phase 4 study. Eligible subjects who had been on IR pregabalin for 4 weeks were randomized to 1:1 ratio to either continue with twice-daily IR pregabalin (75 mg), or to switch to once-daily SR pregabalin (150 mg). Primary efficacy endpoint was the change in visual analogue scale (VAS) scores after 8 weeks of treatment compared to baseline in both SR and IR pregabalin groups. RESULTS: Among 130 randomized subjects, 125 patients were included in full analysis set. For the change in VAS pain score, the least squares (LS) mean were -17.95 (SR pregabalin) and -18.74 (IR pregabalin) and the LS mean difference between both groups was 0.79, with the upper limit of the 95 % confidence interval [-5.99, 7.58] below the pre-specified non-inferiority margin of 9.2 mm. CONCLUSIONS: This study demonstrates that the new once-daily SR pregabalin formulation is not different to the twice-daily IR pregabalin in alleviating DPN pain, indicating its potential as a promising treatment for DPN pain with a comparable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05624853.

Effectiveness of low-intensity atorvastatin 5 mg and ezetimibe 10 mg combination therapy compared with moderate-intensity atorvastatin 10 mg monotherapy: A randomized, double-blinded, multi-center, phase III study.

BACKGROUND: We compared the efficacy and safety of low-intensity atorvastatin and ezetimibe combination therapy with moderate-intensity atorvastatin monotherapy in patients requiring cholesterol-lowering therapy. METHODS: At 19 centers in Korea, 290 patients were randomized to 4 groups: atorvastatin 5 mg and ezetimibe 10 mg (A5E), ezetimibe 10 mg (E), atorvastatin 5 mg (A5), and atorvastatin 10 mg (A10). Clinical and laboratory examinations were performed at baseline, and at 4-week and 8-week follow-ups. The primary endpoint was percentage change from baseline in low-density lipoprotein (LDL) cholesterol levels at the 8-week follow-up. Secondary endpoints included percentage changes from baseline in additional lipid parameters. RESULTS: Baseline characteristics were similar among the study groups. At the 8-week follow-up, percentage changes in LDL cholesterol levels were significantly greater in the A5E group (49.2%) than in the E (18.7%), A5 (27.9%), and A10 (36.4%) groups. Similar findings were observed regarding the percentage changes in total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B levels. Triglyceride levels were also significantly decreased in the A5E group than in the E group, whereas high-density lipoprotein levels substantially increased in the A5E group than in the E group. In patients with low- and intermediate-cardiovascular risk, 93.3% achieved the target LDL cholesterol levels in the A5E group, 40.0% in the E group, 66.7% in the A5 group, and 92.9% in the A10 group. In addition, 31.4% of patients in the A5E group, 8.1% in E, 9.7% in A5, and 7.3% in the A10 group reached the target levels of both LDL cholesterol < 70 mg/dL and reduction of LDL ≥ 50% from baseline. CONCLUSIONS: The addition of ezetimibe to low-intensity atorvastatin had a greater effect on lowering LDL cholesterol than moderate-intensity atorvastatin alone, offering an effective treatment option for cholesterol management, especially in patients with low and intermediate risks.

Korean guidelines for the management of gout.

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Korean guidelines for the management of gout.

Gout is the most common form of arthritis, with the prevalence increasing worldwide. The present treatment guidelines provide recommendations for the appropriate treatment of acute gout, management during the inter-critical period, and prevention of chronic complications. The guidelines were developed based on evidence-based medicine and draft recommendations finalized after expert consensus. These guidelines are designed to provide clinicians with clinical evidence to enable efficient treatment of gout.

Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study.

AIMS: This study evaluated the efficacy and safety of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor, versus dapagliflozin in Korean patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and gemigliptin. METHODS: In this multicenter, double-blind, randomized study, patients with inadequate response to metformin (≥ 1000 mg/day) plus gemigliptin (50 mg/day) were randomized to receive enavogliflozin 0.3 mg/day (n = 134) or dapagliflozin 10 mg/day (n = 136) in addition to the metformin plus gemigliptin therapy. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS: Both treatments significantly reduced HbA1c at week 24 (-0.92% in enavogliflozin group, -0.86% in dapagliflozin group). The enavogliflozin and dapagliflozin groups did not differ in terms of changes in HbA1c (between-group difference: -0.06%, 95% confidence interval [CI]: -0.19, 0.06) and fasting plasma glucose (between-group difference: -3.49 mg/dl [-8.08;1.10]). An increase in urine glucose-creatinine ratio was significantly greater in the enavogliflozin group than in the dapagliflozin group (60.2 g/g versus 43.5 g/g, P < 0.0001). The incidence of treatment-emergent adverse events was similar between the groups (21.64% versus 23.53%). CONCLUSIONS: Enavogliflozin, added to metformin plus gemigliptin, was well tolerated and as effective as dapagliflozin in the treatment of patients with T2DM.

Type 2 Diabetes Remission with Significant Weight Loss: Definition and Evidence-Based Interventions.

Type 2 diabetes (T2D) has long been regarded as an incurable and chronic disease according to conventional management methods. Clinical and pathophysiological studies on the natural course of T2D have shown that blood glucose control worsens with an increase in the number of required anti-hyperglycemic agents, as ß-cell function progressively declines over time. However, recent studies have shown remission of T2D after metabolic surgery, intensive lifestyle modification, or medications, raising the possibility that ß-cell function may be preserved or the decline in ß-cell function may even be reversible. The World Health Organization as well as the American Diabetes Association and the European Association for the Study of Diabetes recognize remission as an appropriate management aim. In the light of the state of evidence for T2D reversal, physicians need to be educated on treatment options to achieve T2D remission so that they can actively play a part in counseling patients who may wish to explore these approaches to their disease. This review will introduce each of these approaches, summarizing their beneficial effects, supporting evidence, degree of sustainability, and challenges to be addressed in the future.

Effects of cisplatin on mitochondrial function and autophagy-related proteins in skeletal muscle of rats.

Cisplatin is widely known as an anti-cancer drug. However, the effects of cisplatin on mitochondrial function and autophagyrelated proteins levels in the skeletal muscle are unclear. The purpose of this study was to investigate the effect of different doses of cisplatin on mitochondrial function and autophagy-related protein levels in the skeletal muscle of rats. Eight-weekold male Wistar rats (n = 24) were assigned to one of three groups; the first group was administered a saline placebo (CON, n = 10), and the second and third groups were given 0.1 mg/kg body weight (BW) (n = 6), and 0.5 mg/kg BW (n = 8) of cisplatin, respectively. The group that had been administered 0.5 mg cisplatin exhibited a reduced BW, skeletal muscle tissue weight, and mitochondrial function and upregulated levels of autophagy-related proteins, including LC3II, Beclin 1, and BNIP3. Moreover, this group had a high LC3 II/I ratio in the skeletal muscle; i.e., the administration of a high dose of cisplatin decreased the muscle mass and mitochondrial function and increased the levels of autophagy-related proteins. These results, thus, suggest that reducing mitochondrial dysfunction and autophagy pathways may be important for preventing skeletal muscle atrophy following cisplatin administration. [BMB Reports 2021; 54(11): 575-580].

Hepatokines as a Molecular Transducer of Exercise.

Exercise has health benefits and prevents a range of chronic diseases caused by physiological and biological changes in the whole body. Generally, the metabolic regulation of skeletal muscle through exercise is known to have a protective effect on the pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular disease (CVD). Besides this, the importance of the liver as an endocrine organ is a hot research topic. Hepatocytes also secrete many hepatokines in response to nutritional conditions and/or physical activity. In particular, certain hepatokines play a major role in the regulation of whole-body metabolic homeostasis. In this review, we summarize the recent research findings on the exercise-mediated regulation of hepatokines, including fibroblast growth factor 21, fetuin-A, angiopoietin-like protein 4, and follistatin. These hepatokines serve as molecular transducers of the metabolic benefits of physical activity in chronic metabolic diseases, including NAFLD, T2D, and CVDs, in various tissues.

Efficacy and Safety of Treatment with Quadruple Oral Hypoglycemic Agents in Uncontrolled Type 2 Diabetes Mellitus: A Multi-Center, Retrospective, Observational Study.

BACKGROUND: Only few studies have shown the efficacy and safety of glucose-control strategies using the quadruple drug combination. Therefore, the aim of the present study was to investigate the usefulness of the quadruple combination therapy with oral hypoglycemic agents (OHAs) in patients with uncontrolled type 2 diabetes mellitus (T2DM). METHODS: From March 2014 to December 2018, data of patients with T2DM, who were treated with quadruple hypoglycemic medications for over 12 months in 11 hospitals in South Korea, were reviewed retrospectively. We compared glycosylated hemoglobin (HbA1c) levels before and 12 months after quadruple treatment with OHAs. The safety, maintenance rate, and therapeutic patterns after failure of the quadruple therapy were also evaluated. RESULTS: In total, 357 patients were enrolled for quadruple OHA therapy, and the baseline HbA1c level was 9.0%±1.3% (74.9±14.1 mmol/mol). After 12 months, 270 patients (75.6%) adhered to the quadruple therapy and HbA1c was significantly reduced from 8.9%±1.2% to 7.8%±1.3% (mean change, -1.1%±1.2%; P<0.001). The number of patients with HbA1c <7% increased significantly from 5 to 68 (P<0.005). In addition, lipid profiles and liver enzyme levels were also improved whereas no changes in body weight. There was no significant safety issue in patients treated with quadruple OHA therapy. CONCLUSION: This study shows the therapeutic efficacy of the quadruple OHA regimen T2DM and demonstrates that it can be an option for the management of T2DM patients who cannot use insulin or reject injectable therapy.

Melatonin protects INS-1 pancreatic ß-cells from apoptosis and senescence induced by glucotoxicity and glucolipotoxicity.

INTRODUCTION: Melatonin is a hormone known as having very strong anti-oxidant property. Senescence is a biological state characterized by the loss of cell replication and the changes consisting of a pro-inflammatory phenotype, leading to Senescence Associated Secretory Phenotype (SASP) which is now regarded as one of the fundamental processes of many degenerative diseases. Increased cell division count induces cell senescence via DNA damage in response to elevated Reactive Oxygen Species (ROS). We wanted to test whether melatonin could reduce apoptosis and stress induced premature pancreatic ß-cell senescence induced by glucotoxicity and glucolipotoxicity. MATERIALS AND METHOD: Cultured rodent pancreatic ß-cell line (INS-1 cell) was used. Glucotoxicity (HG: hyperglycemia) and glucolipotoxicity (HGP: hyperglycemia with palmitate) were induced by hyperglycemia and the addition of palmitate. The degrees of the senescence were measured by SA-ß-Gal and P16lnk4A staining along with the changes of cell viabilities, cell cycle-related protein and gene expressions, endogenous anti-oxidant defense enzymes, and Glucose Stimulated Insulin Secretion (GSIS), before and after melatonin treatment. RESULTS: Cultured INS-1 cells in HG and HGP conditions revealed accelerated senescence, increased apoptosis, cell cycle arrest, compromised endogenous anti-oxidant defense, and impaired glucose-stimulated insulin secretion. Melatonin decreased apoptosis and expressions of proteins related to senescence, increase the endogenous anti-oxidant defense, and improved glucose-stimulated insulin secretion. CONCLUSION: Melatonin protected pancreatic ß-cell from apoptosis, decreased expressions of the markers related to the accelerated senescence, and improved the biological deteriorations induced by glucotoxicity and glucolipotoxicity.

Exercise-Induced Circulating Irisin Level Is Correlated with Improved Cardiac Function in Rats.

Irisin, a recently identified myokine, plays an important physiological role in modulating energy homeostasis. However, the role of irisin in cardiac function during exercise has not been evaluated. In this study, we investigated the effect of exercise on irisin, pro-inflammatory cytokines, and cardiac function during 12 weeks of exercise in rats. Eight-week-old Sprague-Dawley male rats were randomly divided into two groups (n = 9 per group): sedentary control (CON) and exercise (EXE) groups. The EXE group was trained on a motorized treadmill at 20 m/min, for 60 min/day, five times/week for 12 weeks. The EXE group showed a decrease in abdominal visceral fat (p < 0.05), epididymal fat (p < 0.01), and total cholesterol (TC) (p < 0.05) and an increase in irisin levels (p < 0.01). Irisin negatively correlated with abdominal visceral (p < 0.05) and epididymal fat (p < 0.05) and positively correlated with the ejection fraction (p < 0.05), fractional shortening (p < 0.05), and cardiac output (p < 0.05). In conclusion, exercise decreases the abdominal visceral and epididymal fat and TC levels, possibly caused by elevated irisin levels, thus improving the cardiac function. This suggests that exercise-induced circulating irisin levels correlate with improved cardiac function in rats.

Efficacy and Safety of Pioglitazone versus Glimepiride after Metformin and Alogliptin Combination Therapy: A Randomized, Open-Label, Multicenter, Parallel-Controlled Study.

BACKGROUND: There is limited information regarding the optimal third-line therapy for managing type 2 diabetes mellitus (T2DM) that is inadequately controlled using dual combination therapy. This study assessed the efficacy and safety of pioglitazone or glimepiride when added to metformin plus alogliptin treatment for T2DM. METHODS: This multicenter, randomized, active-controlled trial (ClinicalTrials.gov: NCT02426294) recruited 135 Korean patients with T2DM that was inadequately controlled using metformin plus alogliptin. The patients were then randomized to also receive pioglitazone (15 mg/day) or glimepiride (2 mg/day) for a 26-week period, with dose titration was permitted based on the investigator's judgement. RESULTS: Glycosylated hemoglobin levels exhibited similar significant decreases in both groups during the treatment period (pioglitazone: -0.81%, P<0.001; glimepiride: -1.05%, P<0.001). However, the pioglitazone-treated group exhibited significantly higher high density lipoprotein cholesterol levels (P<0.001) and significantly lower homeostatic model assessment of insulin resistance values (P<0.001). Relative to pioglitazone, adding glimepiride to metformin plus alogliptin markedly increased the risk of hypoglycemia (pioglitazone: 1/69 cases [1.45%], glimepiride: 14/66 cases [21.21%]; P<0.001). CONCLUSION: Among patients with T2DM inadequately controlled using metformin plus alogliptin, the addition of pioglitazone provided comparable glycemic control and various benefits (improvements in lipid profiles, insulin resistance, and hypoglycemia risk) relative to the addition of glimepiride.

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms.

Diabetes mellitus is associated with cardiovascular, ophthalmic, and renal comorbidities. Among these, diabetic cardiomyopathy (DCM) causes the most severe symptoms and is considered to be a major health problem worldwide. Exercise is widely known as an effective strategy for the prevention and treatment of many chronic diseases. Importantly, the onset of complications arising due to diabetes can be delayed or even prevented by exercise. Regular exercise is reported to have positive effects on diabetes mellitus and the development of DCM. The protective effects of exercise include prevention of cardiac apoptosis, fibrosis, oxidative stress, and microvascular diseases, as well as improvement in cardiac mitochondrial function and calcium regulation. This review summarizes the recent scientific findings to describe the potential mechanisms by which exercise may prevent DCM and heart failure.

Aerobic Exercise Training Decreases Hepatic Asprosin in Diabetic Rats.

Asprosin, a novel hormone released from white adipose tissue, regulates hepatic glucose metabolism and is pathologically elevated in the presence of insulin resistance. It is unknown whether aerobic exercise training affects asprosin levels in type 1 diabetes mellitus (T1DM). The aim of this study was to determine whether (1) aerobic exercise training could decrease asprosin levels in the liver of streptozotocin (STZ)-induced diabetic rats and (2) the reduction in asprosin levels could induce asprosin-dependent downstream pathways. Five-week-old male Sprague-Dawley rats were randomly divided into control, STZ-induced diabetes (STZ), and STZ with aerobic exercise training groups (n = 6/group). T1DM was induced by a single dose of STZ (65 mg/kg intraperitoneally (i.p.)). The exercise group was made to run on a treadmill for 60 min at a speed of 20 m/min, 4 days per week for 8 weeks. Aerobic exercise training reduced the protein levels of asprosin, PKA, and TGF-ß but increased those of AMPK, Akt, PGC-1ß, and MnSOD. These results suggest that aerobic exercise training affects hepatic asprosin-dependent PKA/TGF-ß and AMPK downstream pathways in T1DM.

The direct effect of lobeglitazone, a new thiazolidinedione, on pancreatic beta cells: A comparison with other thiazolidinediones.

AIMS: The direct effects of thiazolidinediones (TZDs) on pancreatic beta cells have been controversial. The aim of this study was to find out whether a novel TZD, lobeglitazone, has beneficial effects on pancreatic beta cells and db/db mice compared to those of other TZDs. METHODS: INS-1 cells were incubated at a high-glucose concentration with various concentrations of troglitazone, rosiglitazone, pioglitazone, and lobeglitazone. Apoptosis and proliferation of beta cells, markers for ER stress and glucose-stimulated insulin secretion (GSIS) were assessed. In addition, C57BL/6 db/db mice were treated with pioglitazone or lobeglitazone for 4 weeks, and metabolic parameters and the configuration of pancreatic islets were also examined. RESULTS: Lobeglitazone and other TZDs decreased INS-1 cell apoptosis in high-glucose conditions. Lobeglitazone and other TZDs significantly decreased hyperglycemia-induced increases in ER stress markers and increased GSIS. Metabolic parameters showed greater improvement in db/db mice treated with pioglitazone and lobeglitazone than in control mice. Islet size, cell proliferation, and beta cell mass were increased, and collagen surrounding the islets was decreased in treated mice. CONCLUSIONS: Lobeglitazone showed beneficial effects on beta cell survival and function against hyperglycemia. The prosurvival and profunction effects of lobeglitazone were comparable to those of other TZDs.

Resistance Exercise Training Attenuates the Loss of Endogenous GLP-1 Receptor in the Hypothalamus of Type 2 Diabetic Rats.

The aim of this study was to investigate the effects of resistance exercise training on hypothalamic GLP-1R levels and its related signaling mechanisms in T2DM. The animals were separated into three groups: a non-diabetic control (CON), diabetic control (DM), and diabetic with resistance exercise (DM + EXE) group. The resistance exercise training group performed ladder climbing (eight repetitions, three days per week for 12 weeks). Body weight was slightly lower in the DM + EXE group than the DM group, but difference between the groups was not significant. Food intake and glucose were significantly lower in the DM + EXE group than in the DM group. The blood insulin concentration was significantly higher and glucagon was significantly lower in the DM + EXE group. The DM + EXE group in the hypothalamus showed significant increases in GLP-1R mRNA, protein kinase A (PKA), glucose transporter 2 (GLUT2), and protein kinase B (AKT) and significant decrease in protein kinase C-iota (PKC-iota). Antioxidant enzymes and apoptosis factors were significantly improved in the DM + EXE group compared with the DM group in the hypothalamus. The results suggest that resistance exercise contributes to improvements the overall health of the brain in diabetic conditions.

High Glucose with Insulin Induces Cell Cycle Progression and Activation of Oncogenic Signaling of Bladder Epithelial Cells Cotreated with Metformin and Pioglitazone.

Metformin and pioglitazone are two commonly prescribed oral hypoglycemic agents for diabetes. Recent evidence suggests that these drugs may contribute to bladder cancer. This study investigated molecular mechanism underlying effects of metformin and pioglitazone in bladder epithelial carcinogenesis in type 2 diabetes. The cells derived from human bladder epithelial cells (HBlEpCs) were treated with metformin or pioglitazone with high glucose and insulin. Cell viability and proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and a bromodeoxyuridine incorporation assay, respectively, while cell cycle regulatory factors and oncogene expression were analyzed using western blotting. Metformin or pioglitazone suppressed cell viability concentration and time dependently, which was reversed by exposure to high glucose with or without insulin. Prolonged exposure to high glucose and insulin enhanced cyclin D, cyclin-dependent kinase 4 (Cdk4), and Cdk2 expression and suppressed cyclin-dependent kinase inhibitors p21 and p15/16 in HBlEpC cotreated with pioglitazone and metformin. Levels of tumor suppressor proteins p53 and cav-1 were downregulated while those of the oncogenic protein as c-Myc were upregulated under high glucose and insulin supplementation in HBlEpC cotreated with pioglitazone and metformin. Prolonged exposure to high glucose with or without insulin downregulated B cell lymphoma 2-associated X (Bax) and failed to enhance the expression of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) in drug-treated cells. These results suggest that hyperglycemic and insulinemic conditions promote cell cycle progression and oncogenic signaling in drug-treated bladder epithelial cells and uncontrolled hyperglycemia and hyperinsulinemia are probably greater cancer risk factors than diabetes drugs.