Carcinogenicity study of CKD-501, a novel dual peroxisome proliferator-activated receptors α and γ agonist, following oral administration to Sprague Dawley rats for 94-101 weeks.

CKD-501 is a peroxisome proliferator-activated receptor (PPAR) agonist. The current study was conducted in Sprague Dawley (SD) rats for 94-101 weeks to investigate the carcinogenic potential of CKD-501. 60 males received 0, 0.03, 0.12, or 1.0mg/kg/day, which was changed after 66 weeks to 0.24 mg/kg/day due to increased mortality, while 60 females received 0, 0.03, 0.06, or 0.12 mg/kg/day throughout the study period. After switching the dosage, no significant changes in the survival rates were observed. Non-neoplastic lesions such as bladder transitional cell hyperplasia and a diminished corpus luteum were observed in females administered 0.12 mg/kg/day and the right chamber dilation and left ventricular hypertrophy were increased dose dependently in both males and females. Non-neoplastic lesions such as bone marrow hypoplasia and fat cell proliferation and neoplastic lesions such as lipomas and liposarcomas observed in males and/or females were considered expected pharmacological effects for this compound. Compared to rosiglitazone, CKD-501 had a 4.4-fold higher margin of safety for tumor induction and did not cause bladder carcinoma as was observed with pioglitazone.

CKD-501, a novel selective PPARγ agonist, shows no carcinogenic potential in ICR mice following oral administration for 104 weeks.

CKD-501 is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is effective for the treatment of diabetes. However, its carcinogenic potential remains controversial. The current carcinogenicity study was conducted over a period of 104 weeks in ICR mice. Three groups, each consisting of 60 male and 60 female mice, received oral CKD-501 dosages of 0.2, 1.0 or 6.0 mg kg(-1) day(-1). The mortality rates of the male control, 0.2, 1.0 and 6.0 mg kg(-1) day(-1) treated groups were 60%, 68%, 58% and 67%, respectively and 57%, 68% and 67% in the female control, 0.2 and 1.0 mg kg(-1) day(-1) treated groups. It was 67% in the female 6.0 mg kg(-1) day(-1) treated group, which was terminated at week 98 due to its increased mortality rate. No significant treatment-related effects were observed on the survival rates, with the exception of females in the 6.0 mg kg(-1) day(-1) group. Body weights increased in females receiving 1.0 and 6.0 mg kg(-1) day(-1) due to the class effects of the PPARγ agonist. Differences were not found in hematology parameters between the CKD-501-treated groups and their corresponding controls, but the histopathological evidence did not reveal any findings attributed to CKD-501. Treated animals exhibited non-neoplastic findings (adipocyte proliferation, bone marrow hypoplasia cardiomyopathy), but all of these were expected changes for this class of compound. There were no treatment-related neoplastic changes in this study. The results of this study therefore demonstrate a lack of carcinogenicity following oral administration of CKD-501 to ICR mice for 104 weeks.

Will lobeglitazone rival pioglitazone? A systematic review and critical appraisal.

BACKGROUND AND AIMS: Lobeglitazone (LGZ), a newly researched thiazolidinedione (TZD) thought to have lesser side effects compared with pioglitazone (PGZ), has been recently approved for the treatment of type 2 diabetes (T2D) in India. We aim to conduct an updated systematic review of LGZ to critically appraise its efficacy and safety in the context of PGZ. METHODS: A systematic literature search was carried out in the electronic database of PubMed until Jan 15, 2023, using specific keywords and MeSH terms. All studies which evaluated LGZ in people with T2D were retrieved and data were synthesized with regard to its efficacy and safety. A comparative critical appraisal was additionally made in the context of PGZ in T2D. RESULTS: Four randomized controlled, one prospective observational, and two real-world studies have evaluated the safety and efficacy of LGZ against placebo or active comparators either as monotherapy or in combination therapy. HbA1c reduction with LGZ 0.5 mg was superior to the placebo but similar to PGZ 15 mg and sitagliptin (SITA) 100 mg. Weight gain with LGZ was significantly higher compared to placebo and SITA but similar to PGZ. Edema was more frequently observed with LGZ compared to placebo, PGZ, and SITA. CONCLUSION: No substantial evidence is yet available that suggests LGZ could be a better alternative to PGZ both in the context of glycemic or extra-glycemic effects. At least in the short-term, adverse events of LGZ are indifferent from PGZ. More data is additionally needed to claim any advantage of LGZ over PGZ.

Histopathological Evaluation of Heart Toxicity of a Novel Selective PPAR-γ Agonists CKD-501 in db/db Mice.

High risk of cardiovascular diseases caused by existing PPAR-γ agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-γ agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p<0.05), while other groups showed a tendency for an increase. All test articles induced significantly the increase of area of cardiomyocytes in heart compared to control (p<0.01), in regular order as pioglitazone > CKD-501 ≥ rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.

Histopathological Evaluation of Heart Toxicity of a Novel Selective PPAR-gamma Agonists CKD-501 in db/db Mice

High risk of cardiovascular diseases caused by existing PPAR-gamma agonists such as rosiglitazone and pioglitazone has been recently reported. CKD-501 is a novel selective PPAR-gamma agonist as a potential target to reduce cardiovascular risk in non-insulin dependent diabetes mellitus (NIDDM). In this study, We investigated potential cardiotoxicity of CKD-501 and compared its toxicity with that of rosiglitazone or pioglitazone using db/db mice. After 12-week repeated administration of CKD-501 at doses of 3, 10 and 30 mg/kg/day or rosiglitazone at doses of 10 and 30 mg/kg/day or pioglitazone at doses of 200 and 540 mg/kg/day, animals were sacrificed for investigation of potential toxicities. Diameters of left ventricles and areas of cardiomyocytes were measured. And lipid accumulation and apoptosis in heart muscle were examined by oil red O staining and TUNEL staining, respectively. Diameters of left ventricles were significantly increased in high dose treatment group of pioglitazone compared to control (p CKD-501 > or = rosiglitazone. However, lipid accumulation and apoptotic changes in heart were not observed in all dosing groups. Taken together, the myocardial cell hypertrophy of CKD-501 are relatively lower than that of pioglitazone and similar to rosiglitazone. And it is suggested that the myocardial cell hypertrophy of CKD-501 are less adverse in clinical use for the management of the NIDDM.