anagliptin + metformin (SK 1501 / Metoana / SK1501)

Metformin triggers ATF4-mediated UPRmt and COX-2 inflammation in adipocytes.

Poothong Juthakorn J, Chiamkunakorn Chutipong C, Suthammarak Wichit W, Phanaksri Teva T et al.

Metformin is the most common drug for type 2 diabetes due to its action to improve insulin sensitivity and enhance glucose uptake in tissues, including adipose tissue. As a mitochondrial complex I inhibitor, treatment with metformin may cause deleterious effects. Here, we demonstrated that treatment of adipocytes 3 T3-L1 cells with a high concentration of metformin (10 mM) led to increased reactive oxygen species (ROS) accumulation and triggered the mitochondrial unfolded protein response (UPRmt), as revealed by increased mRNA expression of UPRmt markers (mtHSP70, Lonp1, and FGF21). High-concentration metformin also induced COX-2 inflammation, as indicated by increased NF-κB phosphorylation and cyclooxygenase-2 (COX-2) expression. By contrast, a lower concentration (1.25 mM) showed no effects. We found that ATF4 was selectively upregulated and was required for UPRmt and COX-2 inflammation induced by metformin. Interestingly, we showed that the integrated stress response inhibitor (ISRIB) effectively inhibited ATF4, mitigated metformin-induced UPRmt, and reduced NF-κB/COX-2 expression. Taken together, our findings point to the undesirable effect of the high-concentration metformin in adipocytes.

Metformin and Severe Post-COVID-19 Outcomes Among Individuals with Diabetes Mellitus.

Butzin-Dozier Zachary Z, Wang Lin-Chiun LC, Ji Yunwen Y, Anzalone A Jerrod AJ et al.

Metformin is one of the most commonly prescribed medications for individuals with diabetes and may provide protection against long-term sequelae of COVID-19. We evaluated a retrospective cohort of individuals in the National Clinical Cohort Collaborative with type 2 diabetes mellitus and COVID-19 who were prescribed metformin or a dipeptidyl peptidase-4 inhibitor (DPP4i) at least 30 days before the onset of acute COVID-19 between October 1, 2021, and November 15, 2023. We compared the 12-month cumulative incidence of Long COVID diagnosis (ICD-10 U09.9: Post COVID-19 condition, unspecified), probable Long COVID (based on a model-derived phenotype), and mortality between individuals prescribed metformin vs. DPP4i. We applied Super Learner and targeted maximum likelihood estimation to obtain risk ratios while adjusting for covariates of interest. In our sample of 53,332 individuals with type 2 diabetes and COVID-19, we found that metformin prescription was associated with a lower risk of all-cause mortality after COVID-19 (adjusted risk ratio [aRR] 0.61, 95% CI 0.51, 0.73). We also observed that metformin users, compared to DPP4i users, had a slightly lower risk of probable Long COVID (aRR 0.87, 95% CI 0.81, 0.94) but did not detect a significant relationship with Long COVID diagnosis (aRR 0.90, 95% CI 0.68, 1.20), although we observed similar point estimates across Long COVID outcomes. These findings support the hypothesis that metformin prescription during acute COVID-19 may be associated with lower mortality among adults with diabetes. These analyses also provide modest evidence of a protective association against Long COVID in adults with diabetes, although estimates were imprecise.

Initial Evaluation of Dihydroartemisinin (DHA), Metformin and Taro Extract in Combination with Cisplatin for Enhanced Cytotoxicity in Triple-Negative Breast Cancer (TNBC) Cell Lines.

Godwin Ada Morgan AM, Ward Na'Turie N, Krauss Christopher C, Banerjee Hirendranath H et al.

This study evaluated the antiproliferative effects of cisplatin, dihydroartemisinin, metformin and taro extract on MDA-MB-231 triple-negative breast cancer (TNBC) cell lines. Cisplatin at half maximal inhibitory concentration, IC50 (20 μM) induced ~45% cell death (p < 0.001 vs control), while metformin (MET), dihydroartemisinin (DHA), and taro extract (TE) alone showed minimal cell death. Combination treatments (Cis + MET, Cis + DHA, and Cis + TE) significantly increased cytotoxicity to ~60% cell death on average (p < 0.01 vs cisplatin alone), with Cis + TE producing the greatest effect (~90%). The triple metabolic combination without cisplatin caused less than10% cell death (p < 0.001 vs cisplatin-containing groups), probably supporting a cisplatin-dependent cell death.

[Expression of Concern] In vitro and in vivo targeting of bladder carcinoma with metformin in combination with cisplatin.

Wang Dong D, Wu Xiaohou X