anagliptin + metformin (SK 1501 / Metoana / SK1501)

Cumulative Metformin Use and Hepatocellular Carcinoma Risk After HCV SVR: A Multicentre Cohort Study.

Calvo-Sánchez Henar H, Jara-Fernández Lorena L, Encijo-Heredia Raquel R, Villarino Irene I et al.

Although sustained virological response (SVR) after hepatitis C virus treatment reduces hepatocellular carcinoma (HCC) incidence, residual risk persists. Metformin has been associated with lower HCC risk, but whether cumulative metformin exposure (CME) lowers post-SVR risk remains unclear. We evaluated whether CME was associated with lower HCC risk after SVR. We analysed a multicentre cohort of 1531 patients who achieved SVR after direct-acting antiviral therapy (median follow-up, 75.5 months). Metformin exposure was modelled as a time-updated cumulative variable in start-stop Cox models to control for immortal-time bias. Stabilised inverse probability weighting addressed confounding by indication and censoring. The overall model was sex-stratified and adjusted for FIB-4, clinically significant portal hypertension (CSPH), type 2 diabetes mellitus (T2DM) and smoking. A prespecified T2DM-restricted analysis used T2DM-specific IPTW plus IPCW, sex stratification and CSPH adjustment. During follow-up, 50 patients developed HCC. Crude incidence was highest among patients with FIB-4 > 3.25, CSPH and T2DM without metformin exposure (4.84 cases per 100 person-years). In the overall weighted model, CME was associated with lower HCC risk (HR, 0.46 per year; 95% CI, 0.27-0.77; p = 0.004). CSPH, T2DM, smoking and FIB-4 > 3.25 independently increased risk. In the T2DM-restricted model, each additional year remained associated with lower HCC hazard (HR, 0.49; 95% CI, 0.29-0.84; p = 0.009), whereas CSPH was associated with higher risk (HR, 6.04; 95% CI, 2.12-17.19; p < 0.001). After SVR, CME was associated with lower HCC risk; this possible duration-dependent inverse association was clinically interpretable only among metformin-eligible patients with T2DM.

Insulin Resistance is Not a Predictor of Response to Low-Dose Oral Metformin Therapy in Patients with CCCA: A Retrospective Review.

Adedeji Opemipooluwa O, Aguh Crystal C

Metformin + Insulin vs. Insulin for GDM and T2DM during pregnancy: systematic review and meta-analysis.

Hallack Christiano C, Nogueira Bernardo Vieira BV, Bomfim Maressa M, Meireles Nathália N et al.

Evaluate the effectiveness and safety of adding metformin to insulin (M+I) versus insulin alone for pregnant women with type 2 diabetes mellitus (T2DM) or gestational diabetes mellitus (GDM), focusing on stillbirth as the primary outcome. PubMed, Embase, and Cochrane Central were searched. No date limits. Last search: January 2025. Randomized clinical trials including women with T2DM or GDM were eligible. Trials restricted to type 1 diabetes were excluded. Two reviewers extracted maternal and neonatal outcomes and assessed risk of bias with the Cochrane RoB 2 tool. Evidence certainty was graded using GRADE. Data were pooled with random-effects models and reported as risk ratios (RRs) or mean differences (MDs) with 95% confidence intervals. Nine RCTs (2,420 women) were included, most with GDM and some with T2DM. Moderate-quality evidence indicated reduced stillbirth risk with M+I (6 RCTs, 2,196 participants; RR 0.36, 95% CI 0.14-0.90; NNT 111). Low-quality evidence suggested lower risks of gestational hypertension (4 RCTs; RR 0.68, 95% CI 0.48-0.97) and neonatal hypoglycemia (7 RCTs; RR 0.49, 95% CI 0.30-0.80). No significant differences were found for cesarean section, preterm delivery, or other neonatal outcomes. Heterogeneity, baseline imbalances, and small samples limited certainty. M+I may reduce stillbirth and some adverse outcomes compared with insulin alone, but most evidence remains low certainty. Further high-quality RCTs are needed.Registered in PROSPERO: CRD42024617330.

Senomorphic agents: Multi-target strategies to tame the senescence-associated secretory phenotype for healthy ageing.

Kong Yue Y, Zhang Qiuyan Q, Zhang Jianzhong J, Fu Qiang Q

Cellular senescence is a central driver of organismal ageing and related pathologies, primarily promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Unlike senolytics, which aim to eliminate senescent cells, senomorphic agents offer a complementary therapeutic strategy by modulating the SASP without clearing the cells, thereby preserving their potential physiological functions. This review systematically elucidates the multi-target mechanisms of senomorphic agents, including the inhibition of key signaling pathways such as NF-κB, mTOR, JAK/STAT, and cGAS-STING. We classify them into three major categories: "old drugs with new uses" and metabolic modulators (e.g., metformin), natural products and their derivatives (e.g., urolithin A), and designed targeted synthetic inhibitors (e.g., ruxolitinib). Furthermore, we review their translational potential in neurodegenerative diseases, cardiovascular ageing, and osteoarthritis, highlighting the advantages of drug repurposing and synergistic therapy with senolytics. Finally, we discuss current challenges-such as the lack of specific biomarkers and targeted delivery systems-and future directions, including precision senotherapy and integrated intervention strategies. This review demonstrates that by 'taming' the senescent microenvironment rather than eliminating cells, senomorphic agents offer a promising strategy for achieving healthy ageing, yet clinical translation remains hindered by the lack of specific biomarkers, tissue-specific delivery systems, and long-term safety data. Here, we summarize current advances and critically analyze the barriers that must be overcome to move senomorphic agents from preclinical models to clinical practice.