Keisuke Mine

Oxaliplatin is a platinum‐based anticancer agent widely used for gastrointestinal malignancies; however, it is known to cause dose‐dependent peripheral neuropathy (OIPN), a characteristic adverse effect. OIPN results in a reduced quality of life and often necessitates dose reduction or discontinuation of oxaliplatin; however, effective preventive strategies for OIPN have yet to be established. Imeglimin, an oral antidiabetic agent belonging to the glimin class, has been suggested to influence key aspects of cellular energy metabolism. Because metformin, which shares structural and mechanistic features with imeglimin, prevents OIPN and exhibits unique pharmacological actions, we investigated whether imeglimin also prevents OIPN using both in vitro and in vivo models. In vitro, imeglimin attenuated oxaliplatin‐induced cell death, axonal shortening, and oxidative stress in F11 neuronal cells. In vivo, imeglimin prevented reductions in withdrawal thresholds to mechanical stimulation and mitigated sciatic nerve axonal injury in a rat OIPN model. Importantly, imeglimin did not diminish the cytotoxicity of oxaliplatin in several cancer cell lines or its antitumor efficacy in tumor‐bearing mice. These findings suggest that imeglimin may prevent OIPN without compromising the antitumor activity of oxaliplatin.

Oxaliplatin‐induced peripheral neuropathy (OIPN) causes numbness and pain in the limbs, often leading to interruption of chemotherapy and representing a significant clinical problem. Previous basic studies have suggested that the dipeptidyl peptidase‐4 (DPP‐4) inhibitor alogliptin may prevent OIPN. To evaluate whether concomitant use of DPP‐4 inhibitors could prevent the development of OIPN in clinical practice, we retrospectively analyzed data from 1180 patients who initiated oxaliplatin treatment at Kyushu University Hospital between January 1, 2009 and December 31, 2019. The primary endpoint was the occurrence of OIPN of any grade. Kaplan–Meier analysis with cumulative doses demonstrated a significantly lower incidence of OIPN in the DPP‐4 inhibitor group ( p = 0.0422). After propensity score matching to adjust for patient backgrounds, the protective association remained significant ( p = 0.0389). Furthermore, Cox proportional hazards analysis incorporating gender, age, regimen, and concomitant DPP‐4 inhibitor use as covariates confirmed that DPP‐4 inhibitor use was an independent protective factor for OIPN (HR = 0.690; 95% CI, 0.490–0.972; p = 0.034). These findings suggest that concomitant use of DPP‐4 inhibitors may moderate the development of OIPN in patients receiving oxaliplatin.

Malnutrition implies a decline in the systemic status and organ function, which is closely related to sarcopenia, frailty, osteoporosis, and prognosis. Diabetes medications work in a multifaceted manner on various tissues, such as the pancreas, muscle, liver, and adipose tissue; these medications affect metabolism, which in turn affects nutritional status. This study aimed to determine the effect of diabetes medications on the scores of the Geriatric Nutrition Risk Index (GNRI) and Controlling Nutritional Status (CONUT) nutritional indices, both cross‐sectionally and longitudinally. This cross‐sectional study included 2146 individuals who were prescribed diabetes medications. Multivariate analysis showed that both GNRI and CONUT scores tended to be improved in patients using sodium‐glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase 4 inhibitors (DPP4i), or biguanide (BG). Additionally, propensity score matching of nutrition‐related laboratory values was performed to assess the variation in nutritional indices over time, which resulted in less deterioration of the GNRI in the SGLT2i and BG groups. In conclusion, this study suggests that SGLT2i and BG prevent the progression of malnutrition and may help in selecting drugs that consider the nutritional status of patients.

Background: Oxaliplatin‐induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN. Methods: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non‐PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan–Meier curve was generated for cumulative doses and evaluated using the log‐rank test and Cox proportional hazards analysis. Results: The log‐rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group ( p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344–0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group ( p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273–0.836, p = 0.0096). Conclusions: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.