Prescription trend and lactic acidosis in patients prescribed metformin before and after the revision of package insert for allowing metformin administration to patients with moderately decreased kidney function based on real-world data from MID-NET® in Japan

IntroductionThis study was conducted to understand the impact of package insert (PI) revision in Japan on 18 June 2019 to allow metformin use for patients with moderately decreased kidney function (30 ≤ estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2).MethodsA new user cohort design was employed to examine the prescription trend and the occurrence of lactic acidosis in patients prescribed metformin before and after PI revision using the Medical Information Database Network (MID-NET®).ResultsFrom 12 May 2016 to 31 March 2020, 5,874 patients (before, n = 4,702; after, n = 1,172) were identified as new metformin users, including 1,145 patients (before, n = 914; after, n = 231) with moderately decreased kidney function. Although no marked changes in metformin prescription were observed before and after PI revision, the daily metformin dose at the first prescription decreased after PI revision. For both before and after PI revision, less than 10 cases of lactic acidosis occurred in all patients prescribed metformin, and no lactic acidosis was observed in patients with moderately decreased kidney function.ConclusionThe results of this study are useful for understanding the safety of metformin use in patients with decreased kidney function and suggest no worse impacts of PI revision in Japan, indicating no further safety concerns on metformin use in patients with moderately decreased kidney function under the situation with careful use and safety monitoring of metformin

Baseline characteristics of patients on laboratory test results.

Baseline characteristics of patients on laboratory test results.</p

The percentage of patients with abnormal laboratory test results.

The percentage of patients with abnormal laboratory test results.</p

Trend of prescription pattern of anti-COVID-19 drugs in 2020 and 2021 (first to fifth waves).

Trend of prescription pattern of anti-COVID-19 drugs in 2020 and 2021 (first to fifth waves).</p

Change in prescription patterns of anti-COVID-19 drugs in an individual patient.

Bar, Baricitinib; Dex, dexamethasone; Fav, Favipiravir; Rem, remdesivir. “Other” represents the other prescription patterns. * N1 indicates the number of hospitalized patients with COVID-19 who received at least one anti-COVID-19 drug (entire cohort). The percentage represent the proportion of the number of patients prescribed each prescription pattern to N1. †, ‡ N2 and N3 indicate the number of patients who have changed to subsequent prescribed patterns. The percentage represent the proportion of the number of patients prescribed each prescription pattern to N2 or N3.</p

Patient characteristics of the entire cohort and subcohort at first prescription.

Patient characteristics of the entire cohort and subcohort at first prescription.</p

High levels of fatty acid synthase expression in esophageal cancers represent a potential target for therapy

Fatty acid synthase (FAS) is overexpressed in many human cancers and is considered to be a promising target for therapy. To investigate the expression of this candidate target in esophageal cancer, we evaluated expression of FAS protein in 22 cases of esophageal squamous cancer, 79 cases of esophageal adenocarcinoma and 16 cases of Barrett's esophagus with high-grade dysplasia-a lesion thought to represent a pre-invasive precursor to esophageal cancer. Using immunohistochemistry, we found significantly higher levels of FAS expression in 77% of the squamous cancers, 96% of the adenocarcinomas and 94% of the Barrett's lesions with high-grade dysplasia, when compared to levels in normal esophageal epithelium and non-dysplastic Barrett mucosa. To evaluate the potential for inhibiting this enzyme as a treatment of esophageal cancer, we treated mice bearing xenografts of the Colo680N esophageal squamous cell carcinoma cell line using C93, a rationally designed molecule that inhibits FAS activity. In these experiments, C93 significantly inhibited the growth of orthotopic xenograft tumors without causing anorexia and weight loss in the treated animals. We conclude that, similar to several other common types of human cancer, FAS is expressed at very high levels in esophageal cancer and growth of these cancers can be inhibited by pharmacological agents that target this enzyme. Moreover, this high expression of FAS is also seen in high-risk, pre-invasive lesions of the esophagus, leading us to propose considering FAS-inhibitors for purposes of esophageal cancer chemoprevention