Drug-repurposing identified the combination of Trolox C and Cytisine for the treatment of type 2 diabetes

Abstract Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality. Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index. Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR. Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.

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Drug repurposing: Dipeptidyl peptidase IV (DPP4) inhibitors as potential agents to treat SARS-CoV-2 (2019-nCov) infection

10.21203/rs.3.rs-28134/v1 ◽

2020 ◽

Author(s):

Praveen P. N. Rao ◽

Amy Trinh Pham ◽

Arash Shakeri ◽

Amna El Shatshat ◽

Yusheng Zhao ◽

...

Keyword(s):

Type 2 Diabetes ◽

Treatment Options ◽

Drug Repurposing ◽

Dipeptidyl Peptidase ◽

New Drugs ◽

Viral Protease ◽

Dipeptidyl Peptidase 4 ◽

Dpp4 Inhibitors ◽

Current Outbreak

Abstract The current outbreak of severe acute respiratory distress syndrome (SARS) or nCOVID-19 pandemic, caused by the coronavirus-2 (CoV-2), continues to wreak havoc globally. Unfortunately, there are no concrete treatment options available which has severely hampered the pharmacotherapy of this devastating infection. This calls for an urgent need to consider alternative strategies which can be employed quickly, as discovering new drugs for SARS-CoV-2 infections is a time consuming and expensive proposition. In this regard, drug repurposing is an appealing approach which can provide rapid access to therapeutics with proven record of safety and efficacy. Accordingly, we investigated the drug repurposing potential of a library of dipeptidyl peptidase 4 (DPP4) inhibitors which are currently marketed for type-2 diabetes, to treat SARS-CoV-2 infections. Computational studies were conducted in the crystal structure of the substrate binding site of viral protease, the SARS-CoV-2 Mpro dimer, which led to the identification of three marketed DPP4 inhibitors; gemigliptin, linagliptin and evogliptin exhibiting favorable binding, in the SARS-CoV-2 Mpro dimer, viral protease. These studies support the repurposing of DPP4 class of inhibitors in treating SARS-CoV-2 infections, especially in elderly patients with type-2 diabetes, who are at a greater risk of suffering from increased disease severity and mortality.

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