Metformin's Effect on Drug Metabolism in Patients With Type 2 Diabetes

Summary

Type 2 diabetes is a major public health concern. It is widely established that type 2 diabetes in linked to activated innate immunity and increased levels of C-reactive protein and interleukin-6 (IL-6) in plasma. Studies in humans and in liver cells has shown that IL-6 downregulates important drug metabolizing enzymes in the liver (cytochrome P450 (CYP) enzymes). More than half of the most prescribed drugs are eliminated by biotransformation of these enzymes. The investigators have previously shown that initiating glucose-lowering treatment (e.g. metformin, sulphonylureas and insulin) leads to decreased therapeutic efficacy of the blood-thinning vitamin-K antagonist warfarin. Due to the non-specific effect of glucose lowering drugs, the investigators hypothesize that this is caused by the glucose-lowering effect rather than drug-drug interactions caused by the individual drugs. Based on the proposal that reversal of increased plasma glucose affects drug metabolism, the investigators will perform a clinical pharmacokinetic trial. The purpose of the study is to elucidate whether initiation of glucose-lowering treatment causes altered drug metabolism among patients with type 2 diabetes. The study will include newly diagnosed and untreated type 2 diabetes patients who will ingest a 6-drug cocktail consisting of probes for specific CYP enzymes. Plasma and urine will be drawn over 6 hours to determine concentrations of the drugs and their metabolites. Patients will then initiate metformin treatment and to assess both short- and long-term impact of glucose-lowering, the same 6-drug cocktail will be ingested, and concentrations measured, after three weeks and three months. To help understand the mechanism and the putative involvement of inflammation, markers of inflammation such as cytokines, transcription factors, etc. will also be assesses.

Timeline

Start

2020-09-01

Primary completion

2022-05-10

Completion

2022-05-10

Publications

• Background Stage TB, Pottegard A, Henriksen DP, Christensen MM, Hojlund K, Brosen K, Damkier P. Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study. J Thromb Haemost. 2016 Jan;14(1):129-33. doi: 10.1111/jth.13187. Epub 2015 Dec 29.
• Dunvald AD, Nielsen F, Olsen DA, Ernst MT, Donnelly L, Soto-Pedre E, Kristiansen MR, Nielsen JS, Persson F, Hojlund K, Madsen JS, Sondergaard J, Pearson E, Pottegard A, Stage TB. Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin-But not through altered drug metabolism in patients with type 2 diabetes. Br J Clin Pharmacol. 2023 Aug;89(8):2529-2541. doi: 10.1111/bcp.15725. Epub 2023 Apr 14.

Drugs

Indications