Short summary

We have previously shown that initiation of glucose-lowering treatment leads to altered drug efficacy. To further elucidate this, we will assess the effect of glucose on expression and activity of important drug-metabolizing enzymes. In a clinical pharmacokinetic study a drug cocktail, to asses the drug-metabolizing enzyme activity, will be administered to patients with type 2 diabetes before and after initiation of the glucose-lowering drug metformin. This will uncover whether lowering of glucose causes altered drug metabolism in patients with type 2 diabetes, which may change dosing and monitoring af drugs taken concomitantly with glucose lowering drugs. 

Rationale

Type 2 diabetes (T2D) is one of the greatest public health challenges of the 21st century. It is estimated that 9% of the adult population suffers from diabetes, and the first-line treatment, metformin, is one of the most prescribed drugs in the world. T2D is defined by increased plasma glucose that leads to micro- and macrovascular complications resulting in a shorter life expectancy and increased comorbidity. Comorbidities require treatment with many different drugs, and most T2D patients are exposed to polypharmacy and hence are at an increased risk of drug-drug interactions.

Pathophysiologically, it is widely established that T2D is linked to activated innate immunity. Patients with T2D have increased levels of C-reactive protein (CRP) and proinflammatory cytokines. Initiation of glucose-lowering treatment leads to reduced CRP and interleukin 6 (IL-6) in plasma of T2D patients with poor glycemic control. IL-6 is a pro-inflammatory cytokine which is released by macrophages during the acute immune respons. In hepatocytes, IL-6 induces synthesis of a number of acute phase proteins such as CRP, serum amyloid A, fibrinogen and hepcidin. Additionally, IL-6 downregulates cytochrome P450 enzymes. This means that there is an inverse correlation between IL-6 plasma levels and drug metabolism as observed in patients with heart failure. Exposure of hepatocytes to IL-6 leads to decreased transcription of CYP2C9, CYP3A4, and CYP1A2. We 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, we hypothesize that this is caused by the glucose-lowering effect rather than drug-drug interactions caused by the individual drugs. 

The results of the clinical study will be supported by in vitro hepatocyte studies, to help us understand the cellular mechanisms. To establish the clinical effect of this we will assess the impact of glucose-lowering treatment on the efficacy on concomitant medication among patient in a register-based study. This translational bench-to-bedside approach will assess the putative link between plasma glucose and drug metabolism and the underlying mechanism. This may change dosing and monitoring of drugs taken concomitantly with glucose lowering drugs. Overall, this will lead to improved drug safety and could help to further personalize treatment among the increasing proportion of individuals with T2D. 

Description of the cohort

Patients with type 2 diabetes diagnosed within the past 2 years and naive to antidiabetic treatment. 

Data and biological material

Blood, urine and clinical data.

Collaborating researchers and departments

Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark. 

• Associate Professor, PhD, MSc. Pharm.,Tore Bjerregaard Stage.

Department of Clinical Biochemistry and Pharmacology, Odense University Hospital 

• MD, PhD, Mette Marie Hougaard Christensen.
• Professor, PhD, MD, Kim Brøsen.

Research Unit of General Practice, Department of Public Health, University of Southern Denmark

• Professor, PhD, MD, Jens Søndergaard.

Publications associated with the project

Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study. Journal of Thrombosis and Haemostasis. 14(1):129-33.