Clinical trial NCT04504045: Metformin's Effect on Drug Metabolism in Patients With Type 2 Diabetes
Official title: INFLAMMATION AND DRUG METABOLISM - Does the Effect of Drugs Decrease When Patients With Type 2 Diabetes Initiate Antidiabetic Treatment?
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
First posted: 2020-08-07
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief 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.


Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes, not treated metformin.
* Hemoglobin 1Ac (HbA1c): ≥48 mmol/mol
* Age: 18-75 years
* Body Mass Index (BMI) ≤ 40 kg/m2
* Estimated Glomerular Filtration Rate (eGFR) \> 60 mL/min
* Alanine Aminotransferase (ALAT), bilirubin and hemoglobin within reference range or clinically insignificant differ from this.

Exclusion Criteria:

* Acute or chronic infection or inflammation
* Active cancer
* Glutamic acid decarboxylase (GAD)-antibodies
* Known hypersensitivity to one or several of the drugs
* Intake of medications which can influence the safety of the patient or the results of the study
* Alcohol consumption above the limits recommended by the Danish Health Authorities (Men 14 units/week, women 7 units/week)
* Participation in other trials with interventions.
* Women: Positive pregnancy test at inclusion or on one of the test-days.

Primary outcomes:
measure: Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 12.
timeFrame: Baseline and Week 12.
Secondary outcomes:
measure: Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in HbA1c at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in HbA1c at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in insulin resistance at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in insulin resistance at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interleukin-1-B at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interleukin-1-B at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interleukin-2 at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interleukin-2 at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interleukin-6 at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interleukin-6 at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interleukin-10 at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interleukin-10 at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interferon-a at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interferon-a at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interferon-B at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interferon-B at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Interferon-y at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Interferon-y at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in Tumor Necrosis Factor-a at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in Tumor Necrosis Factor-a at Week 12.
timeFrame: Baseline and Week 12.
measure: Change from Baseline in High Sensitivity C-Reactive Protein at Week 3.
timeFrame: Baseline and Week 3.
measure: Change from Baseline in High Sensitivity C-Reactive Protein at Week 12.
timeFrame: Baseline and Week 12.
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: University of Southern Denmark
state: Region Of Southern Denmark
Study officials:
affiliation: University of Southern Denmark
name: Ann-Cathrine Dunvald, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.