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

INFLAMMATION AND DRUG METABOLISM - Does the Effect of Drugs Decrease When Patients With Type 2 Diabetes Initiate Antidiabetic Treatment?

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.

Study Overview

• Status: Terminated
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Metformin; Drug: Caffeine; Drug: Efavirenz; Drug: Losartan; Drug: Omeprazol; Drug: Metoprolol; Drug: Midazolam

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Region Of Southern Denmark
    • Odense, Region Of Southern Denmark, Denmark, 5000
      • University of Southern Denmark

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Metformin; Patients will receive metformin 1000-2000 mg daily for 12 weeks.

Drug: Metformin; 500 mg tablet; Other Names: Glucose lowering treatment; Drug: Caffeine; As part of a 6-drug cocktail caffeine 100 mg tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP1A2 activity.; Drug: Efavirenz; As part of a 6-drug cocktail efavirenz 50 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2B6 activity.; Drug: Losartan; As part of a 6-drug cocktail losartan 12.5 mg coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C9 activity.; Drug: Omeprazol; As part of a 6-drug cocktail Omeprazol 10 mg enteric-coated tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2C19 activity.; Drug: Metoprolol; As part of a 6-drug cocktail metoprolol 12.5 mg release tablet will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP2D6 activity.; Drug: Midazolam; As part of a 6-drug cocktail midazolam 2 mg oral solution will be administered as a single dose before the initiation of metformin treatment and 3 weeks and 12 weeks after. The drug will be used as a probe to assess CYP3A4 activity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 3.	Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 3 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Midazolam (CYP3A4) at Week 12.	Change in activity of the drug metabolizing enzyme CYP3A4 following treatment with the glucose lowering drug metformin in 12 weeks. Assessment of the change is based on a change in the metabolic rate, which is the ratio between the concentration of midazolam and its primary metabolite is plasma (Probe drug for CYP3A4).	Baseline and Week 12.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 3.	Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 12.	Change in activity of the drug metabolizing enzymes CYP1A2 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug caffeine.	Baseline and Week 12.
Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 3.	Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 12.	Change in activity of the drug metabolizing enzymes CYP2B6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Efavirenz.	Baseline and Week 12.
Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 3.	Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 12.	Change in activity of the drug metabolizing enzymes CYP2C9 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Losartan.	Baseline and Week 12.
Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 3.	Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Omeprazole (CYP2C19) at Week 12.	Change in activity of the drug metabolizing enzymes CYP2C19 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Omeprazole.	Baseline and Week 12.
Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 3.	Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 3 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.	Baseline and Week 3.
Change from Baseline in Metabolic Rate of Metoprolol (CYP2D6) at Week 12.	Change in activity of the drug metabolizing enzymes CYP2D6 following treatment with the glucose lowering drug metformin after 12 weeks. The change in activity is based on the metabolic rate for the probe drug Metoprolol.	Baseline and Week 12.
Change from Baseline in HbA1c at Week 3.	Change in the regulation of blood glucose over time assessed by HbA1c	Baseline and Week 3.
Change from Baseline in HbA1c at Week 12.	Change in the regulation of blood glucose over time assessed by HbA1c	Baseline and Week 12.
Change from Baseline in insulin resistance at Week 3.	An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.	Baseline and Week 3.
Change from Baseline in insulin resistance at Week 12.	An oral glucose tolerance test will be performed and glucose, insulin and c-peptide will be measured and combined by the Homeostatic Model Assessment (HOMA) to report insulin resistance.	Baseline and Week 12.
Change from Baseline in Interleukin-1-B at Week 3.	Change in patients inflammatory status assessed by measurement of Interleukin-1-B.	Baseline and Week 3.
Change from Baseline in Interleukin-1-B at Week 12.	Change in patients inflammatory status assessed by measurement of Interleukin-1-B.	Baseline and Week 12.
Change from Baseline in Interleukin-2 at Week 3.	Change in patients inflammatory status assessed by measurement of Interleukin-2.	Baseline and Week 3.
Change from Baseline in Interleukin-2 at Week 12.	Change in patients inflammatory status assessed by measurement of Interleukin-2.	Baseline and Week 12.
Change from Baseline in Interleukin-6 at Week 3.	Change in patients inflammatory status assessed by measurement of Interleukin-6.	Baseline and Week 3.
Change from Baseline in Interleukin-6 at Week 12.	Change in patients inflammatory status assessed by measurement of Interleukin-6.	Baseline and Week 12.
Change from Baseline in Interleukin-10 at Week 3.	Change in patients inflammatory status assessed by measurement of Interleukin-10.	Baseline and Week 3.
Change from Baseline in Interleukin-10 at Week 12.	Change in patients inflammatory status assessed by measurement of Interleukin-10.	Baseline and Week 12.
Change from Baseline in Interferon-a at Week 3.	Change in patients inflammatory status assessed by measurement of Interferon-a.	Baseline and Week 3.
Change from Baseline in Interferon-a at Week 12.	Change in patients inflammatory status assessed by measurement of Interferon-a.	Baseline and Week 12.
Change from Baseline in Interferon-B at Week 3.	Change in patients inflammatory status assessed by measurement of Interferon-B.	Baseline and Week 3.
Change from Baseline in Interferon-B at Week 12.	Change in patients inflammatory status assessed by measurement of Interferon-B.	Baseline and Week 12.
Change from Baseline in Interferon-y at Week 3.	Change in patients inflammatory status assessed by measurement of Interferon-y.	Baseline and Week 3.
Change from Baseline in Interferon-y at Week 12.	Change in patients inflammatory status assessed by measurement of Interferon-y.	Baseline and Week 12.
Change from Baseline in Tumor Necrosis Factor-a at Week 3.	Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.	Baseline and Week 3.
Change from Baseline in Tumor Necrosis Factor-a at Week 12.	Change in patients inflammatory status assessed by measurement of Tumor Necrosis Factor-a.	Baseline and Week 12.
Change from Baseline in High Sensitivity C-Reactive Protein at Week 3.	Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.	Baseline and Week 3.
Change from Baseline in High Sensitivity C-Reactive Protein at Week 12.	Change in patients inflammatory status assessed by measurement of High Sensitivity C-Reactive Protein.	Baseline and Week 12.

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Investigators: Principal Investigator: Ann-Cathrine Dunvald, MD, University of Southern Denmark

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): May 10, 2022
• Study Completion (Actual): May 10, 2022

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: August 6, 2020
• First Posted (Actual): August 7, 2020

Study Record Updates

• Last Update Posted (Actual): June 16, 2022
• Last Update Submitted That Met QC Criteria: June 14, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Cytochrome P-450 CYP2C19 Inhibitors; Midazolam; Metformin; Losartan; Metoprolol; Caffeine; Efavirenz
• Other Study ID Numbers: AKF-395; 2020-000162-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual participant data cannot be shared due to general data protection regulation (GDPR).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No