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

NCT04504045 | Terminated Phase 1 DMC

• 2 other identifiers: AKF-3952020-000162-42
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (32)

• Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 3.

  Baseline and Week 3.

• Change from Baseline in Metabolic Rate of Caffeine (CYP1A2) at Week 12.

  Baseline and Week 12.

• Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 3.

  Baseline and Week 3.

• Change from Baseline in Metabolic Rate of Efavirenz (CYP2B6) at Week 12.

  Baseline and Week 12.

• Change from Baseline in Metabolic Rate of Losartan (CYP2C9) at Week 3.

  Baseline and Week 3.

Study Arms (1)

Metformin

EXPERIMENTAL

Patients will receive metformin 1000-2000 mg daily for 12 weeks.

Drug: Metformin; Drug: Caffeine; Drug: Efavirenz; Drug: Losartan; Drug: Omeprazol; Drug: Metoprolol; Drug: Midazolam

Interventions

Metformin DRUG

500 mg tablet

Also known as: Glucose lowering treatment

Metformin

Caffeine DRUG

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.

Metformin

Efavirenz DRUG

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.

Metformin

Losartan DRUG

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.

Metformin

Omeprazol DRUG

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.

Metformin

Metoprolol DRUG

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.

Metformin

Midazolam DRUG

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.

Metformin

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Southern Denmark: lead

Study Sites (1)

University of Southern Denmark

Odense, Region Syddanmark, 5000, Denmark

Location

Related Publications (2)

• 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.

  PMID: 26559049 BACKGROUND

• 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.

  PMID: 36967527 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin; Caffeine; efavirenz; Losartan; Omeprazole; Metoprolol; Midazolam

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Tetrazoles; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Pyridines; Benzimidazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines; Benzodiazepines; Benzazepines

Study Officials

• Ann-Cathrine Dunvald, MD

  University of Southern Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: August 7, 2020
• Study Start: September 1, 2020
• Primary Completion: May 10, 2022
• Study Completion: May 10, 2022
• Last Updated: June 16, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)