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

Study Overview
=================
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.

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

Conditions
-----------------
Diabetes Mellitus, Type 2

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Caffeine
* Drug: Efavirenz
* Drug: Losartan
* Drug: Omeprazol
* Drug: Metoprolol
* Drug: Midazolam


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Patients will receive metformin 1000-2000 mg daily for 12 weeks. | Drug: Metformin<br>* 500 mg tablet<br>* Other names: Glucose lowering treatment;Drug: Caffeine<br>* 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.<br>Drug: Efavirenz<br>* 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.<br>Drug: Losartan<br>* 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.<br>Drug: Omeprazol<br>* 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.<br>Drug: Metoprolol<br>* 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.<br>Drug: Midazolam<br>* 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.<br>|

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. |