Back to resultsEffects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study (MAKROTAD)
Primary Purpose
Diabetes Mellitus, Type 2
Status
Completed
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Tadalafil
Placebo
Sponsored by
About this trial
This is an interventional supportive care trial for Diabetes Mellitus, Type 2
Eligibility Criteria
Inclusion Criteria:
- T2D patient, previously diagnosed by fasting or 2-hr OGTT plasma glucose levels
- Age females: 55-70 yrs (post-menopausal state defined as natural amenorrhea for at least 12 months); Age males: 40-70 yrs
- BMI: 27-40 kg/m2
- HbA1c < 60 mmol/mol
- Type 2 diabetes duration > 3 months and < 10 yrs
- Understand and speak Swedish
Exclusion Criteria:
- Diabetes treatment with glitazones, GLP-1 analogues or DPP-IV inhibitors
- Anti-hypertensive therapy with beta-blockers, ACE-inhibitors and/or angiotensin-II receptor blockers
- Significant microvascular complications e.g. nephropathy (GFR<60), proliferative retinopathy and symptomatic neuropathy e.g. postural hypotension
- Previous significant vascular disease including angina pectoris and myocardial infarction, cerebral artery disease e.g. history of transient ischemic attacks and peripheral artery disease with no palpable pulses
- Smoking > 10 cig/day and/or smokeless tobacco > one can per 2 days
- Concurrent use of nitrates or NO donors, or an apparent risk that there may be a need of such medication
- Cardiac failure (stages NYHA II-IV)
- Uncontrolled hypertension > 170/105 mm Hg
- Apparent ECG-pathology indicating current or previous myocardial ischemia;
- Males with erectile dysfunction
- Hemophilia or a history of bruises or hepatic failure (> 2-fold increase upper limit normal values of ASAT/ALAT)
- Hypotension
- Treatment with doxazosin
- Anything in the contact with the patient that makes the doctor to believe that he/she will be uncompliant to the protocol.
Sites / Locations
- Sahlgrenska University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Tadalafil
Placebo
Arm Description
Per oral intake of tadalafil 20 mg o.d. for six weeks
Per oral intake of placebo
Outcomes
Primary Outcome Measures
insulin sensitivity
To evaluate the effect (difference in glucose disposal rate (mg/kg/min)) of daily administration of 20 mg tadalafil for 6 weeks ("chronic" treatment) on insulin sensitivity in muscle by assessing glucose disposal rate during a 3-hour euglycemic hyperinsulinemic glucose clamp (120 mU/m2/min) in T2D patients
Secondary Outcome Measures
Mean glucose (HbA1c, mmol/mol) in blood
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by mean blood glucose (HbA1c)
Fasting plasma glucose levels (mmol/l)
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by circulating glucose levels
Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood
Glucose metabolism and beta-cell function as measured by arginine-induced insulin secretion (difference in AUC, mU/l/min).
Levels interstitial insulin
levels interstitial insulin (mU/l)
Lactate concentrations in insulin sensitive tissues
Lactate concentrations (micromoles/l) in insulin sensitive tissues
Levels of inflammatory markers in blood
Difference in endothelin-1 levels (pg/ml)
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia
Full Information
NCT ID
NCT02601989
First Posted
October 26, 2015
Last Updated
February 10, 2020
Sponsor
Göteborg University
Collaborators
Vastra Gotaland Region
1. Study Identification
Unique Protocol Identification Number
NCT02601989
Brief Title
Effects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
Acronym
MAKROTAD
Official Title
Effects on Insulin Resistance With the Phosphodiesterase-5 Inhibitor Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
Study Type
Interventional
2. Study Status
Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
November 2015 (Actual)
Primary Completion Date
January 2019 (Actual)
Study Completion Date
January 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Göteborg University
Collaborators
Vastra Gotaland Region
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The aim is to continue our program on PDE5 inhibition by evaluating effects on insulin resistance, including glucose metabolism and subclinical inflammation, after a 6-week administration of tadalafil in T2D patients. The primary objective is to study the effect of tadalafil compared with placebo on insulin sensitivity during a euglycemic hyperinsulinemic clamp.
This is a double-blind, placebo-controlled crossover study with one study site. Twenty-five T2D patients will be recruited and randomized to per oral intake of tadalafil 20 mg o.d. for six weeks and after a wash-out period of eight weeks intake of placebo for another six weeks, or vice versa. At the end of each 6 week treatment period a glucose clamp, subcutaneous needle biopsies as well as muscle and subcutaneous microdialysis will be performed. Endothelial function tests and arginin stimulation of insulin secretion tests will be performed after 3 weeks in each treatment arm.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2
7. Study Design
Primary Purpose
Supportive Care
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
23 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Tadalafil
Arm Type
Experimental
Arm Description
Per oral intake of tadalafil 20 mg o.d. for six weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Per oral intake of placebo
Intervention Type
Drug
Intervention Name(s)
Tadalafil
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Per oral intake of placebo for six weeks
Primary Outcome Measure Information:
Title
insulin sensitivity
Description
To evaluate the effect (difference in glucose disposal rate (mg/kg/min)) of daily administration of 20 mg tadalafil for 6 weeks ("chronic" treatment) on insulin sensitivity in muscle by assessing glucose disposal rate during a 3-hour euglycemic hyperinsulinemic glucose clamp (120 mU/m2/min) in T2D patients
Time Frame
6 week treatment with drug or placebo
Secondary Outcome Measure Information:
Title
Mean glucose (HbA1c, mmol/mol) in blood
Description
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by mean blood glucose (HbA1c)
Time Frame
Up to 6 weeks after start of treatment.
Title
Fasting plasma glucose levels (mmol/l)
Description
Evaluation the effect of chronic tadalafil treatment on glucose metabolism and beta-cell function as measured by circulating glucose levels
Time Frame
Up to 6 weeks after start of treatment.
Title
Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood
Description
Glucose metabolism and beta-cell function as measured by arginine-induced insulin secretion (difference in AUC, mU/l/min).
Time Frame
3 weeks after start of treatment.
Title
Levels interstitial insulin
Description
levels interstitial insulin (mU/l)
Time Frame
Up to 6 weeks after start of treatment.
Title
Lactate concentrations in insulin sensitive tissues
Description
Lactate concentrations (micromoles/l) in insulin sensitive tissues
Time Frame
Up to 6 weeks after start of treatment.
Title
Levels of inflammatory markers in blood
Description
Difference in endothelin-1 levels (pg/ml)
Time Frame
Up to 6 weeks after start of treatment.
Title
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia
Time Frame
3 weeks after start of treatment.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
T2D patient, previously diagnosed by fasting or 2-hr OGTT plasma glucose levels
Age females: 55-70 yrs (post-menopausal state defined as natural amenorrhea for at least 12 months); Age males: 40-70 yrs
BMI: 27-40 kg/m2
HbA1c < 60 mmol/mol
Type 2 diabetes duration > 3 months and < 10 yrs
Understand and speak Swedish
Exclusion Criteria:
Diabetes treatment with glitazones, GLP-1 analogues or DPP-IV inhibitors
Anti-hypertensive therapy with beta-blockers, ACE-inhibitors and/or angiotensin-II receptor blockers
Significant microvascular complications e.g. nephropathy (GFR<60), proliferative retinopathy and symptomatic neuropathy e.g. postural hypotension
Previous significant vascular disease including angina pectoris and myocardial infarction, cerebral artery disease e.g. history of transient ischemic attacks and peripheral artery disease with no palpable pulses
Smoking > 10 cig/day and/or smokeless tobacco > one can per 2 days
Concurrent use of nitrates or NO donors, or an apparent risk that there may be a need of such medication
Cardiac failure (stages NYHA II-IV)
Uncontrolled hypertension > 170/105 mm Hg
Apparent ECG-pathology indicating current or previous myocardial ischemia;
Males with erectile dysfunction
Hemophilia or a history of bruises or hepatic failure (> 2-fold increase upper limit normal values of ASAT/ALAT)
Hypotension
Treatment with doxazosin
Anything in the contact with the patient that makes the doctor to believe that he/she will be uncompliant to the protocol.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Per-Anders Jansson, MD
Organizational Affiliation
Göteborg University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sahlgrenska University Hospital
City
Gothenburg
ZIP/Postal Code
41345
Country
Sweden
12. IPD Sharing Statement
Learn more about this trial
Effects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study
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