Effects on Insulin Resistance With Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study (MAKROTAD)

Effects on Insulin Resistance With the Phosphodiesterase-5 Inhibitor Tadalafil in Type 2 Diabetes - a Double-blind, Placebo-controlled Crossover Study

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Tadalafil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden, 41345
    • Sahlgrenska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. T2D patient, previously diagnosed by fasting or 2-hr OGTT plasma glucose levels
2. Age females: 55-70 yrs (post-menopausal state defined as natural amenorrhea for at least 12 months); Age males: 40-70 yrs
3. BMI: 27-40 kg/m2
4. HbA1c < 60 mmol/mol
5. Type 2 diabetes duration > 3 months and < 10 yrs
6. Understand and speak Swedish

Exclusion Criteria:

1. Diabetes treatment with glitazones, GLP-1 analogues or DPP-IV inhibitors
2. Anti-hypertensive therapy with beta-blockers, ACE-inhibitors and/or angiotensin-II receptor blockers
3. Significant microvascular complications e.g. nephropathy (GFR<60), proliferative retinopathy and symptomatic neuropathy e.g. postural hypotension
4. 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
5. Smoking > 10 cig/day and/or smokeless tobacco > one can per 2 days
6. Concurrent use of nitrates or NO donors, or an apparent risk that there may be a need of such medication
7. Cardiac failure (stages NYHA II-IV)
8. Uncontrolled hypertension > 170/105 mm Hg
9. Apparent ECG-pathology indicating current or previous myocardial ischemia;
10. Males with erectile dysfunction
11. Hemophilia or a history of bruises or hepatic failure (> 2-fold increase upper limit normal values of ASAT/ALAT)
12. Hypotension
13. Treatment with doxazosin
14. Anything in the contact with the patient that makes the doctor to believe that he/she will be uncompliant to the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tadalafil; Per oral intake of tadalafil 20 mg o.d. for six weeks	Drug: Tadalafil
Placebo Comparator: Placebo; Per oral intake of placebo	Drug: Placebo; Per oral intake of placebo for six weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 week treatment with drug or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Up to 6 weeks after start of treatment.
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	Up to 6 weeks after start of treatment.
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).	3 weeks after start of treatment.
Levels interstitial insulin	levels interstitial insulin (mU/l)	Up to 6 weeks after start of treatment.
Lactate concentrations in insulin sensitive tissues	Lactate concentrations (micromoles/l) in insulin sensitive tissues	Up to 6 weeks after start of treatment.
Levels of inflammatory markers in blood	Difference in endothelin-1 levels (pg/ml)	Up to 6 weeks after start of treatment.
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia		3 weeks after start of treatment.

Collaborators and Investigators

• Sponsor: Göteborg University
• Collaborators: Vastra Gotaland Region
• Investigators: Principal Investigator: Per-Anders Jansson, MD, Göteborg University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2015
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): January 1, 2019

Study Registration Dates

• First Submitted: October 26, 2015
• First Submitted That Met QC Criteria: November 9, 2015
• First Posted (Estimate): November 11, 2015

Study Record Updates

• Last Update Posted (Actual): February 11, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Tadalafil
• Other Study ID Numbers: 2015-09-14; 2015-000573-12 (EudraCT Number)