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

Phase 2

Completed

• Conditions: Diabetes Mellitus, Type 2
• Interventions: Drug: Placebo; Drug: Tadalafil

• Registration Number: NCT02601989
• Lead Sponsor: Göteborg University

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-10-26
• Study Start: 2015-11
• Study First Submitted QC: 2015-11-09
• Study First Posted: 2015-11-11
• Primary Completion: 2019-01
• Study Completion: 2019-01
• Status Verified: 2020-02
• Last Update Submitted: 2020-02-10
• Last Update Posted: 2020-02-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 23

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Per oral intake of placebo
Tadalafil	Tadalafil	Per oral intake of tadalafil 20 mg o.d. for six weeks

Primary Outcome Measures

Name	Time	Method
insulin sensitivity	6 week treatment with drug or placebo	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

Name	Time	Method
Mean glucose (HbA1c, mmol/mol) in blood	Up to 6 weeks after start of treatment.	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)	Up to 6 weeks after start of treatment.	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	3 weeks after start of treatment.	Glucose metabolism and beta-cell function as measured by arginine-induced insulin secretion (difference in AUC, mU/l/min).
Levels interstitial insulin	Up to 6 weeks after start of treatment.	levels interstitial insulin (mU/l)
Lactate concentrations in insulin sensitive tissues	Up to 6 weeks after start of treatment.	Lactate concentrations (micromoles/l) in insulin sensitive tissues
Levels of inflammatory markers in blood	Up to 6 weeks after start of treatment.	Difference in endothelin-1 levels (pg/ml)
Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia	3 weeks after start of treatment.

Trial Locations

Locations (1)

Sahlgrenska University Hospital; 🇸🇪 Gothenburg, Sweden