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

Diabetes Mellitus, Type 2 Clinical Trial

— MAKROTAD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02601989
• Other study ID #: 2015-09-14
• Secondary ID: 2015-000573-12
• Status: Completed
• Phase: Phase 2
• Start date: November 2015
• Est. completion date: January 2019

Study information

• Verified date: February 2020
• Source: Göteborg University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: January 2019
• Est. primary completion date: January 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Insulin Resistance

Intervention

Drug:
• Tadalafil

• Placebo
Per oral intake of placebo for six weeks

Locations

Country	Name	City	State
Sweden	Sahlgrenska University Hospital	Gothenburg

Sponsors (2)

Lead Sponsor	Collaborator
Göteborg University	Vastra Gotaland Region

Country where clinical trial is conducted

Sweden, 

Outcome

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