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

Study Overview
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Brief Summary
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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.

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

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Tadalafil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tadalafil<br>Per oral intake of tadalafil 20 mg o.d. for six weeks | Drug: Tadalafil<br> <br> |
| Placebo Comparator: Placebo<br>Per oral intake of placebo | Drug: Placebo<br>* Per oral intake of placebo for six weeks<br>|

What is the study measuring?
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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. |