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Completed

NCT Number: NCT02601989

Effects on Insulin Resistance With 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.

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Key information

Conditions

Diabetes Mellitus, Type 2 Diabetes Mellitus Endocrine System Diseases Glucose Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

40 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Sahlgrenska University Hospital

Gothenburg, 41345, Sweden

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Tadalafil

Drug

Placebo

Drug

Per oral intake of placebo for six weeks

Primary outcomes

  1. insulin sensitivity

    Time frame: 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 outcomes

  1. Mean glucose (HbA1c, mmol/mol) in blood

    Time frame: 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)

  2. Fasting plasma glucose levels (mmol/l)

    Time frame: 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

  3. Arginine-induced insulin secretion (area under curve, AUC, mU/l/min) in blood

    Time frame: 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).

  4. Levels interstitial insulin

    Time frame: Up to 6 weeks after start of treatment.

    levels interstitial insulin (mU/l)

  5. Lactate concentrations in insulin sensitive tissues

    Time frame: Up to 6 weeks after start of treatment.

    Lactate concentrations (micromoles/l) in insulin sensitive tissues

  6. Levels of inflammatory markers in blood

    Time frame: Up to 6 weeks after start of treatment.

    Difference in endothelin-1 levels (pg/ml)

  7. Endothelial function in peripheral arteries measured with EndoPAT, measured as difference in reactive hyperemia

    Time frame: 3 weeks after start of treatment.

Sponsors and collaborators

Lead sponsor

Göteborg University

Other

Collaborators

  • Vastra Gotaland Region

Registry information

Official study title

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

Acronym: MAKROTAD

Important dates

Study start
2015
Primary completion
2019
Study completion
2019
First posted
Nov 11, 2015
Registry last updated
Feb 11, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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