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Trial record 22 of 809 for:    APOB

Effect of Linagliptin on TRL Metabolism

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ClinicalTrials.gov Identifier: NCT02280174
Recruitment Status : Unknown
Verified November 2014 by MD/PhD Nogueira, Juan Patricio, Ministry of Public Health, Argentina.
Recruitment status was:  Recruiting
First Posted : October 31, 2014
Last Update Posted : November 4, 2014
Sponsor:
Collaborators:
Aix Marseille Université
Instituto de Biología y Medicina Experimental, IBYME, Buenos Aires, Argentina
Information provided by (Responsible Party):
MD/PhD Nogueira, Juan Patricio, Ministry of Public Health, Argentina

Brief Summary:

Overproduction of intestinally derived triglyceride-rich lipoproteins (TRLs) (chylomicrons) has recently been described in type 2 diabetes (T2DM), as is known for hepaticTRL (very-low-density lipoprotein) production.

There is an interest in identifying therapies that would favourably influence postprandial concentrations of lipids in T2DM.

linagliptin is a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-IV), and has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes mainly through incretin hormone-mediated improvements in islet function.

Although clinical studies to date indicate that fasting lipid levels are minimally affected by DPP-IV inhibitor treatment, animal studies suggested that DPP-IV inhibition reduce intestinal triglycerides (TG) absorption and apolipoprotein (apo) production and increased chylomicron catabolism. Interestingly, a recent study supporting this hypothesis showed that vildagliptin therapy was able to reduce postprandial intestinal TRL particles in patients with type 2 diabetes. Recently, it had reported that sitagliptin treatment significantly reduced plasma apoB-48 and TG concentrations in the postprandial state.

The action of DPP-IV inhibitors may be explained by insulin secretion or action of glucagon-like peptide (GLP-1) on metabolism of TRL.

Therefore, the present study was designed to examine the effects of linagliptin treatment (LT) vs standard treatment (ST) on the metabolism of TRL apoB-48 in patients with type 2 diabetes over a 12 weeks-period.

The investigators will study the patients in three different moments defined as: Time 0 (2 weeks before LT or ST, Time 1 (4 weeks after LT or ST), Time 2 (12 weeks after LT or ST). With areas under the curve (AUCs) of apoB48 in postprandial conditions.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: linagliptin Phase 4

Detailed Description:

Uncontrolled type 2 Diabetes patients with HbA1c between 7 and 10% Patients must have received the maximum tolerated dose of metformin for at least 3 months before randomization. Patients will be randomised to receive linagliptin or standard therapy.

A total of seven study visits will be scheduled: at screening, at weeks -4, -2, 0, 4, 6, 12 and 24 week follow-up. During each visit, an endocrinologist will make the physical and metabolic assessment. Safety and tolerability data will be collected at screening and throughout the study, and includes incidence of serious and non serious adverse events (AEs) in linagliptin arms and standard arms. Clinical laboratory data, vital signs, and 12-lead electrocardiogram parameters at each visit, will be collected. The causal relationships between study drugs and AEs will be evaluated by the investigators at site. All drug-related AEs occurring during the study will be followed up until relieved or judged to be no longer clinically significant. Changes in body weight from baseline until week 12 will also be assessed. Hypoglycaemic event intensity will be defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤ 50 mg/dl.

The investigators will study the patients in three different moments defined as: Time 0 (2 weeks before LT or ST), Time 1 (4 weeks after LT or ST), Time 2 (12 weeks after LT or ST). T1 show the direct effect (independent of metabolic changes) and T2 show indirect effect (depend of metabolic changes).

In each phase, following an overnight fast, an intravenous catheter will be inserted into a superficial vein in each forearm for blood sampling. After an overnight fast, subjects were admitted in the research unit for a 24-h period and received un isocaloric (900 kcal), mixed meals (75 g carbohydrates, 50 g fat (60% saturated), 35 g protein), at time points 7.00 a.m. (breakfast). Blood samples will drawn before and 2, 4, 6, 8, after the meal. The area under curve (AUC) and incremental AUC (IAUC) for postprandial variables will calculate in each phase.

In the morning after each phase study: basal (T0) and incretin conditions (T1 and T2), subjects will undergo hyperglycaemic clamp and hyperinsulinaemic clamp, successively. The insulin secretion rate and insulin sensitivity index will be measured during the last 30 minutes of the clamp, respectively in two arms of the study.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Effect of Linagliptin on Intestinal Triglyceride-rich-lipoprotein Metabolism in Type 2 Diabetic Patients
Study Start Date : September 2014
Actual Primary Completion Date : November 2014
Estimated Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Linagliptin

Arm Intervention/treatment
Experimental: Drug: linagliptin
linagliptin 5 mg/d for 12 weeks
Drug: linagliptin
linagliptin 5 mg/d for12 weeks
Other Name: Trajenta®

No Intervention: Drug: standard treatment
sulfonylurea treatment for 12 weeks



Primary Outcome Measures :
  1. Measurement of the Area Under the Curve of Plasma apoB-48 Levels During Postprandial Period (Time 0,2,4,6,8 Hours) [ Time Frame: At the end of the 12-week interventions ]


Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 60 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men from 40 to 65 years old. (excluding women because of hormonal changes in post menopause period could be influenced lipid parameters)
  • Type 2 diabetes as defined by the American Diabetes Association.
  • Body mass index between 25 and 40.0 kg/m².
  • Baseline glycated hemoglobin A1c (HbA1c) between 7 and 10 %.
  • Patients having received stable doses of metformin for at least 3 months before randomization.
  • Non-smoker.
  • Subject without cardiovascular events 6 months ago. (the treatment with lipid lowering agents and beta blockers in this condition could be perturbed the lipids parameters)
  • Subject is informed and is consented.
  • Plasma without severe dyslipidaemia: plasma triglyceride levels <4.51mmol/L (<400 mg/dl), plasma HDL levels >1.0 mmol/L (>40 mg/dl), LDL-cholesterol <5.10 mmol/L (<200 mg/dl).

Exclusion Criteria:

  • Patients having received or being treated with pioglitazone, GLP-1 analogues, insulin or anti-obesity drugs (orlistat) within the past 3 months will be excluded
  • Patients taking any other hypoglycemic agent, other than metformin.
  • Patients with type 1 diabetes, secondary diabetes or acute metabolic diabetic complications will be excluded.
  • Subjects will be excluded if they have cardiovascular disease (coronary heart disease, cerebrovascular disease or peripheral arterial disease) or if they are taking other medications known to affect lipoprotein metabolism (e.g. steroids, beta blockers, thiazide diuretics, lipid lowering agents: (statins, fibrates, ezetimibe, niacin), significant alcohol intake etc.).
  • Subjects who are in a situation or have any condition that, in the opinion of the investigator, may interfere with optimal participation in the study.
  • Individuals with a history of mental instability, individuals who have been treated or are being treated for severe psychiatric illness that, in the opinion of the investigator, may interfere with optimal participation in the study.
  • History of alcohol or drug abuse within the past 2 years. Patients must not take alcohol during the study.
  • Disorders of the hematologic, digestive, or central nervous systems, including cerebrovascular disease and degenerative disease, that would limit study evaluation or participation.
  • Known impairment of renal function (serum creatinine levels > 1.7 mg/dL for men), dysproteinemia, nephrotic syndrome, or other renal disease (24-hour urinary protein ≥3 ± 1 g).
  • Active or chronic hepatobiliary or hepatic disease. In addition, patients with aspartate aminotransferase or alanine aminotransferase >2 x upper limit of the laboratory reference range will be excluded.
  • Subjects with coagulopathy, prothrombin time (PT) or partial thromboplastin time (PTT) at Visit 1 >1.5 times control.
  • Subjects with hemoglobin >2 x the lower limit of the laboratory reference range will be excluded.
  • Patients who are known to have tested positive for human immunodeficiency virus (HIV).
  • Patients who are currently enrolled in another clinical study.
  • Patients who have used any investigational drug within 30 days of the first clinic visit.
  • Congestive heart failure New York Heart Association (NYHA) Class III or IV. Uncontrolled cardiac arrhythmias within 3 months of study entry.
  • Other endocrine or metabolic disease known to influence serum lipids or lipoproteins.
  • known hypersensitivity or allergy to linagliptin or its excipients, metformin
  • Unwillingness or language barrier precluding adequate understanding or cooperation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02280174


Contacts
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Contact: Juan Pa Nogueira, MD/PhD 00543704425447 nogueirajuanpatricio@gmail.com
Contact: Hugo Or Molinas, PhD 00543704425447 hugomolinas@hotmail.com

Locations
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Argentina
National University of Formosa Recruiting
Formosa, Argentina, 3600
Contact: Juan Pa Nogueira, MD/PhD    00543704425447    nogueirajuanpatricio@gmail.com   
Sponsors and Collaborators
Ministry of Public Health, Argentina
Aix Marseille Université
Instituto de Biología y Medicina Experimental, IBYME, Buenos Aires, Argentina
Investigators
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Principal Investigator: Juan Nogueira, MD/PhD Medico Moving Center Institute, Formosa, Argentina

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Responsible Party: MD/PhD Nogueira, Juan Patricio, MD/PhD, Ministry of Public Health, Argentina
ClinicalTrials.gov Identifier: NCT02280174     History of Changes
Other Study ID Numbers: IS000586
First Posted: October 31, 2014    Key Record Dates
Last Update Posted: November 4, 2014
Last Verified: November 2014
Keywords provided by MD/PhD Nogueira, Juan Patricio, Ministry of Public Health, Argentina:
Apo B-48
TRL
Linagliptin
Additional relevant MeSH terms:
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Linagliptin
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action