Effect of Linagliptin on TRL Metabolism

Type 2 Diabetes Clinical Trial

Official title: Effect of Linagliptin on Intestinal Triglyceride-rich-lipoprotein Metabolism in Type 2 Diabetic Patients

Status Recruiting

Clinical Trial 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.

Clinical Trial 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. ;

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Type 2 Diabetes

• NCT number: NCT02280174
• Study type: Interventional
• Source: Ministry of Public Health, Argentina
• Contact: Juan Pa Nogueira, MD/PhD
• Phone: 00543704425447
• Email: nogueirajuanpatricio@gmail.com
• Status: Recruiting
• Phase: Phase 4
• Start date: September 2014
• Completion date: October 2016