Type 2 Diabetes Clinical Trial
Official title:
Effect of Linagliptin on Intestinal Triglyceride-rich-lipoprotein Metabolism in Type 2 Diabetic Patients
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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