Effect of Linagliptin on TRL Metabolism
Effect of Linagliptin on TRL Metabolism
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.
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.