Sitagliptin improves plasma apolipoprotein profile in type 2 diabetes: A randomized clinical trial of sitagliptin effect on lipid and glucose metabolism (SLIM) study

Abstract

Aim

This study aims to evaluate the effect of dipeptidyl peptidase-4 inhibitors on lipid metabolism in patients with type 2 diabetes mellitus (T2D).

Methods

This is a multicenter, open-labeled, randomized controlled study. T2D patients with HbA1c 6.9–8.9% (52–74 mmol/mol) who were under treatment with sulfonylurea were randomly allocated to either the sitagliptin group or the non-sitagliptin group. Glucose and lipid metabolism parameters including apolipoproteins (apo), sterols, and urinary albumin were assessed at baseline, 3, and 6 months of the treatment.

Results

A total of 164 patients completed the 6-month observation (n = 81 for sitagliptin and n = 83 for non-sitagliptin). HbA1c decreased in the sitagliptin group but not in the non-sitagliptin group. Serum TG and total, LDL and HDL cholesterol levels did not change in either group. Apo B-48, apo CII, and apo CIII levels decreased in the sitagliptin group, but not in the non-sitagliptin group. The change in urinary albumin was significantly different between the groups with a preferable change in the sitagliptin group. There were no changes in serum sterols levels in the two groups.

Conclusions

The treatment of sitagliptin for 6 months improves the metabolism of glucose and chylomicron and reduces plasma levels of atherogenic lipoproteins in patients with T2D.

Introduction

Diabetes is a common risk factor for atherosclerotic diseases, and the risk of coronary events is 2–4 times higher among diabetic patients compared to non-diabetic subjects [1], [2], [3]. Hyperglycemia and postprandial glycemic stress are specific triggers of atherosclerosis in humans [4], [5], [6], [7] and in animal models [8]. Dyslipidemia is an important factor for atherosclerosis. Although statins decrease low-density lipoprotein (LDL) cholesterol levels and prevent atherosclerotic cardiovascular diseases, complete suppression of cardiovascular events is not attainable by lowering LDL cholesterol alone [9], [10], [11]. Hypertriglyceridemia, therefore, is considered to be a part of the residual risk of cardiovascular events [12], [13], [14], [15].

The triglyceride (TG)-rich lipoproteins (TRLs) such as chylomicron (CM), very low-density lipoprotein (VLDL), and their remnants are increased with hypertriglyceridemia. CM particles are synthesized in the intestine and contribute to the exogenous lipid pathway. Apolipoprotein B-48 (apo B-48) is a structural apolipoprotein of CM and CM remnant, one apo B-48 protein being on one CM or CM remnant. The serum level of apo B-48 is a marker of the amounts of CM remnant particles. CM remnant is known to be atherogenic. Apo B-48 is found to be accumulated in human atherosclerotic plaque [16]. Fasting apo B-48 concentrations were shown to correlate with carotid intima-media thickness [17] and coronary artery disease [18].

Type 2 diabetes mellitus (T2D) drives the increase of atherogenic lipoproteins in fasting and postprandial state. Dyslipidemia occurring in T2D is characterized by the increase of TRLs and LDL [19] and the emergence of heterogeneous LDL particles as the qualitative change [20]. Even though serum TG levels are not increased in T2D, remnant particles are usually increased in relation to hyperglycemia [21], [22]. Remnant is a therapeutic target for anti-atherosclerosis in T2D [23], [24].

Glucagon-like peptide-1 (GLP-1) is an incretin hormone, which enhances glucose-dependent insulin secretion, suppresses glucagon secretion, delays gastric emptying and promotes satiety [25]. GLP-1 is rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors act in delaying the degradation of GLP-1, enhance the physiological effects of GLP-1, and improves glycemic control. Recently, GLP-1 agonists and DPP-4 inhibitors have been reported to improve not only hyperglycemia but also dyslipidemia. GLP-1 agonists decreased both fasting and postprandial TG [26] and DPP-4 inhibitors decreased postprandial TG [27], [28]. DPP-4 inhibitors also decrease postprandial levels of apo B and apo B-48 levels in patients with T2D [27], [28] and in healthy subjects [29], [30]. Thus, DPP-4 inhibitors decrease postprandial lipid levels. However, the effects of the DPP-4 inhibitor on fasting lipids remain poorly defined. Although there are few reports showing the effects of DPP-4 inhibitors on fasting TG, apo B, and apo B-48, such reports include a limited number of subjects [31], [32]. We designed this current large-scale study for determining the effect of DPP-4 inhibitor sitagliptin on fasting lipids and apolipoproteins of uncontrolled T2D with sulfonylurea treatment.