Effect of sitagliptin on intrahepatic lipid content and body fat in patients with type 2 diabetes

https://doi.org/10.1016/j.diabres.2015.04.008Get rights and content

Highlights

Abstract

Aims

To evaluate the effect of the DPP-4 inhibitor sitagliptin on intrahepatic lipid (IHL) content and body fat in overweight Japanese patients with type 2 diabetes.

Methods

A prospective, 24-week, single-center, open-label comparative study enrolled 20 Japanese patients with type 2 diabetes (male: 11, female: 9) with a BMI  25 kg/m2 or fatty liver. Subjects were randomly assigned to receive treatment with sitagliptin (25 mg titrated up to 50 mg: S) or glimepiride (0.5 mg titrated up to 1 mg: G). After starting each treatment, IHL and total fat mass were evaluated by 1H-magnetic resonance spectroscopy (1H-MRS) and dual energy X-ray absorptiometry (DEXA), respectively at baseline and at 12 weeks and 24 weeks.

Results

After 24 weeks, HbA1c levels showed a similar significant decrease in both groups from 7.2 (7.0, 7.5) to 6.6 (6.4, 6.8)%, (54 (53, 56) to 48(47, 49) mmol/mol) with S and 7.3(6.8, 7.4) to 6.6 (6.3, 6.7)%, (55 (51, 56) to 48 (46, 49) mmol/mol) with G, median (interquartile range), p < 0.05 vs. baseline, with no significant differences between the two groups. The IHL and total body fat mass were decreased in S group from 24.5(18.9, 36.6) to 20.5 (14.6, 28.5)% (p = 0.009) and 22.5 (20.6, 33.7) to 21.6 (19.7, 32.4)kg (p = 0.028), respectively, but not in G group.

Conclusions

Our findings indicate that sitagliptin and glimepiride achieved similar glycemic control, but only sitagliptin reduced IHL and total body fat (UMIN: 000013356).

Introduction

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have published a position statement on type 2 diabetes mellitus (T2DM) that stresses the importance of a patient-centered approach [1], [2]. In this statement, metformin (MET) is recommended as initial drug therapy to be provided simultaneously with or soon after commencing lifestyle modification because of its high efficacy for reducing HbA1c, low cost, low risk of hypoglycemia, and neutral effect on body weight (or weight loss). If the target HbA1c is not achieved, the second and third agents to be combined with MET are selected from among five drug classes: sulfonylureas (SU), thiazolidinediones (TZD), dipeptidyl peptidase-4 inhibitors (DPP-4I), glucagon-like peptide-1 (GLP-1) agonists, or basal insulin. The unique and important point of the statement is comparison of the characteristics of these five drug classes to allow selection of suitable therapy for each patient.

In the statement, DPP-4I are characterized as showing intermediate efficacy for HbA1c reduction, with a low risk of hypoglycemia, neutral effect on body weight, and few major side effects. DPP-4I increase the plasma concentration of active GLP-1, which increases insulin secretion in a glucose-dependent manner and simultaneously suppresses the secretion of glucagon. Thus, DPP-4I reduce fasting and postprandial plasma glucose levels with a relatively low risk of hypoglycemia [4], [5]. A recent study showed that HbA1c reduction by DPP-4I is greater in Asian patients than Caucasians [3], so these agents are widely used for Japanese patients.

The GLP-1 receptor (GLP-1R) has been detected on human hepatocytes and adipocytes [6], and a GLP-1 analog (exendin-4) has been demonstrated to attenuate triglyceride synthesis by primary cultured human hepatocyte [7]. Furthermore, another GLP-1 agonist (liraglutide) achieved 42% reduction of the intrahepatic lipid (IHL) content and 11% reduction of the visceral fat volume in obese patients with T2DM after 6 months of treatment [8]. However, the plasma concentration of active GLP-1 is much lower during DPP4-I treatment compared with the levels during treatment with these GLP-1 agonists [9], [10]. According to the ADA/EASD statement, the effect of DPP4-I on body weight is neutral, but not marked [1], [2]. The effects of DPP-4I on body weight and hepatic fat accumulation have not been fully evaluated in patients with diabetes, although animal experiments have shown attenuation of hepatic steatosis by DPP-4I administration [11], [12].

Therefore, the aim of the present study was to investigate the effects of sitagliptin, one of the DPP-4I, on IHL and body fat compared with low-dose SU therapy using glimepiride in Japanese patients with type 2 diabetes with a BMI  25 kg/m2 or fatty liver on abdominal ultrasonography.

Section snippets

Subjects

The subjects were 20 Japanese patients with T2DM (11 men and 9 women aged 58.5 (40.0, 77.0) years, median (interquartile range (IQR)) with a BMI  25 kg/m2 or fatty liver detected by ultrasonography. The ultrasonography was carried out by using convex-array probe (3.5 MHz) for assessing the liver, and after a fasting period of 12 h. Diagnosis of fatty liver was attempted based on the difference between the echo intensities of the liver and kidney [13]. They were recruited from the outpatient clinic

Results

The baseline clinical characteristics of the patients are shown in Table 1. There were no significant differences between the two groups with regard to the age, blood pressure, BMI, HbA1c, GA, FPG, LDL-C, HDL-C, TG, FFA, HMW-Ad, leptin, and hsCRP. A comparison of laboratory parameters between the two groups during study period is displayed in Table 2. At 24 weeks, HbA1c and GA showed a similar significant decrease from their baseline levels in both groups. FPG was significantly decreased from

Discussion

The present study demonstrated that the reduction of HbA1c and GA was similar after treatment with sitagliptin or low-dose glimepiride for 24 weeks, but only sitagliptin (not glimepiride) significantly decreased IHL and total body fat mass.

In the liver, TG are not only produced from free fatty acids (FFA) that are released from adipose tissue by lipolysis, but also by intrahepatic fatty acid synthesis from dietary glucose via the malonyl–CoA pathway. Intake of a carbohydrate (CH)-restricted low

Conflict of interest statement

The authors declare that they have no conflict of interest.

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