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

doi:10.1016/j.diabres.2015.04.008

Diabetes Research and Clinical Practice

Volume 109, Issue 1, July 2015, Pages 199-205

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

Highlights

•
The subjects were Japanese patients with T2DM with a BMI ≥ 25 kg/m2 or fatty liver.
•
A prospective, 24-week, single-center, open-label comparative study enrolled.
•
Treatment with sitagliptin or glimepiride reduced HbA1c and GA similarly.
•
After 24 weeks, only sitagliptin decreased IHL and total body fat mass.

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.

References (30)

Y.A. Jung et al.
Sitagliptin attenuates methionine/choline-deficient diet-induced steatohepatitis
Diabetes Res Clin Pract
(2014)
E. Kirk et al.
Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction
Gastroenterology
(2009)
S. Ben-Shlomo et al.
Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase
J Hepatol
(2011)
Y. Aso et al.
Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea
Transl Res
(2012)
S.E. Inzucchi et al.
Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
Diabetologia
(2012)
S.E. Inzucchi et al.
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
Diabetes Care
(2012)
Y.G. Kim et al.
Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis
Diabetologia
(2013)
R.E. Amori et al.
Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis
JAMA
(2007)
J.J. Neumiller et al.
Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus
Pharmacotherapy
(2010)
N.A. Gupta et al.
Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway
Hepatology
(2010)

G. Svegliati-Baroni et al.

Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signaling alteration induced by a high-fat diet in nonalcoholic steatohepatitis

Liver Int

(2011)

D.J. Cuthbertson et al.

Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists

PLoS ONE

(2012)

K. Aoki et al.

Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin

Acta Diabetol

(2012)

H. Agersø et al.

The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men

Diabetologia

(2002)

M. Kern et al.

Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity

PLoS ONE

(2012)

Cited by (52)

ZD-2, a novel DPP4 inhibitor, protects islet β-cell and improves glycemic control in high-fat-diet-induced obese mice
2022, Life Sciences
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been extensively used for the treatment of type 2 diabetes mellitus. Nevertheless, side effects like sore throat and diarrhea also occur in DPP-4 inhibitors treatment. The study aims to identify and develop novel DPP-4 inhibitors with better therapeutic profiles.
Here we synthesized a series of vildagliptin analogs, and among which, ZD-2 showed the moderate inhibition of DPP-4 activity compared with vildagliptin. High-fat-diet (HFD) mice were treated with ZD-2 (4.5 and 7.5 mg/kg) or vildagliptin (6 mg/kg) for 7 weeks following the examinations of metabolic index and pancreatic β-cell function. Mouse pancreatic cell line MIN6 was used to evaluate β-cell function, and intestinal enteroendocrine cell line STC-1 was used to evaluate the expression of gut hormones.
The IC₅₀ of ZD-2 was over 30-fold higher than vildagliptin. However, both ZD-2 and vildagliptin treatment showed comparable effects on improving glucose tolerance and reducing the steatosis of liver and fat mass in HFD mice. Moreover, ZD-2 exerted β-cell-protective actions by preserving islet β-cell mass and increasing the expression of functional β-cell-related genes. Additionally, ZD-2 also stimulated the expression of gut hormones in STC-1 cells.
ZD-2 showed comparable anti-diabetic activities in HFD-fed mice although its lower potency on inhibition of DPP-4 compared with vildagliptin. Protection of β-cell function might contribute to its anti-diabetic effects.
Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis
2020, Metabolism: Clinical and Experimental
Citation Excerpt :
Vildagliptin was shown to decrease hepatic triglyceride levels and ALT during 6 months of therapy. On the contrary, other studies in patients with NAFLD demonstrated that sitagliptin had no beneficial effect on liver enzymes [62,63], liver steatosis [64,65] or liver stiffness [63]. SGLT-2i decrease blood glucose by inhibiting renal glucose reabsorption, thereby inducing glycosuria, which in turn promotes weight loss.
Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease and important unmet medical need. Current guidelines recommend, under specific restrictions, pioglitazone or vitamin E in patients with NASH and significant fibrosis, but the use of both remains off-label. We summarize evidence on medications for the treatment of nonalcoholic steatohepatitis (NASH), since NASH has been mainly associated with higher morbidity and mortality. Some of these medications are currently in phase 3 clinical trials, including obeticholic acid (a farnesoid X receptor agonist), elafibranor (a peroxisome proliferator activated receptor [PPAR]-α/δ dual agonist), cenicriviroc (a CC chemokine receptor antagonist), MSDC-0602 K (a PPAR sparing modulator), selonsertib (an apoptosis signal-regulating kinase-1 inhibitor) and resmetirom (a thyroid hormone receptor agonist). A significant research effort is also targeting PPARs and selective PPAR modulators, including INT131 and pemafibrate, with the expectation that novel drugs may have beneficial effects similar to those of pioglitazone, but without the associated adverse effects. Whether these and other medications could offer tangible therapeutic benefits, alone or in combination, apparently on a background of lifestyle modification, i.e. exercise and a healthy dietary pattern (e.g. Mediterranean diet) remain to be proven. In conclusion, major advances are expected for the treatment of NASH.
The efficacy and safety of dipeptidyl peptidase-4 inhibitors compared to other oral glucose-lowering medications in the treatment of type 2 diabetes
2020, Metabolism: Clinical and Experimental
The dipeptidyl peptidase-4 inhibitors (DPP-4is), which belong to the class of incretin-based medications, are recommended as second or third-line therapies in guidelines for the management of type 2 diabetes mellitus. They have a favorable drug tolerability and safety profile compared to other glucose-lowering agents.
This review discusses data concerning the use of DPP-4is and their cardiovascular profile, and gives an updated comparison with the other oral glucose-lowering medications with regards to safety and efficacy. Currently available original studies, abstracts, reviews articles, systematic reviews and meta-analyses were included in the review.
DPP4is are moderately efficient in decreasing the HbA1c by an average of 0.5% as monotherapy, and 1.0% in combination therapy with other drugs. They have a good tolerability and safety profile compared to other glucose-lowering drugs. However, there are possible risks pertaining to acute pancreatitis and pancreatic cancer.
Cardiovascular outcome trials thus far have proven the cardiovascular safety for ischemic events in patients treated with sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin. Data showing increased rate of hospitalisation in the case of saxagliptin did not seem to be a class effect.
Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box!
2019, Metabolism: Clinical and Experimental
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.
From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options
2019, JHEP Reports
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to have reached 25% or more in adults. NAFLD is prevalent in obese individuals, but may also affect non-obese insulin-resistant individuals. NAFLD is associated with a 2- to 3-fold increased risk of developing type 2 diabetes (T2D), which may be higher in patients with more severe liver disease – fibrosis increases this risk. In NAFLD, not only the close association with obesity, but also the impairment of many metabolic pathways, including decreased hepatic insulin sensitivity and insulin secretion, increase the risk of developing T2D and related comorbidities. Conversely, patients with diabetes have a higher prevalence of steatohepatitis, liver fibrosis and end-stage liver disease. Genetics and mechanisms involving dysfunctional adipose tissue, lipotoxicity and glucotoxicity appear to play a role. In this review, we discuss the altered pathophysiological mechanisms that underlie the development of T2D in NAFLD and vice versa. Although there is no approved therapy for the treatment of NASH, we discuss pharmacological agents currently available to treat T2D that could potentially be useful for the management of NASH.
Molecular mechanisms by which GLP-1 RA and DPP-4i induce insulin sensitivity
2019, Life Sciences
Citation Excerpt :
They can potentially modulate some microRNAs (miR) involved in lipid metabolism such as miR-200b, miR-200c, miR-34a, miR-338 and miR-21 [113–116]. Therefore, recent evidence suggested these hypoglycemic medications are promising therapeutic agents for dyslipidemia-induced disorders such as NAFLD (non-alcoholic fatty liver disease) and atherosclerosis in the diabetic milieu [117–120]. Ejarque et al. in 2019 demonstrated that GLP-1 expressed on adipocytes regulates the adipose tissue metabolism leading to higher insulin sensitivity [121].
Glucagon-like peptide-1 is a peptide of incretin family which is used in the management of diabetes as glucagon-like peptide-1 receptor agonist (GLP-1RA). Dipeptidyl peptidase-4 enzyme metabolizes glucagon-like peptide-1 and various dipeptidyl peptidase-4 enzyme inhibitors (DPP-4i) are also used in the management of diabetes. These antidiabetic agents provide anti-hyperglycemic effects via several molecular mechanisms including promoting insulin secretion, suppression of glucagon secretion and slowing the gastric emptying. There is some research suggesting that they can induce insulin sensitivity in peripheral tissues. In this study, we review the possible molecular mechanisms by which GLP-1RA and DPP-4i can improve insulin resistance and increase insulin sensitivity in insulin-dependent peripheral tissues.

View all citing articles on Scopus

View full text

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

Highlights

Abstract

Aims

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Conflict of interest statement

Diabetes Res Clin Pract

Gastroenterology

J Hepatol

Transl Res

Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Diabetologia

Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Diabetes Care

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

Diabetologia

Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis

JAMA

Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus

Pharmacotherapy

Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway

Hepatology

Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signaling alteration induced by a high-fat diet in nonalcoholic steatohepatitis

Liver Int

Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists

PLoS ONE

Miglitol administered before breakfast increased plasma active glucagon-like peptide-1 (GLP-1) levels after lunch in patients with type 2 diabetes treated with sitagliptin

Acta Diabetol

The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men

Diabetologia

Linagliptin improves insulin sensitivity and hepatic steatosis in diet-induced obesity

PLoS ONE