The present study demonstrated that short-term liraglutide treatment significantly affected visceral fat adiposity, appetite, food preference, and cardiovascular biomarkers in Japanese patients with type 2 diabetes.
The LEAD-2 trial showed that liraglutide at 1.2 and 1.8 mg/day significantly decreased waist circumference and eVFA compared to the 4 mg/day glimepiride after 26 weeks from introduction, while there was no significant difference in the reductions of waist circumference and eVFA between liraglutide group and placebo group [17
]. In the LEAD-3 substudy, a long-term liraglutide monotherapy significantly reduced body weight and fat mass from baseline while body weight and fat mass were increased in the glimepiride group [18
]. In the present study, waist circumference, W/H ratio, and eVFA did not change while patients were treated with insulin and/or oral glucose-lowering agents (Figure ). However, treatment with liraglutide significantly reduced these physical parameters. Furthermore, the daily reduction of waist circumferences was significantly larger during liraglutide treatment than before liraglutide introduction, suggesting that liraglutide effectively decreased visceral fat adiposity. Previous studies reported the lack of GLP-1 receptor expression on adipocytes [19
], but recent work has demonstrated GLP-1 receptor expression on adipocytes [20
]. Although GLP-1 action and GLP-1 receptor signaling in adipocytes have not been fully elucidated, the present study demonstrated that liraglutide reduced visceral fat adiposity in a direct or indirect fashion. The results also point to a possible anti-atherosclerotic effect for liraglutide partly through reduction of eVFA. Treatment with exenatide, another GLP-1 receptor agonist, exhibited a significant weight reduction when used for 3 years [21
]. Previous study showed that body weight did not change following the use of liraglutide by Japanese type 2 diabetes patients, but the mean BMI of those patients was only 23.9 kg/m2
]. As shown in Table the mean BMI of our patients was 28.3 kg/m2
, suggesting that the effect of liraglutide on weight reduction is limited to obese type 2 diabetics.
Several studies have demonstrated that GLP-1 promotes satiety and suppresses energy intake both in animals [23
] and human subjects [25
], however, the effect of liraglutide on eating behavior has not been examined in human type 2 diabetics. The present study demonstrated that liraglutide reduced food intake and changed external eating behavior and food preference. Liraglutide significantly reduced the intake for staple food, e.g., rice and/or bread. Interestingly, liraglutide significantly decreased the scores for external eating behavior and food preference (Figure and ). Questions on external eating behavior evaluate appetite increase through sight and smell senses. Questions about food preference measure foods directly associated with obesity. Such improvement in eating behavior induced by liraglutide has not been reported for other glucose-lowering agents. Furthermore, liraglutide significantly reduced the urge for fat intake (Figure ). Although the findings of epidemiological studies on the association of total dietary fat with type 2 diabetes have been inconsistent [29
], dietary fat intake impairs glucose metabolism [5
] and is strongly related to cardiovascular risk in type 2 diabetes [6
]. A high intake of saturated fat is considered to associate with type 2 diabetes and cardiovascular diseases [7
]. In this sense, liraglutide may be beneficial in reducing fat preference, related to obese type 2 diabetes, although the long-term effects of liraglutide on eating behavior remain to be elucidated. It would be better to refine the questions on food preference to identify the types of fat.
GLP-1 receptor agonist exerts glucose-lowering effect mainly by stimulating glucose-mediated secretion of insulin from β-cells. Insulin secretion is often deteriorated in various degrees in Japanese and the other Asian patients with type 2 diabetes compared to Caucasian [2
], and thus the effect of liragulutide on insulin secretion is worth evaluating in Japanese type 2 diabetes subjects. As shown in Table liraglutide treatment increased sCPR and C-peptide Index, indicating that insulin secretion was enhanced by liraglutide. Such changes may appear the increases of HOMA-IR and Matsuda Index, suggesting that these indices may not exactly reflect insulin sensitivity under liraglutide treatment. There is a possibility that long-term liraglutide treatment may ameliorate insulin resistance by weight reduction through decrease of appetite. Further clinical investigations may be needed in future.
The extrapancreatic actions of GLP-1 have been demonstrated, especially the beneficial its effect on the cardiovascular system [4
]. GLP-1 has a protective action on heart function and/or cardiomyocytes, although the GLP-1 action on the vascular system has not been fully evaluated especially in human. Treatment with GLP-1 improved endothelial dysfunction in type 2 diabetics with ischemic heart diseases [33
]. Interestingly, GLP-1 treatment improved postprandial hyperlipidemia, suggesting the possibility that GLP-1 administration may reduce cardiovascular disease risk in type 2 diabetes [34
]. A recent experiment showed that GLP-1 treatment protected against the development of atherosclerosis both in vivo
and in vitro
]. In the present study, liraglutide decreased serum hsCRP and sICAM-1 levels, while no such changes were observed following treatment with other glucose-lowering agents with insulin (n = 6), biguanide (BG) (n = 4), α-glucosidase inhibitor (αGI) (n = 3), dipeptidyl peptidase-4 inhibitors (DPP-4i) (n = 3), and sulfonylurea (SU) (n = 2) (data not shown). These results suggest that the decrease in hsCRP and sICAM-1 levels may be due to the pleiotropic effects of liraglutide, beneficial for protection against the development of atherosclerosis.
The present study has several limitations. The study is not a randomized clinical trial (RCT) and is not a crossover study. A crossover clinical trial will confirm present results. In addition, present study was performed in a small population. The effects of liraglutide on visceral fat adiposity, appetite, and cardiovascular biomarkers were examined in a hospitalized term. Collectively, a long-term RCT in obese Japanese type 2 diabetics should be conducted to confirm the efficacy of liraglutide on visceral fat adiposity, appetite, food behavior, and cardiovascular events.
In summary, short-term treatment with liraglutide effectively reduced visceral fat adiposity, appetite, and cardiovascular biomarkers in obese Japanese patients with type 2 diabetes. Longer term randomized clinical trials are warranted to more thoroughly elucidate the effect of liraglutide on these parameters.