Letter: The Effect of DPP-4 Inhibitors on Metabolic Parameters in Patients with Type 2 Diabetes (Diabetes Metab J 2014;38:211-9).

Incretin-based therapies are now widely used for the treatment of type 2 diabetes mellitus. Beyond its glucose-lowering effect, the pleiotropic actions of the glucagon-like peptide-1 (GLP-1) analogue and dipeptidyl peptidase-4 (DPP-4) inhibitors are being discovered, raising the possibilities for their role in the management of various comorbidities associated with diabetes mellitus [1,2]. Another point of interest is whether or not the different DPP-4 inhibitors exert the same glycemic and nonglycemic effects [3].

In the article entitled "The effect of DPP-4 inhibitors on metabolic parameters in patients with type 2 diabetes," Choe et al. [4] compared the effects of sitagliptin and vildagliptin on glucose and lipid parameters. They described that there were no differences in the glucose- and lipid-lowering efficacy between two agents. However, when compared with the baseline data, patients in the vildagliptin-treated group showed significant improvements in their total cholesterol and triglyceride (TG) levels after 24 weeks of follow-up, but no differences were observed in sitagliptin-treated group. This interesting article merits much attention, although some points need to be discussed.

Firstly, it is unclear whether the lipid-lowering effect of DPP-4 inhibitors is a direct phenomenon of DPP-4 inhibition per se or not. Previous experimental studies showed that infusion of GLP-1 or inhibition of DPP-4 activity acutely decreases postprandial TG and apolipoprotein B (ApoB)-48, supporting the direct role of GLP-1 in lipoprotein synthesis and secretion [5,6]. However, because many other factors may affect lipid homeostasis, it would be helpful to provide information regarding whether there were any changes in body weight or the degree of insulin resistance in the study subjects.

Secondly, whether the significant improvements of lipid parameters in patients treated with vildagliptin but not in those treated with sitagliptin can be explained by the differences in their pharmacologic profiles remains elusive. A 4 week, randomized study in patients with type 2 diabetes receiving vildagliptin (50 mg twice daily) demonstrated improvements in postprandial plasma TG and ApoB-48-containing TG-rich lipoprotein particle metabolism in response to a fat-rich test meal [7]. Similarly, a 6-week, cross-over study using 100 mg/day of sitagliptin also showed a significant reduction in the circulating levels of postprandial TG, ApoB-48, and free fatty acid [8]. Although the results are inconsistent across trials, a meta-analysis indicated possible beneficial effects of DPP-4 inhibitors on the total cholesterol and TG levels, suggesting that incretins modulate lipid metabolism [9]. Interestingly, when the effect of individual DPP-4 inhibitors was analyzed, a significantly lower total cholesterol level was observed in subjects treated with vildagliptin and alogliptin, but not sitagliptin or saxagliptin. This data is in line with the observation by Choe et al. [4], although further studies are needed to clarify this issue.

Lastly, it seems that the changes in the total cholesterol levels from baseline to the end of the study varies greatly among subjects. It would be interesting to identify the differences between the patients who showed reductions in their lipid levels and the patients who did not. Some external factors such as diet, exercise, and use of other medications also should be considered.

Accumulating evidence suggest a promising view for DPP-4 inhibitors in controlling some well-recognized cardiovascular risk factors, including dyslipidemia. Although the questions raised above might not be answered by a single study, further investigations are warranted to enhance our understanding on the benefits of incretin-based therapies.