Discussion
This study directly compared HbA1c and the pleiotropic effects of sitagliptin with voglibose added to concurrent treatment in Japanese patients with type 2 diabetes who could not achieve adequate glycemic control through diet therapy or a single OHA. The novelty of the present study is as follows: First, dynamic randomization is methodologically novel. It is useful to adjust for demographic differences between each group. In this open-label, randomized, parallel-group study with dynamic allocation, we compared sitagliptin with voglibose, not only as a monotherapy, but also as an add-on therapy to SU, BG or TZD. Second, pleiotropic effects of sitagliptin and voglibose include previously yet-recognized findings.
Regarding the primary endpoint, sitagliptin was superior to voglibose in lowering HbA1c levels in monotherapy and in combination with each concurrent agent. A similar reduction in HbA1c was also observed in previous 12-week studies.18–20
Regarding the secondary end points, sitagliptin and voglibose exerted unique pleiotropic effects in the present study. Sitagliptin, but not voglibose, significantly increased the markers of β-cell function (HOMA-β and proinsulin/insulin ratio). Preclinical studies have shown that GLP-1 stimulates β-cell differentiation and proliferation, inhibits apoptosis of β-cells,21 ,22 and stimulates β-cell neogenesis and survival in streptozotocin-treated rats.23 In fact, several reviews have indicated that DPP-4 inhibitors consistently improve markers of β-cell function in type 2 diabetes patients.20 ,24 ,25 A decrease in the fasting proinsulin-to-insulin ratio, consistent with improved β-cell function, was observed in association with sitagliptin treatment in a previous study.26
Sitagliptin compared with voglibose significantly reduced the counts of lymphocytes and increased those of neutrophils in the present study, as observed in the previous study.27 DPP-4 is highly expressed by T-cells, especially CD4+ T-cells. Sitagliptin decreases CD4+ T-cells in a glucose-independent manner.27 Whether DPP-4 inhibitors suppress immunity by reducing the number of circulating CD4+ T-cells should be examined in future. Sitagliptin significantly increased serum levels of Cre, cys-C and uric acid, and decreased eGFRcreat, whereas voglibose had no effect on these parameters in the present study. These results might relate to the Na-diuretic action of GLP-1,28 although we observed no reduction in blood pressure in the present study. Therefore, it is possible that sitagliptin impairs renal function. In fact, during a much longer, 54-week study, it was found that 18.8% of patients in the sitagliptin group with moderate renal insufficiency at baseline transitioned to severe renal insufficiency status over the course of the study.29 On the other hand, in our study, deterioration of eGFRcys was not observed. After 12 weeks, sitagliptin, but not voglibose, decreased ALP levels relative to baseline without affecting BAP levels. Although it is not certain whether this sitagliptin-mediated decrease in ALP is related to bone metabolism, the decrease in ALP from baseline significantly correlated with a decrease in HbA1c levels, as observed in previous studies.30 ,31
Both sitagliptin and voglibose significantly increased plasma adiponectin levels, as stated in previous reports.32 ,33 There was a negative correlation between ΔHbA1c and Δadiponectin (table 3), suggesting that glycemic control at least partly contributes to the increase in adiponectin levels. The increased adiponectin levels might improve endothelial function and likely yield anti-atherosclerotic effects.34 In addition, baseline levels of adiponectin were negatively correlated with ΔHbA1c only in the sitagliptin group, suggesting that adiponectin level might be a predictive maker for the effect of sitagliptin in glycemic control. Serum EPA concentrations are reported to be associated with the glucose-lowering effect of DPP-IV inhibitors in Japanese patients with type 2 diabetes.35 However, in our study, baseline EPA levels were not correlated with the change in HbA1c in the sitagliptin group (table 3). On the other hand, sitagliptin significantly decreased polyunsaturated fatty acids, especially ω6 fatty acids, whereas voglibose altered serum levels of many kinds of fatty acids, unlike in a previous study with acarbose.36 Notably, voglibose, but not sitagliptin, increased Δ-5 desaturase activity. Several cross-sectional studies showed that the Δ-5 desaturase activity index, which refers to the ratio of arachidonic acids to dihomo-γ-linolenic acids, is positively associated with insulin sensitivity37 ,38 and the onset of newly diagnosed type 2 diabetes,39 and is negatively associated with several metabolic risk factors in patients with metabolic syndrome.40 High Δ-5 desaturase activity was associated with reduced coronary heart disease risk.41 Conversely, voglibose decreased Δ-6 desaturase activity. Δ-6 desaturase activity was associated with an increased probability of metabolic syndrome.40 These findings suggest the possibility that voglibose, rather than sitagliptin, might reduce coronary heart disease risk by altering fatty acids profiling. However, as a limitation, because the present 3-month, open-label study was designed to compare the antihyperglycemic effects of sitagliptin and voglibose, the study duration may be insufficient to evaluate some of the pleiotropic effects. In the subgroup analysis, concomitant antidiabetic agents did not affect the results in glycemic parameters.
In summary, we showed that sitagliptin is superior to voglibose in terms of improving glycemic control as a first/second-line therapy in Japanese people with type 2 diabetes. However, both agents exert unique pleiotropic effects on surrogate cardiovascular risks, which suggests a theoretical basis for potential benefits through combined therapy. A large-scale clinical trial on cardiovascular events is required to test this hypothesis.