Discussion
This is the first report showing the feasibility of substituting an OHA for insulin injection therapy in an open-label randomized, parallel-group study. Our results show that FPG increased significantly in participants receiving mitiglinide, whereas no changes were observed in those administered sitagliptin. Mealtime bolus insulin monotherapy was superior to sitagliptin and mitiglinide for controlling HbA1c. Sitagliptin acted on FPG, whereas mitiglinide may act on the postprandial plasma glucose level to achieve a similar HbA1c after the switch from a bolus insulin regimen.
The majority of patients with type 2 diabetes treated with insulin have difficulty achieving or maintaining target glycemic control without an associated weight gain.29 In this study, body weight, BMI, and waist circumference decreased significantly in both OHA groups after the switch from insulin. OHAs are more effective than bolus insulin monotherapy for maintaining weight in patients with type 2 diabetes at high risk for cardiovascular disease. We did not show a positive effect of OHAs on lipid profiles or blood pressure control. This could be related to the limitation that the observation period was too short to detect beneficial effects on lipid profiles or blood pressure. Sitagliptin-mediated and mitiglinide-mediated improvements in glycemic control were independent of the lipid profile or insulin secretion (see online supplementary table S2), suggesting that unique and as yet unrecognized mechanisms may underlie the actions. Indeed, insulin secretion during the arginine challenge and lipid meal tests decreased significantly in the sitagliptin group after the switch from insulin. The effects of glucagon-like peptide-1 on glucagon secretion, gastric emptying, and the autonomic nervous system may explain such an effect of sitagliptin.30 In addition, our results suggest that glinides also have a glucose-lowering effect independent of their effect on insulin secretion.
In contrast to a previous report,31 DHA and EPA levels did not predict the sitagliptin-mediated improvement in glycemic control (see online supplementary table S2). In addition, this is the first study to demonstrate sitagliptin-mediated and mitiglinide-mediated changes in serum fatty acid profiles in humans or animals. Sitagliptin, but not mitiglinide, dynamically altered fatty acid composition; it increased serum levels of fatty acids, such as lauric acid, myristic acid, γ-linolenic acid, α-linolenic acid, eicosatrienoic acid, dihomo-γ-linolenic acid, and erucic acid. The effects of sitagliptin on fatty acid profiles were independent of its effects on glycemic control, insulin sensitivity, and cardiovascular markers (data not shown). D5D and D6D catalyze the synthesis of long-chain n-6 and n-3 polyunsaturated fatty acids (PUFAs), and their activities can be estimated using PUFA product-to-precursor ratios.32 ,33 The D5D activity index is negatively associated with insulin resistance,33 ,34 onset of newly diagnosed type 2 diabetes,32 and an adverse profile of several metabolic risk factors in patients with metabolic syndrome35 in cross-sectional studies. Insulin activates D5D in patients with diabetes.36 However, another cross-sectional study showed that patients with poorly controlled type 2 diabetes have a higher D5D activity index,37 and improving glycemic control with intensive insulin therapy significantly decreases D5D in patients with type 2 diabetes.38 Our study is the first to show the effect of a dipeptidyl peptidase-4 (DPP-4) inhibitor on D5D and D6D. After the switch from insulin, sitagliptin significantly decreased D5D, whereas it significantly increased D6D. Neither the baseline levels of D5D nor D6D predicted the sitagliptin-mediated improvement in glycemic control. Thus, sitagliptin, but not mitiglinide, may exert unique pleiotropic effects on fatty acid composition. The molecular mechanisms underlying the sitagliptin-mediated effects on fatty acid metabolism should be pursued in future studies.
Finally, patients who took sitagliptin or mitiglinide after switching from insulin ameliorated overall QOL as assessed by the DTSQ. The DTSQ was developed to enable respondents to evaluate their current treatment in relation to their previous treatment. Among the DTSQ subscale scores, convenience of treatment, flexibility of treatment, and satisfaction to continue current treatment showed a significant increase after switching from insulin in both groups. Previously, it was reported that less treatment satisfaction is related to insulin treatment.39 In addition, the satisfaction with treatment is reported to significantly correlate with adherence.40 Therefore, in this study, convenience of OHAs may contribute to satisfaction with treatment.
Patient factors associated with changes in HbA1c remain unclear after switching from a bolus insulin regimen to an OHA. Total insulin doses before switching from mealtime bolus insulin monotherapy to either sitagliptin or mitiglinide predicted changes in HbA1c in both groups. Interestingly, total insulin doses/body weight predicted changes in HbA1c only in the sitagliptin group, but not in the mitiglinide group, whereas body weights did so only in the mitiglinide group, but not in the sitagliptin group. This may be because the effect of mitiglinide, but not sitagliptin, is dependent on plasma drug concentration that is decreased in increased body weight.
The baseline CPI significantly predicted changes in HbA1c only in the sitagliptin group. One study reported that the CPI is associated with pancreatic β-cell function in Japanese patients with type 2 diabetes; patients with CPI<0.8 usually require insulin therapy.41 Our study is the first to prospectively demonstrate usefulness of the CPI for “tailor-made” diabetic medicine. Patients with a CPI<1.4 had worse HbA1c levels after switching to sitagliptin.
Our study has some limitations. First, mealtime dosing of rapid-acting insulin analog monotherapy may be a less common regimen in the diabetes treatment strategy. However, we previously showed that approximately one-half of the Japanese patients with type 2 diabetes retain β-cell function enough to achieve appropriate control of FPG by rapid-acting insulin analog monotherapy.1 We hypothesized that such patients may be considered switch to DPP-4 inhibitors or glinides. Second, it was unexpected that all the study participants experienced exacerbation in glycemic control after switching from bolus insulin regimen to OHAs. However, as a result, the potent effect of mealtime dosing of rapid-acting insulin analog monotherapy on glycemic control was confirmed in patients with type 2 diabetes. As we showed in this study, insulin doses and β-cell function may predict feasibility to sitagliptin therapy. Third, we intended to compare the efficacy of sitagliptin versus mitiglinide in controlling FPG after switching from insulin therapy. Therefore, we designed a parallel group study just comparing these agents. However, setting the control group that continued the insulin therapy further enables one to compare the efficacy of bolus insulin and OHAs in controlling FPG and HbA1c.
In conclusion, nadir FPG and HbA1c were exacerbated in patients receiving sitagliptin or mitiglinide after switching from mealtime dosing of a rapid-acting insulin analog. Mean FPG increased significantly in the mitiglinide group, whereas it remained unchanged in the sitagliptin group, but participants achieved similar glycemic control after switching from the bolus insulin regimen. In contrast, switching to sitagliptin or mitiglinide decreased BMI and waist circumference and increased QOL. Sitagliptin, but not mitiglinide, may exert unique pleiotropic effects on fatty acid composition. Patients whose mean total daily doses of rapid-acting insulin analog were 16.6 and 17.8 units were switched to sitagliptin and mitiglinide, respectively, without a change in the HbA1c level. Additional therapy to sitagliptin or mitiglinide is clearly required to obtain equivalent glycemic control in patients using higher dosing of insulin.⇑