To the best of our knowledge, this is the first randomized trial comparing the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in Japanese T2D patients. We found that HbA1c and FPG levels decreased significantly from baseline to week 12 with both alogliptin/metformin and vildagliptin/metformin combination treatments. However, there were no significant differences in the changes in HbA1c and FPG levels from baseline to week 12 between the two treatment groups. This suggests that both combinations of DPP-4 inhibitor and metformin were useful for glycemic control in Japanese T2D patients, with no obvious differences.
The intervention of the current study was a switch from metformin monotherapy to a combination of DPP-4 inhibitors and metformin. Previous studies that examined the effects of addition of alogliptin or vildagliptin to metformin monotherapy on glycemic control demonstrated a greater decrease in HbA1c and FPG compared to the present study [17, 18]. These differences in the findings between the present and previous studies could be explained by the differences in study participants and design. The participants in the present study had lower HbA1c levels (median 7.6%) and BMI (median 25.7 kg/m2), in addition to a shorter treatment period (12 weeks). In addition, the previous studies added alogliptin or vildagliptin to high doses of metformin (≥ 1500 mg/day) [17, 18]. Hence, our findings cannot be unconditionally compared to the results of the previous studies.
DPP-4 inhibitors exhibit glucose-lowering effects by increasing the circulating levels of the active form of incretins, such as glucose-dependent insulinotropic polypeptide and GLP-1, which are secreted from small intestine in response to meal ingestion and stimulate insulin secretion in a glucose-dependent manner. Moreover, DPP-4 inhibitors also inhibit glucagon secretion from islet α cells by increasing circulating active GLP-1 levels . Metformin exhibits glucose-lowering effects by suppressing hepatic glucose output via inhibition of gluconeogenesis in hepatocytes . In addition, metformin treatment has also been shown to increase circulating active GLP-1 levels . Thus, combined treatment with DPP-4 inhibitors and metformin was expected to enhance glycemic control by glucose-dependent insulin secretion and suppression of glucagon secretion associated with increased GLP-1 levels. Interestingly, Solis-Herrera et al. demonstrated that combined therapy with DPP-4 inhibitor, sitagliptin, and metformin additively reduced glycemia, along with enhancement of GLP-1 secretion and β cell function, decrease in glucagon secretion, and inhibition of endogenous glucose production, compared to metformin or sitagliptin monotherapy in T2D patients . Moreover, combined therapy with DPP-4 inhibitors and metformin additively decreased HOMA-IR in T2D patients . Hence, we employed HOMA-IR and HOMA-β, as well as glucagon/insulin ratio, which has been reported as an indicator of inappropriate hyperglucagonemia in diabetes [22–27], as indices to assess the underlying mechanisms of the glucose-lowering effects of the two treatments.
We anticipated that the glucose-lowering effects of vildagliptin/metformin were superior to alogliptin/metformin, with decreased fasting glucagon/insulin ratio. This was because, compared to the morning administration of alogliptin 25 mg/metformin 500 mg combination tablet, the twice daily administration of vildagliptin 50 mg/metformin 250 mg was presumed to have a greater inhibitory effect on inappropriate glucagon secretion during the night. We expected that vildagliptin/metformin treatment group would show a greater decrease in FPG due to reduced gluconeogenesis by suppression of the action of glucagon during the night. However, there were no significant differences in the changes in FPG levels and glucagon/insulin ratio between the two groups. There were also no significant differences in the changes in HOMA-IR and HOMA-β from baseline to week 12 between the two groups.
Kanto et al. demonstrated that administration of different dosages of metformin resulted in different blood concentrations, but the efficacy of metformin did not differ between treatment groups with different dosages . On the other hand, there have been no reports of the effects of different dosages of DPP-4 inhibitors on glycemic control. Conceivably, like other drugs, the potency of DPP-4 inhibitors in glycemic control is expected to depend on their half-life and blood concentrations. Alogliptin has a longer half-life compared to vildagliptin . Therefore, it shows the expected glucose-lowering effects with once-daily administration, whereas vildagliptin requires twice-daily administration. We considered the half-lives of DPP-4 inhibitors and based the dosage on it to ensure the effectiveness of the combination tablets in glucose-lowering therapy.
We further found no significant differences in the glycemic status, evaluated using isCGM, including TIR, TBR, and TAR, between the two treatment groups. Moreover, both treatment groups achieved the recommended target TIR (> 70%), TBR (< 4%), and TAR (< 25%) . In addition, there were no reports of symptoms that could be considered adverse events, including hypoglycemia, or abnormal laboratory findings during the study. These results not only demonstrated the usefulness of both combinations in glycemic control, but also their safety considering the risk for hypoglycemia.
Interestingly, there was a significant decrease in γ-GTP levels at week 12 in the vildagliptin/metformin treatment group. Alogliptin/metformin treatment group also showed decreasing tendency for γ-GTP levels. Although detailed verification of the findings was not performed in this study, we proposed a possible reason to explain these results. Carbone et al. demonstrated that incretin-based therapies, including DPP-4 inhibitors, improved liver function, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-GTP levels, probably through improved insulin resistance and anti-inflammatory effects in non-alcoholic fatty liver disease (NAFLD) patients . In the present study, we did not evaluate the prevalence of NAFLD in our participants. However, because we observed high HOMA-IR at baseline and a decrease after treatment in both treatment groups, we hypothesized that the beneficial effects of DPP-4 inhibitors on insulin resistance could be involved in the decrease in γ-GTP levels at week 12 in T2D patients of the current study, as well as NAFLD patients in the previous study .
T2D patients tend to be polypharmacy because of other comorbidities, such as hypertension and dyslipidemia. Previous reports have demonstrated the relationship between medication adherence and glycemic control , and adverse outcomes  in diabetic patients. Therefore, glucose-lowering therapy with attention to medication adherence is required. In the present study, we demonstrated that both combinations of DPP-4 inhibitors and metformin with different dosages were useful and safe in pharmacotherapy for T2D patients, with no obvious differences in efficacies. From the viewpoint of medication adherence, alogliptin/metformin combination tablet, which is administered once a day, may be a convenient drug than vildagliptin/metformin combination tablet, which requires twice daily administration.
There were several limitations to the present study. First, it had a small sample size and short treatment period. Therefore, further studies with larger sample size and longer treatment period are required. Second, there were sex differences between the two treatment groups. Because we essentially evaluated the changes in various parameters from baseline to week 12, the sex differences between the two groups were expected to have little impact on these results. Meanwhile, we also hypothesized that this difference may be the cause of the tendency of the laboratory data for safety evaluation at baseline in alogliptin/metformin treatment group to be lower compared to the vildagliptin/metformin treatment group. Third, although we compared the efficacy of the two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in accordance with the package insert of each drug, it might be no more than a comparison of efficacy between alogliptin and vildagliptin in terms of pharmacotherapy.