Efficacy of alogliptin/metformin fixed-dose combination tablets and vildagliptin/metformin fixed-dose combination tablets on glycemic control in real-world clinical practice for the patients with type 2 diabetes: A multicenter, open-label, randomized, parallel group, comparative trial

Abstract

Background: This study was aimed to compare the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D).

Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20-79 years with glycated hemoglobin (HbA1c) levels of 6.5-10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. Incidence of adverse events during the study were also evaluated.

Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (–0.3% and –0.4%, P = 0.309) or the FPG level (–9.0 mg/dL and –15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group.

Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D.

Trial registration: The study was approved by University Hospital Medical Information Network Clinical Trial Registry on the 23rd of August 2018 (Registration No. 000033867).

Background

The high prevalence of chronic complications associated with type 2 diabetes mellitus (T2D) has led to a global increase in medical costs. Prospective cohort studies, including those done in the Japanese population, have demonstrated that intensive glycemic control can decrease the rates of micro- and macrovascular complications in T2D patients [1–5]. Meanwhile, hypoglycemia and weight gain are clinical challenges in achieving optimal glycemic control with glucose-lowering therapy [6].

The biguanide metformin suppresses gluconeogenesis through activation of the AMP-activated protein kinase in hepatocytes and has a glucose-lowering effect [7]. It is recommended as the first-line treatment for T2D by the American Diabetes Association guidelines because of its high efficacy and low cost, as well as fewer concerns about hypoglycemia and weight gain [8, 9].

Incretin-based drugs, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, were introduced in the 2000s as newer glucose-lowering agents. These are considered safe and effective because of the lower risk for hypoglycemia, inhibitory effects on glucagon secretion, and fewer concerns about weight gain [10].

Because both metformin and incretin-based drugs have a lower risk for hypoglycemia and weight gain, a combination of these drugs is expected to be safe and effective for optimal glycemic control.

Multiple glucose-lowering agents are often required to achieve and maintain glycemic control in T2D patients. These patients often have other comorbidities, such as hypertension and dyslipidemia, and tend to be polypharmacy. There are several reports on the medication compliance of diabetic patients. Paes et al. reported that a reduction of dose frequency decreases total noncompliance [11]. Rozenfeld et al. demonstrated that improved medication adherence led to improved glycemic control [12]. Ho et al. also reported that poor medication adherence was prevalent among diabetic patients, and was associated with adverse outcomes [13]. Therefore, physicians need to consider medication compliance while using glucose-lowering therapy in T2D patients.

Several recent combination drugs are expected to improve medication adherence and reduce medical costs. Various combinations of DPP-4 inhibitors and metformin are currently available. Although these drugs are expected to be effective for T2D patients, the differences in their efficacies for glycemic control remain to be elucidated.

In this study, we compared the efficacies of two DPP-4 inhibitor and metformin combination tablets, alogliptin/metformin and vildagliptin/metformin, for glycemic control in T2D patients.

Methods

Study Participants

The present study was performed in Japanese T2D patients in accordance with the principles of the Declaration of Helsinki. The participants were ambulatory T2D patients who presented to Asahikawa Medical University Hospital (Asahikawa, Hokkaido), Caress Sapporo Hokko Memorial Clinic (Sapporo, Hokkaido), or Keiyukai Yoshida Hospital (Asahikawa, Hokkaido). The participants were recruited between September 2018 and July 2020. Written informed consent was obtained from all participants. The inclusion criteria were outpatients; T2D patients with glycated hemoglobin (HbA1c) levels of 6.5–10%, with the use of glucose-lowering agents other than insulin, over 4 weeks before enrollment; age 20–79 years; and those who provided written informed consent for participation. The exclusion criteria were contraindication for alogliptin, vildagliptin, or metformin; type 1 diabetes and diabetics with other causes; diabetic ketoacidosis; history of severe hypoglycemic symptoms with coma or loss of consciousness; severe infection or trauma; poorly controlled hypertension despite medications; severe renal, hepatic, or heart disease; proliferative diabetic retinopathy; history of malignant tumors; patients judged to be unsuitable because of serious complications; pregnancy or breastfeeding; patients otherwise judged to be inappropriate for participation.

Randomization And Intervention

Enrollment and randomization were performed centrally. After consent and enrollment, a 4-to 12-week run-in period of treatment with metformin alone was set prior to intervention with combination tablets to comply with the usage described in the package insert in Japan. At the end of the run-in period, baseline data were collected, and the participants were randomly assigned to the alogliptin/metformin or vildagliptin/metformin treatment groups at a 1:1 ratio using the central envelope method. A confirmation document with the anonymized study-specific identification number and treatment group was issued. Participants allocated to the alogliptin/metformin group were given alogliptin 25 mg/metformin 500 mg combination tablet orally once a day for 12 weeks. Participants allocated to the vildagliptin/metformin group were given vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day for 12 weeks. The addition of new drugs or discontinuation and changes in the dose of these combination tablets were not allowed during the study. Insulin and GLP-1 receptor agonists were prohibited during the study period. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12, the last 2 weeks of the treatment period, to evaluate glycemic variability in each group (Fig. 1). The isCGM system used was the Freestyle Libre Pro™ (Abbott Laboratories, Chicago, IL, USA).

Outcomes And Measurements

The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12. The secondary endpoints were change in body mass index (BMI); change in homeostasis model assessment insulin resistance (HOMA-IR); change in homeostasis model assessment of beta-cell function (HOMA-β); change in fasting glucagon/insulin ratio; change in systolic blood pressure (SBP); glycemic status evaluated using the isCGM system; and incidence of adverse events, including abnormal laboratory findings. HOMA-IR and HOMA-β calculations were based on a previous report¹⁴. Estimated glomerular filtration rate (eGFR) as a measure of the renal function was calculated with serum creatinine, sex, and age using the established equation for Japanese subjects [15]. Plasma glucagon levels were measured at a central clinical laboratory (SRL Inc., Hachioji, Japan). Other laboratory data were measured locally at each institution. Time in target glucose range (TIR), time below target glucose range (TBR), and time above target glucose range (TAR) were defined as glucose levels 70–180 mg/dL, < 70 mg/dL, and > 180 mg/dL, respectively [16].

Data Management

Clinical data were managed using anonymized study-specific identification numbers generated by an independent data center. The data center was an independent instructor from Asahikawa Medical University, and was not involved in the treatment, data collection, or analysis. Participant enrollment, randomization, and data registration and storage were performed by the data center. Researchers and the heads of the institutions archived the information related to the study for 5 years from the date of completion of the study.

Results

Primary Endpoints

From baseline to week 12, HbA1c levels were significantly decreased in both alogliptin/metformin treatment group (7.5% [6.8, 7.9%] to 7.2% [6.6, 7.8%], P < 0.0001) and vildagliptin/metformin treatment group (7.6% [6.9, 8.0%] to 7.0% [6.5, 7.5%], P < 0.0001) (Fig. 3A). The changes in HbA1c level from baseline to week 12 in alogliptin/metformin treatment group and vildagliptin/metformin treatment group were − 0.3% (–0.5, − 0.1%) and − 0.4% (–0.7, − 0.2%), respectively, and there were no significant differences between the two groups (P = 0.309) (Fig. 3B and Table 2). FPG levels also decreased significantly in both alogliptin/metformin treatment group (158.0 mg/dL [137.0, 195.8 mg/dL] to 140.0 mg/dL [132.0, 178.0 mg/dL], P < 0.0001) and vildagliptin/metformin treatment group (162.5 mg/dL [128.5, 194.0 mg/dL] to 135.0 mg/dL [124.0, 155.8 mg/dL], P = 0.0116) from baseline to week 12 (Fig. 3C). The changes in FPG level from baseline to week 12 in alogliptin/metformin treatment group and vildagliptin/metformin treatment group were − 9.0 mg/dL (–43.0, − 5.0 mg/dL) and − 15.0 mg/dL (–44.5, 6.5 mg/dL), respectively, and there were no significant differences between the two groups (P = 0.789) (Fig. 3D and Table 2).

Secondary Endpoints

The changes in BMI, HOMA-IR, HOMA-β, glucagon/insulin ratio, and SBP from baseline to week 12 in alogliptin/metformin treatment group and vildagliptin/metformin treatment group were − 0.1 ± 0.6 kg/m² and 0.1 ± 0.6 kg/m² (P = 0.097), − 0.2 (–1.4, 0.4) and − 1.0 (–2.5, − 0.3) (P = 0.210), 6.0% (–1.7, 14.0%) and − 0.2% (–11.7, 12.2%) (P = 0.160), 1.0 (–4.7, 4.4) and 5.7 (–0.4, 16.0) (P = 0.065), and 0.0 mmHg (–12.0, 11.0 mmHg) and 0.0 mmHg (–8.8, 15.0 mmHg) (P = 0.855), respectively (Table 2). Thus, no significant differences were observed in the changes in these clinical parameters from baseline to week 12 between the two groups.

Next, glycemic status was evaluated using the blinded isCGM system from week 10 to 12 (Table 3). A total of 18 and 25 participants in the alogliptin/metformin and vildagliptin/metformin treatment groups completed the isCGM examination, respectively. The mean glucose, TIR, TBR, and TAR on isCGM in alogliptin/metformin and vildagliptin/metformin treatment groups were 136.0 mg/dL (110.3, 167.5 mg/dL) and 132.0 mg/dL (120.5, 142.5 mg/dL) (P = 0.604), 76.5% (63.3, 86.8%) and 86.0% (80.5, 91.5%) (P = 0.126), 0.0% (0.0, 3.8%) and 1.0% (0.0, 2.5%) (P = 0.326), and 14.5% (4.5, 36.8%) and 10.0% (6.5, 18.0%) (P = 0.570), respectively (Table 3). There were no significant differences in the glycemic indices between the two groups.

Adverse Events

There were no reports of any adverse events, including symptoms of hypoglycemia, during the study. Table 4 shows the laboratory data for safety evaluation. In both alogliptin/metformin and vildagliptin/metformin treatment groups, there were no abnormalities in blood cells and biochemical parameters at week 12 compared to the baseline. Only serum gamma-glutamyl transpeptidase (γ-GTP) decreased significantly from baseline to week 12 in the vildagliptin/metformin treatment group (37.0 U/L [25.5, 65.5 U/L] to 29.5 U/L [24.8, 45.5 U/L], P = 0.001).

Discussion

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 [10]. Metformin exhibits glucose-lowering effects by suppressing hepatic glucose output via inhibition of gluconeogenesis in hepatocytes [7]. In addition, metformin treatment has also been shown to increase circulating active GLP-1 levels [19]. 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 [20]. Moreover, combined therapy with DPP-4 inhibitors and metformin additively decreased HOMA-IR in T2D patients [21]. 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 [28]. 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 [29]. 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%) [16]. 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 [30]. 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 [30].

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 [12], and adverse outcomes [13] 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.

Conclusions

In conclusion, this was 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 in accordance with the package insert. The present study demonstrated that there were no significant differences in the efficacy of the two combination tablets with different dosages on glycemic control in patients with T2D.

Abbreviations

T2D: Type 2 diabetes mellitus; GLP-1: Glucagon-like peptide-1; DPP-4: Dipeptidyl peptidase-4; HbA1c: Glycated hemoglobin; isCGM: Intermittently scanned continuous glucose monitoring; FPG: Fasting plasma glucose; BMI: Body mass index; HOMA-IR: Homeostasis model assessment insulin resistance; HOMA-β: Homeostasis model assessment of beta-cell function; SBP: Systolic blood pressure; eGFR: Estimated glomerular filtration rate; TIR: Time in target glucose range; TBR: Time below target glucose range; TAR: Time above target glucose range; SEM: Standard error of the mean; SD: Standard deviation; γ-GTP: Gamma-glutamyl transpeptidase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; NAFLD: Non-alcoholic fatty liver disease.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of Asahikawa Medical University (Approval number: 17225). Written informed consent was obtained from all participants.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

Competing interests

 IS received an honorarium for a lecture from GlaxoSmithKline K.K. and research funding from Kowa Company, Ltd. YTakiyama was supported by foundation grants from Nippon Boehringer Ingelheim Co., Ltd., Taisho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., and MSD K.K. TA, YTakeda, MO, AS, RB, MSato, HK, and MSakurai have no conflicts of interest to disclose.

Funding

Not applicable.

Authors’ contributions

All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article. All authors significantly contributed to the completion of the study. YTakeda and IS contributed to developing the study protocol including the study design, intervention, inclusion and exclusion criteria, and variables and endpoints. TA, YTakeda, IS, MO, AS, RB, MSato, HK, and YTakiyama contributed to participant enrollment and data acquisition. YTakeda had full access to all the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. All statistical analysis was planned and performed by MSakurai. TA and YTakeda wrote and revised the manuscript of this article. All authors read and approved the final version of the manuscript.

Acknowledgements

We would like to express our deep gratitude to Professor Tsuguhito Ota for the opportunity to carry out the present study. We also thank all of the study participants.

Authors’ information

 ¹Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology / Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan. ²Caress Sapporo Hokko Memorial Clinic, Sapporo, Japan. ³Keiyukai Yoshida Hospital, Asahikawa, Japan. ⁴Department of Social and Environmental Medicine, Kanazawa Medical University, Uchinada, Japan.

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Tables

Table 1: Clinical characteristics and parameters of the subjects at baseline.

Table 2: Change in clinical parameters from baseline to week 12.

Table 3: Indices in intermittently scanned continuous glucose monitoring.

Table 4: Laboratory data for safety evaluation.