J Clin Med Res
Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc
Journal website http://www.jocmr.org

Short Communication

Volume 9, Number 8, August 2017, pages 719-724


Effect of Switching From an Anti-Diabetic Loose Dose Combination to a Fixed Dose Combination Regimen at Equivalent Dosage for 6 Months on Glycemic Control in Japanese Patients With Type 2 Diabetes: A Pilot Study

Kazutaka Aokia, b, j, Mieko Nagakurac, Masataka Tagurid, Hiroshi Kamiyamab, Makoto Masumurae, Tadashi Furuief, Masanao Okag, Kazunari Kamikob, Shigeru Nakajimah, Noriko Akemai, Yasuo Terauchib, j

aDepartment of Internal Medicine, Kanagawa Dental University, Yokosuka, Japan
bDepartment of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
cNagakura Clinic, Yokohama, Japan
dDepartment of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
eMasumura Naika Clinic, Yokohama, Japan
fFuruie Naika Clinic, Yokohama, Japan
gOka Naika Clinic, Yokohama, Japan
hNakajima Naika Clinic, Yokosuka, Japan
iIHI Yokohama Clinic, Yokohama, Japan
jCorresponding Author: Kazutaka Aoki, Department of Internal Medicine, Kanagawa Dental University, 82 Inaoka, Yokosuka 238-8580, Japan; Yasuo Terauchi, Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan

Manuscript submitted May 3, 2017, accepted May 24, 2017
Short title: FDC and Type 2 Diabetes
doi: https://doi.org/10.14740/jocmr3067w

Abstract▴Top 

Background: Patients with type 2 diabetes mellitus often take multiple anti-diabetic drugs for a long period. Fixed dose combination (FDC) therapy is expected to improve drug adherence for patients with diabetes. The effect of switching from a loose dose combination (LDC) regimen to an FDC regimen at equivalent dosage on glycemic control has not been evaluated fully. Therefore, we investigated the effect of switching from LDC to FDC at equivalent dosage for 6 months on glycemic control in Japanese patients with type 2 diabetes.

Methods: Thirty-eight Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including pioglitazone + metformin, pioglitazone + alogliptin, or pioglitazone + glimepiride were enrolled. These drugs were switched to an FDC of Metact®, Liobel® or Sonias®, respectively, at equivalent dosage. Other anti-diabetic drugs and units of insulin were not changed during the study if possible. HbA1c and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of the FDC regimen.

Results: HbA1c levels at 2, 4, and 6 months were not significantly changed compared with prior to switching from an LDC to FDC regimen. Moreover, 74.2% of patients considered decreasing the number of drugs to be “very good” or “good”.

Conclusion: HbA1c levels did not differ between patients receiving LDC and FDC therapy at equivalent dosage in this study.

Keywords: Fixed dose combination; Loose dose combination; Type 2 diabetes

Introduction▴Top 

Patients with type 2 diabetes often take multiple anti-diabetic drugs for a long period. As they often have comorbidities such as hypertension and hyperlipidemia, they may take other drugs daily as well. Medication non-adherence is prevalent among patients with diabetes mellitus and is associated with adverse clinical outcomes such as increased risks for all-cause hospitalization and all-cause mortality [1]. Therefore, the maintenance of good long-term adherence is important for the treatment of diabetes. Good adherence may be difficult to obtain, particularly among patients with busy social lives.

Recently, we investigated how to improve the drug adherence of patients with type 2 diabetes who are taking alpha glucosidase inhibitors, glinides, and dipeptidyl peptidase-4 (DPP-4) inhibitors [2-4]. Fixed dose combination (FDC) therapy or a weekly DPP-4 inhibitor is expected to improve drug adherence for patients with diabetes [5, 6]. Many FDC regimens for hypertension are available in Japan, but only five for diabetes. In retrospective studies, switching from loose dose combination (LDC) therapy to FDC therapy improved adherence [7, 8]. In another retrospective study, the most recent HbA1c level of patients who took an FDC of DPP-4 inhibitor and metformin was lower than that of patients who took an LDC of DPP-4 inhibitor and metformin free form [9]. Glycemic control may be improved by increased drug adherence due to the administration of FDC therapy. However, the effect of switching from an LDC to an FDC at equivalent dosage on glycemic control has not been evaluated fully. Therefore, we investigated the effect of switching from an LDC to an FDC at equivalent dosage for 6 months on glycemic control in Japanese patients with type 2 diabetes.

Materials and Methods▴Top 

This study was a prospective observational study to investigate the clinical effects of FDC therapy in patients with type 2 diabetes. After obtaining approval from the Institutional Ethics Review Committee of Yokohama City University, the objective of the study was explained to all subjects, and written informed consent was obtained prior to the start of the study. A total of 38 patients were recruited during the study registration period (from February 2013 to March 2016) and their data were analyzed in a pilot study (Figure 1).

Figure 1.
Click for large image
Figure 1. Study design. Thirty-eight Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including LDC such as pioglitazone + metformin, pioglitazone + alogliptin, or pioglitazone + glimepiride were enrolled. These drugs were switched to an FDC of Metact®, Liobel® or Sonias®, respectively, at equivalent dosage. No patients in the study took mitiglinide + voglibose, which can be switched to Glubes®. HbA1c and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of the FDC regimen.

Japanese patients with type 2 diabetes who were taking anti-diabetic drugs including pioglitazone + metformin, pioglitazone + alogliptin, pioglitazone + glimepiride, or mitiglinide + voglibose were enrolled between February 2013 and March 2016. The hospital or clinics that participated this study were Yokohama City University Hospital, Nagakura Clinic, Nakajima Naika Clinic, Oka Naika Clinic, Furuie Naika Clinic, IHI Yokohama Clinic, and Masumura Naika Clinic. Herein, a regimen comprising 15 mg of pioglitazone and 500 mg of metformin was switched to Metact® LD (FDC at equivalent doses of pioglitazone and metformin). Similarly, 30 mg of pioglitazone and 500 mg of metformin were switched with Metact® HD (FDC at equivalent doses of pioglitazone and metformin), 15 mg of pioglitazone and 25 mg of alogliptin were switched with Liobel® LD (FDC at equivalent doses of pioglitazone and alogliptin), 30 mg of pioglitazone and 25 mg of alogliptin were switched with Liobel® HD (FDC at equivalent doses of pioglitazone and alogliptin), 15 mg of pioglitazone and 1 mg of glimepiride were switched with Sonias® LD (FDC at equivalent doses of pioglitazone and glimepiride), 30 mg of pioglitazone and 1 mg of glimepiride were switched with Sonias® HD (FDC at equivalent doses of pioglitazone and glimepiride) and 10 mg of mitiglinide and 0.2 mg of voglibose were switched with Glubes® (FDC at equivalent doses of mitiglinide and voglibose). Other anti-diabetic drugs and units of insulin were not changed through the study if possible.

The HbA1c level and body weight were measured 0, 2, 4 and 6 months after switching from an LDC to FDC. We also conducted a questionnaire survey 2 months after the start of FDC. Question 1: How do you feel about the decrease in the number of drugs? Question 2: Has the number of medicine doses you have forgotten decreased? Question 3: How much of a benefit have you experienced in decreasing drug costs? Question 4: Do you feel there has been a change in your glycemic control? Question 5: Which do you prefer to take: FDC or LDC?

Data are expressed as the mean ± standard error. SAS software (SAS Institute Inc., Cary, NC, USA) was used for the statistical analysis. The HbA1c levels and body mass index (BMI) of patients were analyzed using a mixed model; we compared each value at 2, 4, and 6 months with that at 0 months and differences with P values less than 0.05 were considered significant.

Results▴Top 

Baseline characteristics

A total of 38 patients (29 male and nine female) with a mean age of 63.0 ± 1.5 years and a mean body mass index (BMI) of 26.7 ± 2.7 kg/m2 were enrolled. The mean HbA1c level was 6.8±0.1%, and the average duration of diabetes was 8.3 ± 0.8 years.

The number of types of all drugs taken was 5.3 ± 0.3, and the number of all drugs taken was 8.1 ± 0.8. The number of types of anti-diabetic drugs taken was 2.9 ± 0.1, and the number of anti-diabetic drugs taken was 4.6 ± 0.8.

Changes in HbA1c level and body weight

In this study, five patients took 15 mg of pioglitazone and 500 mg of metformin, which were switched to Metact® LD, and two patients took 30 mg of pioglitazone and 500 mg of metformin, which were switched to Metact® HD. Nineteen patients took 15 mg of pioglitazone and 25 mg of alogliptin, which were switched to Liovel® LD, and 11 patients took 30 mg of pioglitazone and 25 mg of alogliptin, which were switched to Liovel® HD. One patient took 15 mg of pioglitazone and 1 mg of glimepiride, which were switched to Sonias® LD. No patients in the study took mitiglinide and voglibose, which can be switched to Glubes®. Five patients dropped out of the study. Two patients did not visit the hospital or clinic at 2 or 6 months, respectively. One patient had another anti-diabetic drug added to the regimen. One patient stopped taking Sonias® LD due to edema. One patient stopped taking Metact® HD because of the increasing drug cost (generics for pioglitazone and metformin are available in Japan).

As shown in Figure 2a and b, HbA1c levels and body weight were not significantly different at 2, 4, and 6 months compared to that at 0 months. As shown Figure 2c, HbA1c levels did not differ at 2, 4, and 6 months compared to that at 0 months in the Metact® (n = 7) group or Liobel® group (n = 30). As shown in Figure 3a, HbA1c levels were not different at 2, 4, and 6 months compared to that at 0 months in the group taking more than eight tablets in total (n = 17) and the group taking less than eight tablets in total (n = 21). As shown in Figure 3b, HbA1c levels were not different at 2, 4, and 6 months compared to that at 0 months in the group taking more than five anti-diabetic tablets (n = 16). In the group taking less than five anti-diabetic tablets (n = 22), the HbA1c levels were significantly decreased at 4 months compared to that at 0 months; however, the HbA1c levels were not different at 2 and 6 months compared to that at 0 months (Fig. 3b).

Figure 2.
Click for large image
Figure 2. Changes in HbA1c and body weight after switching from an LDC to FDC. (a) HbA1c levels of all patients. (b) Body weight of all patients. (c) HbA1c levels of patients taking Metact® (FDC of pioglitazone and metformin, n = 7) or Liobel® (FDC of pioglitazone and alogliptin, n = 30).

Figure 3.
Click for large image
Figure 3. Changes in HbA1c after switching from an LDC to FDC. (a) HbA1c levels of patients taking more than eight tablets (n = 17) or less than eight tablets (n = 21) in total. (b) HbA1c levels of patients taking more than five anti-diabetic tablets (n = 16) or less than five anti-diabetic tablets (n = 22). *P < 0.05 vs. 0 months in each group.

Questionnaire

With respect to question 1, 74.2% of subjects responded “very good” or “good” (Table 1). With respect to question 2, 54.8% selected “decreased” or “decreased a little”, but 45.2% of patients selected “not changed”. With respect to question 3, 38.7% of patients saw significant or modest benefits; however, 61.3% of patients saw “almost no benefit” or “no benefit or unchanged”. With respect to question 4, 42% of patients answered “improved” or “improved slightly”, but 54.8% of patients answered “not changed”. With respect to question 5, 54.8% of patients preferred to receive an FDC, and 41.9% of patients answered “either”.

Table 1.
Click to view
Table 1. Questionnaire Survey
 
Discussion▴Top 

The most important finding in our study was the fact that the HbA1c level did not significantly differ after switching from an LDC to FDC at equivalent dosage.

In Japan, FDC for anti-diabetic drugs comprise combinations of pioglitazone + metformin, pioglitazone + glimepiride, pioglitazone + alogliptin, and voglibose + mitiglinide; recently, metformin + vildagliptin has become available as well. The benefits of an FDC are 1) a decrease in the number of drugs, 2) decreased drug costs in most cases, and 3) an improvement in drug adherence due to 1) and 2). In fact, an FDC regimen was shown to improve medication adherence in a meta-analysis [10]. A 10% increase in adherence to anti-diabetic drugs is associated with a 0.1% decrease in HbA1c level [11]. In a retrospective study, patients with type 2 diabetes treated with FDC had a low rate of non-persistence [7]. Drug adherence was reported to increase when patients were switched from LDC therapy with pioglitazone and metformin to analogous FDC therapy [8]. It was reported that treatment with FDC was associated with lower costs and increased possibility of achieving the target HbA1c in a retrospective study [12]. Indeed, the HbA1c level of patients who took an FDC of DPP-4 inhibitor and metformin was lower than that of patients who took an LDC of DPP-4 inhibitor and metformin free form in the retrospective study [9]. However, whether switching from an anti-diabetic LDC to FDC regimen at equivalent dosages in patients with type 2 diabetes improves glycemic control remains poorly understood. We evaluated this prospective observational pilot study and HbA1c levels did not significantly differ after switching from an LDC to FDC at equivalent dosage. HbA1c levels were not different at 2, 4, and 6 months compared to that at 0 months in both the group taking more than eight tablets and the group taking less than eight tablets in total. HbA1c levels were not different at 2, 4, 6 months compared to that at 0 months in the group taking more than five anti-diabetic tablets. In the group taking less than five anti-diabetic tablets, HbA1c levels were significantly decreased at 4 months compared to that at 0 months; however, HbA1c levels were not different at 2 and 6 months compared to that at 0 months. When the number of anti-diabetic drugs taken is low, switching from an LDC to FDC regimen may be effective; however, this effect is limited.

As the mean number of all drugs taken was 8.1 ± 0.8, the effect of switching from an LDC to FDC regimen on drug adherence and glycemic control by decreasing the number of drugs might be small. On the questionnaire, many patients indicated that decreasing the number of drugs is preferable; however, the effects of switching from an LDC to FDC regimen on the number of forgotten doses of medicine and on costs are limited. Therefore, 41.9% of patients said either FDC or LDC would be best. We would like to evaluate this switching effect in patients who are taking two or three anti-diabetic drugs.

The present study had several limitations. As the number of subjects in this study was small and the term of the study was short, larger-scale and longer-term studies are needed in the future. We also would like to evaluate adherence after switching from an LDC to FDC in a further study.

In conclusion, many patients felt positively about decreasing the number of drugs they took, and HbA1c levels did not differ after switching from an LDC to FDC at an equivalent dosage in this study.

Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research (C) 16K09806, (B) 21390282, and (B) 24390235 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and a Medical Award from the Japan Medical Association.

Conflicts of Interest

Yasuo Terauchi received honoraria for lectures from MSD; Ono Pharmaceutical Co. Ltd; Boehringer Ingelheim GmbH; Takeda Pharmaceutical Company Ltd; Tanabe-Mitsubishi Pharma; Daiichi-Sankyo Company Ltd; Sanwa Kagaku Kenkyusho Co., Ltd; Novo Nordisk Pharma Ltd; Eli Lilly and Company; Sanofi; DaiNippon-Sumitomo; Shionogi & Co., Ltd; Bayer Yakuhin Ltd; Astellas Pharma Inc.; and Astra Zeneca and obtained research support from MSD; Ono Pharmaceutical Co. Ltd; Boehringer Ingelheim GmbH; Takeda Pharmaceutical Company Ltd; Tanabe-Mitsubishi Pharma; Daiichi-Sankyo Company Ltd; Sanwa Kagaku Kenkyusho Co., Ltd; Novo Nordisk Pharma Ltd; Eli Lilly and Company; Sanofi; Astellas Pharma Inc.; and Astra Zeneca. Kazutaka Aoki obtained research support from Sanwa Kagaku Kenkyusho Co., Ltd.


References▴Top 
  1. Ho PM, Rumsfeld JS, Masoudi FA, McClure DL, Plomondon ME, Steiner JF, Magid DJ. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166(17):1836-1841.
    doi pubmed
  2. Aoki K, Nakajima S, Nezu U, Shinoda K, Terauchi Y. Comparison of pre- vs. postmeal administration of miglitol for 3 months in type 2 diabetic patients. Diabetes Obes Metab. 2008;10(10):970-972.
    doi pubmed
  3. Kamiyama H, Aoki K, Nakajima S, Shinoda K, Kamiko K, Taguri M, Terauchi Y. Effect of Switching from Sulphonylurea to Repaglinide Twice or Three Times Daily for 4 Months on Glycemic Control in Japanese Patients with Type 2 Diabetes. Intern Med. 2016;55(13):1697-1703.
    doi pubmed
  4. Kamiko K, Aoki K, Kamiyama H, Taguri M, Shibata E, Ashiya Y, Minagawa F, et al. Comparison of the administration of teneligliptin every day versus every other day in Japanese patients with type 2 diabetes: a randomized non-inferior test. J Clin Pharmacol. 2015;55(2):144-151.
    doi pubmed
  5. Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011;27(6):1157-1168.
    doi pubmed
  6. Kaku K. First novel once-weekly DPP-4 inhibitor, trelagliptin, for the treatment of type 2 diabetes mellitus. Expert Opin Pharmacother. 2015;16(16):2539-2547.
    doi pubmed
  7. Barner JC. Adherence to oral antidiabetic agents with pioglitazone and metformin: comparison of fixed-dose combination therapy with monotherapy and loose-dose combination therapy. Clin Ther. 2011;33(9):1281-1288.
    doi pubmed
  8. Lokhandwala T, Smith N, Sternhufvud C, Sorstadius E, Lee WC, Mukherjee J. A retrospective study of persistence, adherence, and health economic outcomes of fixed-dose combination vs. loose-dose combination of oral anti-diabetes drugs. J Med Econ. 2016;19(3):203-212.
    doi pubmed
  9. Benford M, Milligan G, Pike J, Anderson P, Piercy J, Fermer S. Fixed-dose combination antidiabetic therapy: real-world factors associated with prescribing choices and relationship with patient satisfaction and compliance. Adv Ther. 2012;29(1):26-40.
    doi pubmed
  10. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-719.
    doi pubmed
  11. Rozenfeld Y, Hunt JS, Plauschinat C, Wong KS. Oral antidiabetic medication adherence and glycemic control in managed care. Am J Manag Care. 2008;14(2):71-75.
    pubmed
  12. Williams SA, Buysman EK, Hulbert EM, Bergeson JG, Zhang B, Graham J. Hemoglobin A1c outcomes and health care resource use in type 2 diabetes mellitus patients treated with combination oral antidiabetic drugs through step therapy and loose-dose and fixed-dose combinations. Manag Care. 2012;21(7):40-48.
    pubmed


This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Journal of Clinical Medicine Research is published by Elmer Press Inc.



 

 

 

 

Browse  Journals  

 

Journal of clinical Medicine Research

Journal of Endocrinology and Metabolism

Journal of Clinical Gynecology and Obstetrics

 

World Journal of Oncology

Gastroenterology Research

Journal of Hematology

 

Journal of Medical Cases

Journal of Current Surgery

Clinical Infection and Immunity

 

Cardiology Research

World Journal of Nephrology and Urology

Cellular and Molecular Medicine Research

 

Journal of Neurology Research

International Journal of Clinical Pediatrics

 

 
       
 

Journal of Clinical Medicine Research, monthly, ISSN 1918-3003 (print), 1918-3011 (online), published by Elmer Press Inc.                 
The content of this site is intended for health care professionals.
This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC-BY-NC 4.0)


This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.jocmr.org   editorial contact: editor@jocmr.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada

© Elmer Press Inc. All Rights Reserved.