Masayuki Kobayashi, Shoko Tsukube^*, Yukio Ikeda, Yujin Shuto

Show more
Sanofi K.K., Tokyo, Japanc.
Sanofi K.K., Tokyo, Japan.
Show less

Abstract: Aims: In the Add-on Lantus® to Oral Hypoglycaemic Agents 2 (ALOHA 2) Study in Japanese adults with type 2 diabetes mellitus (T2DM), data on the safety and efficacy of combination therapy with insulin glargine (Lantus®) and oral anti-hyperglycaemic drugs (OADs) including dipeptidyl peptidase-4 (DPP-4) inhibitors in a real-life setting were collected and analyzed. Methods: This postmarketing surveillance was a prospective, observational, 24-week study that complied with the pharmaceutical affairs law and the ministerial ordinance of “Good Post-Marketing Study Practice (GPSP)” in Japan. Safety, efficacy and patient-reported outcomes (PROs); patients’ satisfaction with treatment (DTSQs and DTSQc) and patients’ self-reported health (EQ-5D and EQ-VAS) of combination therapy of insulin glargine and OADs were evaluated. Results: A total of 2,630 patients were enrolled. Of the 2,602 patients in the safety analysis population, 161 patients experienced 175 cases of adverse drug reactions, and the major adverse drug reaction was hypoglycaemia (140 patients, 5.38%). Out of those with hypoglycaemia, 11 patients (0.42%) had severe hypoglycaemia and the incidence rate (episodes per patient-year) was 0.019. Basal supported oral therapy (BOT) with insulin glargine substantially reduced the HbA1c, FPG and 2 hour-PPG levels for 24 weeks by -1.61%, -54.4 mg/dL and -74.5 mg/dL respectively. The mean weight was increased, however the change was +0.50 kg. In addition, the treatment satisfaction scores of DTSQs (mean treatment satisfaction score increased 3.6 from baseline to last observation) and DTSQc, EQ-5D index scores and EQ-VAS scores were significantly improved. Conclusion: Insulin glargine and OADs combination therapy was suggested to be effective and well tolerated. Patients’ satisfaction with treatment and their self-reported health improved in spite of the addition of injections to oral agents. The combination therapy of insulin glargine and OADs including DPP-4 inhibitors is likely to be considered an important therapeutic option in the diabetic patients.

Keywords: ALOHA 2, Insulin Glargine, Patient-Reported Outcomes, Post-Marketing Surveillance Study, Type 2 Diabetes

Cite this paper: Kobayashi, M. , Tsukube, S. , Ikeda, Y. and Shuto, Y. (2014) Safety and Efficacy of Combination Therapy with Insulin Glargine and Oral Hypoglycaemic Agents Including DPP-4 Inhibitors in Japanese T2DM Patients: ALOHA 2 Study, a Post-Marketing Surveillance for Lantus^®. Journal of Diabetes Mellitus, 4, 273-289. doi: 10.4236/jdm.2014.44039.

References

[1]   Inzucchi, S.E., Bergenstal, R.M., Buse, J.B., Diamant, M., Ferrannini, E., Nauck, M., et al. (2012) Management of Hyperglycaemia in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia, 55, 1577-1596. http://dx.doi.org/10.1007/s00125-012-2534-0

[2]   Kramer, W. (1999) New Approaches to the Treatment of Diabetes. Experimental and Clinical Endocrinology Diabetes, 107, S52-S61. http://dx.doi.org/10.1055/s-0029-1212151

[3]   Heinemann, L., Linkeschova, R., Rave, K., Hompesch, B., Sedlak, M. and Heise, T. (2000) Time-Action Profile of the Long-Acting Insulin Analog Insulin Glargine (HOE901) in Comparison with Those of NPH Insulin and Placebo. Diabetes Care, 23, 644-649. http://dx.doi.org/10.2337/diacare.23.5.644

[4]   Lepore, M., Pampanelli, S., Fanelli, C., Porcellati, F., Bartocci, L., Di Vincenzo, A., et al. (2000) Pharmacokinetics and Pharmacodynamics of Subcutaneous Injection of Long-Acting Human Insulin Analog Glargine, NPH Insulin and Ultralente Human Insulin and Continuous Subcutaneous Infusion of Insulin Lispro. Diabetes, 49, 2142-2148. http://dx.doi.org/10.2337/diabetes.49.12.2142

[5]   Yki-J?rvinen, H., Dressler, A. and Ziemen, M., HOE 901/300s Study Group (2000) Less Nocturnal Hypoglycemia and Better Post-Dinner Glucose Control with Bedtime Insulin Glargine Compared with Bedtime NPH Insulin during Insulin Combination Therapy in Type 2 Diabetes. Diabetes Care, 23, 1130-1136. http://dx.doi.org/10.2337/diacare.23.8.1130

[6]   Riddle, M.C., Rosenstock, J. and Gerich, J., on Behalf of the Inslin Glargine 4002 Study Investigators (2003) The Treat-to-Target Trial: Randomized Addition of Glargine or Human NPH Insulin to Oral Therapy of Type 2 Diabetic Patients. Diabetes Care, 26, 3080-3086.
http://dx.doi.org/10.2337/diacare.26.11.3080

[7]   Raskin, P., Allen, E., Hollander, P., Lewin, A., Gabbay, R.A., et al., for the INITIATE Study Group (2005) Initiating Insulin Therapy in Type 2 Diabetes: A Comparison of Biphasic and Basal Insulin Analogs. Diabetes Care, 28, 260-265. http://dx.doi.org/10.2337/diacare.28.2.260

[8]   Ohtani, T. and Ito, T. (2011) Safety and Effectiveness of BOT (Basal Supported Oral Therapy) Using Insulin Glargine in Japanese Patients with Type 2 Diabetes—Results from Post-Marketing Surveillance of Insulin Glargine (ALOHA Study). Shinyaku to Rinsho (Journal of New Remedies & Clinics), 60, 458-475.

[9]   Kadowaki, T., Ohtani, T. and Odawara, M. (2012) Potential Formula for the Calculation of Starting and Incremental Insulin Glargine Doses: ALOHA Subanalysis. PLoS ONE, 7, e41358.
http://dx.doi.org/10.1371/journal.pone.0041358

[10]   Odawara, M., Ohtani, T. and Kadowaki, T. (2012) Dosing of Insulin Glargine to Achieve the Treatment Target in Japanese Type 2 Diabetes on a Basal Supported Oral Therapy Regimen in Real Life: ALOHA Study Subanalysis. Diabetes Technology Therapeutics, 14, 635-643.
http://dx.doi.org/10.1089/dia.2011.0220

[11]   Kadowaki, T., Ohtani, T. and Odawara, M. (2013) Baseline Predictive Factors for Glycemic Control in Japanese Type 2 Diabetes Patients Treated with Insulin Glargine Plus Oral Antidiabetic Drugs: ALOHA Study Subanalysis. Diabetology International, 4, 16-22. http://dx.doi.org/10.1007/s13340-012-0087-6

[12]   D’Alessio, D. (2011) The Role of Dysregulated Glucagon Secretion in Type 2 Diabetes. Diabetes, Obesity and Metabolism, 13, 126-132. http://dx.doi.org/10.1111/j.1463-1326.2011.01449.x

[13]   McDougall, C., McKay, G.A. and Fisher, M. (2011) Drugs for Diabetes: Part 5 DPP-4 Inhibitors. British Journal of Cardiology, 18, 130-132.

[14]   Seufert, J., Pegelow, K. and Bramlage, P. (2013) Efficacy and Safety of Insulin Glargine Added to a Fixed-Dose Combination of Metformin and a Dipeptidyl Peptidase-4 Inhibitor: Results of the GOLD Observational Study. Vascular Health and Risk Management, 9, 711-717.
http://dx.doi.org/10.2147/VHRM.S54362

[15]   Vilsboll, T., Rosenstock, J., Yki-Jarvinen, H., Cefalu, W.T., Chen, Y., Luo, E., et al. (2010) Efficacy and Safety of Sitagliptin When Added to Insulin Therapy in Patients with Type 2 Diabetes. Diabetes, Obesity and Metabolism, 12, 167-177. http://dx.doi.org/10.1111/j.1463-1326.2009.01173.x

[16]   Bavenholm, P.N. and Efendic, S. (2006) Postprandial Hyperglycaemia and Vascular Damage—The Benefits of Acarbose. Diabetes and Vascular Disease Research, 3, 72-79.
http://dx.doi.org/10.3132/dvdr.2006.017

[17]   Bradley, C. and Lewis, K.S. (1990) Measures of Psychological Well-Being and Treatment Satisfaction Developed from the Responses of People with Tablet-Treated Diabetes. Diabetic Medicine, 7, 445-451. http://dx.doi.org/10.1111/j.1464-5491.1990.tb01421.x

[18]   Howorka, K., Pumprla, J., Schlusche, C., Wagner-Nosiska, D., Schabmann, A. and Bradley, C. (2000) Dealing with Ceiling Baseline Treatment Satisfaction Level in Patients with Diabetes under Flexible, Functional Insulin Treatment: Assessment of Improvements in Treatment Satisfaction with a New Insulin Analogue. Quality of Life Research, 9, 915-930. http://dx.doi.org/10.1023/a:1008921419108

[19]   EuroQol Group (1990) EuroQol—A New Facility for the Measurement of Health-Related Quality of Life. Health Policy, 16, 199-208. http://dx.doi.org/10.1016/0168-8510(90)90421-9

[20]   Sakamaki, H., Ikeda, S., Ikegami, N., Uchigata, Y., Iwamoto, Y., Origasa, H., et al. (2006) Measurement of HRQL Using EQ-5D in Patients with Type 2 Diabetes Mellitus in Japan. Value in Health, 9, 47-53. http://dx.doi.org/10.1111/j.1524-4733.2006.00080.x

[21]   Nozaki, T., Morita, C., Matsubayashi, S., Ishido, K., Yokoyama, H., Kawai, K., et al. (2009) Relation between Psychosocial Variables and the Glycemic Control of Patients with Type 2 Diabetes: A Cross-Sectional and Prospective Study. BioPsychoSocial Medicine, 3, 4. http://dx.doi.org/10.1186/1751-0759-3-4

[22]   Yang, W., Lv, X., Li, Q., Jia, W. and Tian, H. (2012) A Prospective Study to Optimize Insulin Treatment by Switching to Insulin Glargine in Type 2 Diabetic Patients Previously Uncontrolled on Premixed Insulin: The Optimization Study. Current Medical Research and Opinion, 28, 533-541.
http://dx.doi.org/10.1185/03007995.2012.671764

[23]   Kawamori, R., Kadowaki, T., Ishii, H., Iwasaki, M. and Iwamoto, Y. (2009) Efficacy and Safety of Insulin Glulisine in Japanese Patients with Type 1 Diabetes Mellitus. Diabetes, Obesity and Metabolism, 11, 891-899. http://dx.doi.org/10.1111/j.1463-1326.2009.01086.x

[24]   Janssen, M.F., Lubetkin, E.I., Sekhobo, J.P. and Pickard, A.S. (2011) The Use of the EQ-5D Preference-Based Health Status Measure in Adults with Type 2 Diabetes Mellitus. Diabetic Medicine, 28, 395-413. http://dx.doi.org/10.1111/j.1464-5491.2010.03136.x

[25]   Kashiwagi, A., Kasuga, M., Araki, E., Oka, Y., Hanafusa, T., Ito, H., et al. (2012) International Clinical Harmonization of Glycated Hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program Values. Journal of Diabetes Investigation, 3, 39-40.
http://dx.doi.org/10.1111/j.2040-1124.2012.00207.x

[26]   Bradley, C., Plowright, R., Stewart, J., Valentine, J. and Witthaus, E. (2007) The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) Evaluated in Insulin Glargine Trials Shows Greater Responsiveness to Improvements than the Original DTSQ. Health and Quality of Life Outcomes, 5, 57. http://dx.doi.org/10.1186/1477-7525-5-57

[27]   Caire, P., Plowright, R., Conway, K. and Bradley, C. (2010) Is It Necessary to Adapt the UK English Original of the Diabetes Treatment Satisfaction Questionnaire (DTSQs) before Use in Other Countries? 2010 International Society for Quality of Life Research Meeting Abstracts. Quality of Life Research, 19, 63.

[28]   Ishii, H., Bradley, C., Riazi, A., Barendse, S. and Yamamoto, T. (2000) The Japanese Version of the Diabetes Treatment Satisfaction Questionnaire (DTSQ): Translation and Clinical Evaluation. Journal of Clinical and Experimental Medicine, 192, 809-814.

[29]   Ikegami, N., Fukuhara, S., Shimozuma, K. and Ikeda, S. (2001) Handbook of QOL Assessment for Clinical. Igaku-Shoin Ltd., Tokyo.

[30]   Tsuchiya, A., Ikeda, S., Ikegami, N., Nishimura, S., Sakai, I., Fukuda, T., et al. (2002) Estimating an EQ-5D Population Value Set: The Case of Japan. Health Economics, 11, 341-353.
http://dx.doi.org/10.1002/hec.673

[31]   Japanese EuroQol Translation Team (1998) The Development of the Japanese EuroQol Instrument. Iryo to Shakai, 8, 109-123.

[32]   Namba, M., Kaku, K., Yoshioka. N., Yamada, Y., Watada, H., Ueki, K., et al. (2012) The PREDICTIVETM Study: A Multinational, Prospective Observational Study to Evaluate the Safety and Efficacy of Insulin Detemir Treatment in Patients with Type 1 and 2 Diabetes—Data from the Japan Cohort. Diabetology International, 3, 11-20. http://dx.doi.org/10.1007/s13340-011-0051-x

[33]   Schreiber, S.A. and Haak, T. (2007) Insulin Glargine Benefits Patients with Type 2 Diabetes Inadequately Controlled on Oral Antidiabetic Treatment: An Observational Study of Everyday Practice in 12,216 Patients. Diabetes, Obesity and Metabolism, 9, 31-38.
http://dx.doi.org/10.1111/j.1463-1326.2006.00593.x

[34]   Kothny, W., Foley, J., Kozlovski, P., Shao, Q., Gallwitz, B. and Lukashevich, V. (2013) Improved Glycaemic Control with Vildagliptin Added to Insulin, with or without Metformin, in Patients with Type 2 Diabetes Mellitus. Diabetes, Obesity and Metabolism, 15, 252-257.
http://dx.doi.org/10.1111/dom.12020