Switching from Sitagliptin to Alogliptin under Treatment with Pioglitazone Increases High Molecular Weight Adiponectin in Type 2 Diabetes: A Prospective Observational Study


Background: There are few clinical trials addressing the difference in pleiotropic effects among dipeptidyl peptidase (DPP)-4 inhibitors. We aimed to identify difference in effects on biochemical markers of inflammation, oxidative stress, and atherosclerosis between two DPP-4 inhibitors in patients with type 2 diabetes. Methods: We prospectively observed twenty subjects with type 2 diabetes before and after a practical medication change from a treatment with pioglitazone and sitagliptin 50 mg to a combination tablet containing the same dose of pioglitazone and alogliptin 25mg, which was actually identical to switching from sitagliptin to alogliptin. After 3 months, changes from baseline in clinical data and various biochemical markers were evaluated. In particular, body mass index (BMI) and hemoglobin A1c (HbA1c) were additionally followed after 12 months for evaluation of chronic outcomes. Results: Among markers, serum levels of high molecular weight (HMW) adiponectin significantly increased from 6.9 ± 3.6 μg/ml to 8.2 ± 4.0 μg/ml (P = 0.0045). Although no clinical data changed after 3 months, significant improvements in HbA1c and BMI were observed after 12 months. Their rates of changes tended to inversely correlate with the increased percentages of serum HMW adiponectin levels during initial 3 months, but they did not reach statistical significance. Conclusions: In spite of pretreatment with pioglitazone, additional increase in serum HMW adiponectin levels was demonstrated after switching from sitagliptin to alogliptin. Given multiple favorable roles of adiponectin in metabolic and cardiovascular states, alogliptin, at least when combined with pioglitazone, would be beneficial in treatment of type 2 diabetes.

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Tokito, A. , Koriyama, N. , Ijuin, A. , Ogiso, K. , Nishio, Y. and Jougasaki, M. (2015) Switching from Sitagliptin to Alogliptin under Treatment with Pioglitazone Increases High Molecular Weight Adiponectin in Type 2 Diabetes: A Prospective Observational Study. Journal of Diabetes Mellitus, 5, 258-266. doi: 10.4236/jdm.2015.54032.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Hotamisligil, G.S. (2006) Inflammation and Metabolic Disorders. Nature, 444, 860-867.
[2] Palmieri, V.O., Grattagliano, I., Portincasa, P. and Palasciano, G. (2006) Systemic Oxidative Alterations Are Associated with Visceral Adiposity and Liver Steatosis in Patients with Metabolic Syndrome. The Journal of Nutrition, 136, 3022-3026.
[3] Rocha, V.Z. and Libby, P. (2009) Obesity, Inflammation, and Atherosclerosis. Nature Reviews Cardiology, 6, 399-409.
[4] Matsuzawa, Y., Funahashi, T. and Nakamura, T. (1999) Molecular Mechanism of Metabolic Syndrome X: Contribution of Adipocytokines Adipocyte-Derived Bioactive Substances. Annals of the New York Academy of Sciences, 892, 146-154.
[5] Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., et al. (1999) Paradoxical Decrease of an Adipose-Specific Protein, Adiponectin, in Obesity. Biochemical and Biophysical Research Communications, 257, 79-83.
[6] Hotta, K., Funahashi, T., Arita, Y., Takahashi, M., Matsuda, M., Okamoto, Y., et al. (2000) Plasma Concentrations of a Novel, Adipose-Specific Protein, Adiponectin, in Type 2 Diabetic Patients. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 1595-1599.
[7] Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., et al. (2001) The Fat-Derived Hormone Adiponectin Reverses Insulin Resistance Associated with Both Lipoatrophy and Obesity. Nature Medicine, 7, 941-946.
[8] Okamoto, Y., Arita, Y., Nishida, M., Muraguchi, M., Ouchi, N., Takahashi, M., et al. (2000) An Adipocyte-Derived Plasma Protein, Adiponectin, Adheres to Injured Vascular Walls. Hormone and Metabolic Research = Hormonund Stoffwechselforschung= Hormones et metabolisme, 32, 47-50.
[9] Ouchi, N., Kihara, S., Arita, Y., Okamoto, Y., Maeda, K., Kuriyama, H., et al. (2000) Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial Nf-Kappab Signaling through a Camp-Dependent Pathway. Circulation, 102, 1296-1301.
[10] Hara, K., Horikoshi, M., Yamauchi, T., Yago, H., Miyazaki, O., Ebinuma, H., et al. (2006) Measurement of the High-Molecular Weight Form of Adiponectin in Plasma Is Useful for the Prediction of Insulin Resistance and Metabolic Syndrome. Diabetes Care, 29, 1357-1362.
[11] Lara-Castro, C., Luo, N., Wallace, P., Klein, R.L. and Garvey, W.T. (2006) Adiponectin Multimeric Complexes and the Metabolic Syndrome Trait Cluster. Diabetes, 55, 249-259.
[12] Drucker, D.J. and Nauck, M.A. (2006) The Incretin System: Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes. The Lancet, 368, 1696-1705.
[13] Campbell, J.E. and Drucker, D.J. (2013) Pharmacology, Physiology, and Mechanisms of Incretin Hormone Action. Cell Metabolism, 17, 819-837.
[14] Zhao, Y., Yang, L. and Zhou, Z. (2014) Dipeptidyl Peptidase-4 Inhibitors: Multitarget Drugs, Not Only Antidiabetes Drugs. Journal of Diabetes, 6, 21-29.
[15] Fujita, H., Taniai, H., Murayama, H., Ohshiro, H., Hayashi, H., Sato, S., et al. (2014) Dpp-4 Inhibition with Alogliptin on Top of Angiotensin Ii Type 1 Receptor Blockade Ameliorates Albuminuria via Up-Regulation of Sdf-1α in Type 2 Diabetic Patients with Incipient Nephropathy. Endocrine Journal, 61, 159-166.
[16] Rizzo, M.R., Barbieri, M., Marfella, R. and Paolisso, G. (2012) Reduction of Oxidative Stress and Inflammation by Blunting Daily Acute Glucose Fluctuations in Patients with Type 2 Diabetes: Role of Dipeptidyl Peptidase-IV Inhibition. Diabetes Care, 35, 2076-2082.
[17] Takeshita, Y., Takamura, T., Kita, Y., Otoda, T., Kato, K., Wakakuri, H., et al. (2015) Vildagliptin vs. Liraglutide as a Second-Line Therapy Switched from Sitagliptin-Based Regimens in Patients with Type 2 Diabetes: A Randomized, Parallel-Group Study. Journal of Diabetes Investigation, 6, 192-200.
[18] Hirose, H., Kawai, T., Yamamoto, Y., Taniyama, M., Tomita, M., Matsubara, K., et al. (2002) Effects of Pioglitazone on Metabolic Parameters, Body Fat Distribution, and Serum Adiponectin Levels in Japanese Male Patients with Type 2 Diabetes. Metabolism: Clinical and Experimental, 51, 314-317.
[19] Tonelli, J., Li, W., Kishore, P., Pajvani, U.B., Kwon, E., Weaver, C., et al. (2004) Mechanisms of Early Insulin-Sensitizing Effects of Thiazolidinediones in Type 2 Diabetes. Diabetes, 53, 1621-1629.
[20] Aso, Y., Yamamoto, R., Suetsugu, M., Matsumoto, S., Wakabayashi, S., Matsutomo, R., et al. (2007) Comparison of the Effects of Pioglitazone and Voglibose on Circulating Total and High-Molecular-Weight Adiponectin, and on Two Fibrinolysis Inhibitors, in Patients with Type 2 Diabetes. Diabetic Medicine: A Journal of the British Diabetic Association, 24, 962-968.
[21] Nabeno, M., Akahoshi, F., Kishida, H., Miyaguchi, I., Tanaka, Y., Ishii, S., et al. (2013) A Comparative Study of the Binding Modes of Recently Launched Dipeptidyl Peptidase IV Inhibitors in the Active Site. Biochemical and Biophysical Research Communications, 434, 191-196.
[22] Kim Chung le, T., Hosaka, T., Yoshida, M., Harada, N., Sakaue, H., Sakai, T., et al. (2009) Exendin-4, a Glp-1 Receptor Agonist, Directly Induces Adiponectin Expression through Protein Kinase a Pathway and Prevents Inflammatory Adipokine Expression. Biochemical and Biophysical Research Communications, 390, 613-618.
[23] Masuda, T., Fu, Y., Eguchi, A., Czogalla, J., Rose, M.A., Kuczkowski, A., et al. (2014) Dipeptidyl Peptidase IV Inhibitor Lowers Ppargamma Agonist-Induced Body Weight Gain by Affecting Food Intake, Fat Mass, and Beige/Brown Fat but Not Fluid Retention. American Journal of Physiology Endocrinology and Metabolism, 306, E388-E398.
[24] Indulekha, K., Surendar, J., Anjana, R.M., Gokulakrishnan, K., Balasubramanyam, M., Aravindhan, V., et al. (2012) Circulating Levels of High Molecular Weight (HMW) Adiponectin and Total Adiponectin in Relation to Fat Distribution, Oxidative Stress and Inflammation in Asian Indians. Disease Markers, 33, 185-192.
[25] Turer, A.T. and Scherer, P.E. (2012) Adiponectin: Mechanistic Insights and Clinical Implications. Diabetologia, 55, 2319-2326.
[26] Yamamoto, Y., Hirose, H., Saito, I., Nishikai, K. and Saruta, T. (2004) Adiponectin, an Adipocyte-Derived Protein, Predicts Future Insulin Resistance: Two-Year Follow-Up Study in Japanese Population. The Journal of Clinical Endocrinology and Metabolism, 89, 87-90.

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