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Title: is similar in glycaemic variability more effective in metabolic contPlease check the short title that has been created, or suggest an alternative of fewer than 80 characters including spaces.–>Saxagliptin is similar in glycaemic variability more effective in metabolic cont–>rol than acarbose in aged type 2 inadequately controlled with

Author: Man-man Wang Shuo Lin Yan-ming Chen Jiong Shu Hong-yun Lu Yong-jun Zhang Ru-ying Xie Long-yi Zeng Pan-wei Mu

PII: S0168-8227(15)00122-9 DOI: http://dx.doi.org/doi:10.1016/j.diabres.2015.02.022 Reference: DIAB 6323

To appear in: Diabetes Research and Clinical Practice

Received date: 21-10-2014 Revised date: 26-1-2015 Accepted date: 19-2-2015

Please cite this article as: M.-m. Wang, S. Lin, Y.-m. Chen, J. Shu, H.-y. Lu, Y.-j. Zhang, R.-y. Xie, L.-y. Zeng, P.-w. Mu, Saxagliptin is similar in glycaemic variability more effective in metabolic control than acarbose in aged inadequately controlled with metformin., Diabetes Research and Clinical Practice (2015), http://dx.doi.org/10.1016/j.diabres.2015.02.022

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Full Title: Saxagliptin is similar in glycaemic variability more effective in metabolic control than acarbose in aged type 2 diabetes inadequately controlled with metformin.

Short title: saxagliptin acarbose glycaemic variability

Man-man Wang1, Shuo Lin1, Yan-ming Chen1, Jiong Shu1, Hong-yun Lu2,

Yong-jun Zhang3, Ru-ying Xie1, Long-yi Zeng1, Pan-wei Mu1*

1 Department of Endocrinology, the Third Affiliated Hospital of

Sun Yat-sen University, Guangzhou, 510630, China

2 Department of Endocrinology, the Fifth Affiliated Hospital of

Sun Yat-sen University, Zhuhai, 519000, China

3 Department of Endocrinology, the Fifth Affiliated Hospital of

Zunyi Medical College, Zhuhai, 519100, China

*CorrespondingAccepted author: Prof. Pan-wei ManuscriptMu Tel.: +86-20-85253408; Fax: +86-20-85252160.

E-mail address: [email protected]

Man-man Wang and Shuo Lin contributed equally to this paper.

Page 1 of 13 Abstract

This trial compared the effects on glycaemic variability and control between saxagliptin and acarbose as add-on therapies for aged

T2DM inadequately controlled with metformin alone. The results show that compared with acarbose-metformin, saxagliptin-metformin was more effective in glucose control with similar glycaemic variability.

Key words saxagliptin; acarbose; glycaemic variability; type 2 diabetes mellitus

Accepted Manuscript

Page 2 of 13 Abbreviations

GV: glycaemic variability

HbA1c: glycosylated hemoglobin

T2DM: type 2 diabetes mellitus

FBG: fasting blood glucose

SMBG: self-monitoring of blood glucose

IDF: International Diabetes Federation

SDBG: Standard deviation of blood glucose

LAGE: largest amplitude of glycaemic excursions

DPP-4: dipeptidylpeptidase-4

Accepted Manuscript

Page 3 of 13 1. Introduction

Glycaemic variability (GV) is an HbA1c-independent risk factor in the development of diabetic complications [1]. It should be considered along with HbA1c in the management of diabetes [2]. As an add-on drug, acarbose is known to improve GV [3-4].Saxagliptin is a new anti-diabetic drug, whose effect on GV is still unclear. Therefore we compared the glucose control and GV between saxagliptin and acarbose as add-on therapies for aged type 2 diabetes mellitus (T2DM) inadequately controlled with metformin alone.

2. Research design and methods

Ninety outpatients aged over 60 years, with FBG >8.5 mmol/L and

HbA1c >7.5% (58 mmol/mmol) while treated metformin alone for more than six months, were enrolled. Patients were excluded if they had acute complications or other disorders affecting glucose metabolism. The protocol and informed consent document were approved by the Research

Ethics Board of the Third Affiliated Hospital of Sun Yat-Sen University.

After enrollment, patients were randomized to saxagliptin 5 mg once daily or Acceptedacarbose 50 mg three times daily Manuscript for one year. Seven-point finger blood (fasting, 2 hours after breakfast, pre-lunch, 2 hours after lunch, pre-dinner, 2 hours after dinner, and pre-bedtime) were measured by self-monitoring of blood glucose (SMBG) on three consecutive days at randomization, the 3rd month, the 6th month, and the end of the study. At

Page 4 of 13 the same time physical examinations and laboratory tests were undertaken.

Non-normally distributed variables were log-transformed first.

Paired t-test is performed to examine differences between baseline and post-intervention. For the assessment of differences between two groups, t-test was performed. Chi-square test was used to analyze the differences of incidence of hypoglycaemia and rates of HbA1c<7.0% (53 mol/mmol) between two groups.

3. Results and discussion

Of the ninety patients randomized, eighty-one (90.0%) patients (41 in saxagliptin and 40 in acarbose) completed the study (supplementary data 1). Two groups were similar at randomization for all variables. After adding saxagliptin or acarbose, weight, hepatic and renal function did not change. resistance (HOMA-IR), β-cell function (HOMA-β), and lipid metabolism seemed to ameliorate but without significance. These improvements were more obvious in saxagliptin than in acarbose but of no significance (supplementary data 2). During the study, there were no severe hypoglycaemicAccepted episodes-an event Manuscript requiring another person’s assistance. The proportion of patients with minor hypoglycaemia-defined as having finger blood glucose level below 3.9 mmol/L and prompt recovery after self-administered -was higher in saxagliptin

(4.88%, 2 of 41) than in acarbose (0.00%, 0 of 40) (X2=2.00, P>0.05).

Page 5 of 13 HbA1c and FBG decreased markedly in both groups. This reduction was more noticeably in saxagliptin than in acarbose (P<0.05) (Figure 1).

More patients reached HbA1c<7.0% (53mmol/mol), which is recommended by IDF [5], in saxagliptin (7.32%, 3 of 41) than in acarbose (2.50%, 1 of 40) (X2=1.00, P>0.05) (supplementary data 1).

Standard deviation of blood glucose (SDBG) and largest amplitude of glycaemic excursions (LAGE) decreased significantly with similar end point levels in both groups (P>0.05). Adding saxagliptin or acarbose, both blood glucose curves flatted. The curves of two combinations were similar in fluctuation in each designated corresponding time, respectively.

(Figure 2).

GV is another sign of dysglycaemia. Clinical studies reveal GV is a significant predictor of mortality in T2DM [6-7]. In cellular consequences, intermittent high glucose stimulates a more reactive oxygen species overproduction, a greater adhesion molecules overexpression, and an extra cell apoptosis than constant high glucose [8-10] . As a result, GV is regarded as an important risk factor in the development of diabetic complications.Accepted Our results confirmed previously Manuscript published papers reporting that acarbose reduced GV [3-4,11]. Saxagliptin is a dipeptidylpeptidase-4 (DPP-4) inhibitor, which increase glucose-dependent insulin secretion and suppress glucagons secretion

[12]. Consequently it mainly targets postprandial hyperglycaemia. As a

Page 6 of 13 result, saxagliptin could decrease GV effectively just like acarbose. The present study suggested that saxagliptin was more effective in lowering

HbA1c and FBG than acarbose. This may lie in its insulin-stimulated property. Studies indicated that insulin secretagogues reduced overall glycaemia and FBG superior to acarbose [3,13]. Other reports showed

DPP-4 inhibitors were non-inferior to insulin secretagogues [14-15].

Furthermore, DDP-4 inhibitors have various effects on β-cell: stimulating

β-cell production; inhibiting β-cell apoptosis and restoring islet cell mass

[12,16-17] . Moreover, DDP-4 inhibitors have effects on the : promoting satiety, suppressing food intake and delaying gastric emptying. All of these may contribute to saxagliptin’s more effective in reducing HbA1c and FBG. Other studies reported

DPP-4 inhibitors and α-glucosidase inhibitors have similar glucose-lowering effect [18-19] . This discrepancy may be attributed to the different subjects as well as different background treatments. For example, it is reported DPP-4 inhibitors are more efficacious in Asian

[20]. ThisAccepted study has some limitations. First Manuscript a 7-point glycaemic feature could not comprehensively represent the glycaemic profile of a whole day.

Furthermore we did not use test meal. The patients’ glucose levels could be influenced. However, we collected data on three consecutive days but not on one day, which could lessen the influence. In addition, the data of

Page 7 of 13 daily life instead of load test could rather successfully reflect “real world” in clinical practice. Finally the study indicated some results between saxagliptin and acarbose, but gave little insight as to the mechanism.

Further studies are required to validate the present results and investigate the mechanism.

4. Conclusions

In aged T2DM inadequately controlled with metformin alone, saxagliptin-metformin has similar effect on glucose excursion with acarbose-metformin, and the former has a stronger effect on glucose control than the latter.

5. Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

This study was funded by the Guangdong Pharmaceutical

Association (2012C04). We thank all of the doctors, nurses, technicians, and patients involved for their dedication to the study. Accepted Manuscript

Page 8 of 13 References: [1] A. Ceriello, and M.A. Ihnat, 'Glycaemic variability': a new therapeutic challenge in diabetes and the critical care setting, Diabet Med. 27 (2010) 862-867. [2] L. Monnier, C. Colette, and D.R. Owens, Glycemic variability: the third component of the dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol. 2 (2008) 1094-1100. [3] J.S. Wang, S.D. Lin, W.J. Lee, S.L. Su, I.T. Lee, and S.T. Tu, et al., Effects of acarbose versus on glycemic excursion and oxidative stress in type 2 diabetic patients inadequately controlled by metformin: a 24-week, randomized, open-label, parallel-group comparison, Clin Ther. 33 (2011) 1932-1942. [4] Y. Kusunoki, T. Katsuno, M. Myojin, K. Miyakoshi, T. Ikawa, and T. Matsuo, et al., Effect of additional administration of acarbose on blood glucose fluctuations and postprandial in patients with type 2 diabetes mellitus under treatment with , Endocr J. 60 (2013) 431-439. [5] Global guideline for type 2 diabetes, Diabetes Res Clin Pract. 104 (2014) 1-52. [6] M. Muggeo, G. Zoppini, E. Bonora, E. Brun, R.C. Bonadonna, and P. Moghetti, et al., Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study, Diabetes Care. 23 (2000) 45-50. [7] L.G. Mellbin, K. Malmberg, L. Ryden, H. Wedel, D. Vestberg, and M. Lind, The relationship between glycaemic variability and cardiovascular complications in patients with acute myocardial infarction and type 2 diabetes: a report from the DIGAMI 2 trial, Eur Heart J. 34 (2013) 374-379. [8] L. Piconi, L. Quagliaro, R.R. Da, R. Assaloni, D. Giugliano, and K. Esposito, et al., Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-) polymerase, J Thromb Haemost. 2 (2004) 1453-1459. [9] L. Quagliaro, L. Piconi, R. Assaloni, R.R. Da, A. Maier, and G. Zuodar, et al., Intermittent high glucose enhances ICAM-1, VCAM-1 and E-selectin expression in human umbilical vein endothelial cells in culture: the distinct role of protein kinase C and mitochondrial superoxide production, Atherosclerosis. 183 (2005) 259-267. [10] J. Sun, Y. Xu, S. Sun, Y. Sun, and X. Wang, Intermittent high glucose enhances cell proliferation and VEGF expression in retinal endothelial cells: the role of mitochondrial reactive oxygen species, Mol CellAccepted Biochem. 343 (2010) 27-35. Manuscript [11] M. Shimabukuro, N. Higa, I. Chinen, K. Yamakawa, and N. Takasu, Effects of a single administration of acarbose on postprandial glucose excursion and endothelial dysfunction in type 2 diabetic patients: a randomized crossover study, J Clin Endocrinol Metab. 91 (2006) 837-842. [12] M. Sjostrand, N. Iqbal, J. Lu, and B. Hirshberg, Saxagliptin improves glycemic control by modulating postprandial glucagon and C-peptide levels in Chinese patients with type 2 diabetes, Diabetes Res Clin Pract. 105 (2014) 185-191. [13] S. Fischer, A. Patzak, H. Rietzsch, U. Schwanebeck, C. Kohler, and J. Wildbrett, et al., Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients,

Page 9 of 13 Diabetes Obes Metab. 5 (2003) 38-44. [14] M.A. Nauck, G. Meininger, D. Sheng, L. Terranella, and P.P. Stein, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, , compared with the , , in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial, Diabetes Obes Metab. 9 (2007) 194-205. [15] B. Goke, B. Gallwitz, J. Eriksson, A. Hellqvist, and I. Gause-Nilsson, Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial, Int J Clin Pract. 64 (2010) 1619-1631. [16] J. Mu, J. Woods, Y.P. Zhou, R.S. Roy, Z. Li, and E. Zycband, et al., Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes, Diabetes. 55 (2006) 1695-1704. [17] J. Mu, A. Petrov, G.J. Eiermann, J. Woods, Y.P. Zhou, and Z. Li, et al., Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes, Eur J Pharmacol. 623 (2009) 148-154. [18] D.S. Kania, J.D. Gonzalvo, and Z.A. Weber, Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus, Clin Ther. 33 (2011) 1005-1022. [19] F.A. Van de Laar, P.L. Lucassen, R.P. Akkermans, E.H. Van de Lisdonk, G.E. Rutten, and C. Van Weel, Alpha-glucosidase inhibitors for type 2 diabetes mellitus, Cochrane Database Syst Rev. (2005) D3639. [20] S. Shimoda, S. Iwashita, S. Ichimori, Y. Matsuo, R. Goto, and T. Maeda, et al., Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy, Endocr J. 60 (2013) 1207-1214.

Accepted Manuscript

Page 10 of 13 Hightlight (for review):

In this investigation, we have found some results:

1. Saxagliptin and acarbose have similar effect of glycaemic variability

2. Saxagliptin has stronger effect in lowering glycaemia than acarbose.

3. both saxagliptin and acarbose are effective and safe as add-on

therapies

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Page 11 of 13 Figure

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Page 12 of 13 Figure

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