DIABETES/METABOLISM RESEARCH AND REVIEWS RESEARCH ARTICLE Diabetes Metab Res Rev 2015; 31: 725–733 Published online 16 June 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2661

Glargine insulin/gliclazide MR combination therapy is more effective than premixed insulin monotherapy in Chinese patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs

Jian Zhou1, Fenping Zheng2, Xiaohui Guo3, Huazhang Yang4, Muxun Zhang5, Haoming Tian6, Lixin Guo7, Qiang Li8, Yifei Mo1, Weiping Jia1* 1 Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai, China 2 Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3 Department of Endocrinology and Metabolism, Peking University First Hospital, Beijing, China 4

Department of Endocrinology and Metabolism, Guangdong General Hospital, Guangzhou, Guangdong, China 5

Department of Endocrinology and Metabolism, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China

6 Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China 7

Department of Endocrinology and Metabolism, Beijing Hospital of Ministry of Public Health, Beijing, China 8 Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

*Correspondence to: Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, No. 600 Yishan Road, Shanghai 200233, China. E-mail: [email protected]

Received: 20 September 2014 Accepted: 28 April 2015

Copyright © 2015 John Wiley & Sons, Ltd.

Abstract Background The aim of this study is to compare the efficacy and safety of once-daily insulin glargine plus gliclazide modified release combination therapy versus twice-daily premixed insulin monotherapy in Chinese type 2 diabetic patients insufficiently controlled by oral antidiabetic agents. Methods In a 12-week, multicenter, randomized, parallel-group clinical trial, patients with poor glycaemic control (fasting plasma glucose ≥ 7.0 mmol/L and 7.5% < haemoglobin A1c ≤ 10%) on oral antidiabetic drugs were randomized to the treatment groups for combination therapy (n = 52) or monotherapy (n = 53). Continuous glucose monitoring was carried out over two 72-h periods, at the beginning and the end of the study, and the data were used to calculate the 24-h mean blood glucose, mean amplitude of glycaemic excursions, standard deviation of blood glucose, and the mean of daily differences. Results The mean haemoglobin A1c decrease from baseline to study end was significant for both treatment groups (combination therapy: 1.23 ± 0.92%; insulin monotherapy: 1.02 ± 1.04%); moreover, the combination therapy group showed a significantly more robust haemoglobin A1c decrease (p = 0.0308). Both therapies significantly reduced the 24-h mean blood glucose (both, p < 0.001), but neither produced a significant effect on glycaemic variability, calculated as mean amplitude of glycaemic excursions, standard deviation of blood glucose, and mean of daily differences. In addition, the effects on rates of hypoglycaemic episodes were similar between the two therapies. Conclusions Chinese patients with type 2 diabetes inadequately controlled with oral antidiabetic agents attained greater benefit from once-daily insulin glargine plus gliclazide modified release regimen than from a twice-daily premixed insulin regimen. Copyright © 2015 John Wiley & Sons, Ltd. Keywords 2 diabetes

continuous glucose monitoring; gliclazide MR; premixed insulin; type

Abbreviations T2DM, type 2 diabetes mellitus; A1C, haemoglobin A1c; OAD, oral antidiabetic drugs; CGM, continuous glucose monitoring; FPG, fasting plasma glucose; MR, modified release; 24-h MBG, 24-h mean blood glucose; SDBG, standard deviation of blood glucose; MAGE, mean amplitude of glycaemic excursions

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Introduction Type 2 diabetes mellitus (T2DM) is a metabolic disorder of progressively decreasing secretion of insulin from the pancreatic ß cells and sensitivity of tissues to insulin. Long-term complications of diabetes have been demonstrated as closely related to the level of glycaemic control throughout a patient’s disease course [1–3]. Thus, the primary targets of T2DM management are achieving and maintaining glycaemic control (indicated by haemoglobin A1c (A1C) level of 1.5-fold elevated alanine aminotransferase, aspartate aminotransferase, or direct bilirubin) or renal dysfunction (i.e. plasma creatinine level >115 μmol/L); current diagnosis of cardiovascular disease; allergy to sulfonylureas or glargine; presence of diabetic ketoacidosis; and pregnancy or lactation. The study obtained independent approval from the ethics committees of each participant hospital, in accord with the principle of the Helsinki Declaration II. All study participants provided written informed consent upon study enrolment. This study is registered with ClinicalTrials.gov, number NCT00736515. Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr

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Glargine/gliclazide and Premixed Insulin

Procedures The combination therapy was delivered as initial doses of 60 mg/d of gliclazide MR (Servier (Tianjin) Pharmaceutical Co. Ltd., Tianjin, China) taken before breakfast and 0.2 U/kg/d of insulin glargine (Sanofi-Aventis, Paris, France) taken before sleep. The monotherapy of biphasic human insulin 30 (Novo Nordisk, Bagsvaerd, Denmark) was delivered at an initial total dose of 0.4–0.6 U/kg/d, with half of the total units administered before breakfast and another half units taken before dinner. The dosage adjustment of the gliclazide MR, insulin glargine, and premixed insulin was made by physicians during each visit. Adjustment of the drug dosages was titrated to target FPG < 6.1 mmol/L and predinner blood glucose 7.7–10.0 mmol/L, increase by 4 U/day; and glucose level >10.0 mmol/L, increase by 6 U/day. For both treatment groups, if a hypoglycaemic episode had been reported, the patient was first managed by decreasing the insulin dosage, followed by decreasing the gliclazide MR dosage thereafter (with 30 mg/d being set as the minimum dosage allowed for continued study participation).

Determination of sample size The estimate of sample size was based on the feasibility of conducting a clinical trial. The sample size was calculated assuming a dropout rate of 15%. To attain a power of 81% to detect whether combination therapy was non-inferior to premixed insulin, at least 105 patients were found to be required for the random allocation design for the two treatment groups (α = 0.025, β = 0.2).

Study visits and biochemical measurements Each study participant was required to attend eight clinic visits, including the first visit upon enrolment (baseline measures; week 0), four weekly visits (weeks 1–4), two Copyright © 2015 John Wiley & Sons, Ltd.

biweekly visits (for lab assessment; weeks 6 and 8), and a single one-month visit (for end-point evaluation; week 12). Patients were required to record a six-point glucose profile (i.e. before and 2 h after breakfast, lunch, and dinner) for at least 1 day before each visit as well as any hypoglycaemic episodes in a standardized diary. All adverse events experienced by the patient throughout the study were also reported. Data assessed and recorded for each visit included vital signs, body weight, and FPG level. At weeks 0 and 12, the levels of A1C, triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (7600–020; Hitachi, Tokyo, Japan) were tested and recorded. Measurement of A1C was performed using the Variant II high-performance liquid chromatography system (Bio-Rad Laboratories, Hercules, CA, USA), with inter-assay and intra-assay coefficients of variation of 0.05).

Weight gain Both treatment groups showed a significant increase in weight over the study period, with the combination therapy group increasing from 66.87 ± 11.87 to 68.12 ± 10.68 kg at week 12 (p = 0.0334) and the insulin monotherapy group increasing from 65.05 ± 11.60 to 66.07 ± 10.23 kg (p < 0.001). The increases in weight recorded at clinic visits from week 1 through week 8 were consistently higher for the monotherapy group (all, p < 0.05), but the difference at week 12 was not significantly different from that of the combination therapy group.

Vital signs and biochemical parameters Vital signs, blood pressure, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels remained unchanged compared with baseline in two treatment groups (all, p > 0.05). The premixed insulin monotherapy group had increased high-density lipoprotein cholesterol levels at the end of the study compared with the baseline (1.28 ± 0.36 vs 1.20 ± 0.26 mmol/L, p = 0.0437); No similar change in high-density lipoprotein cholesterol level was observed in the combination group. Copyright © 2015 John Wiley & Sons, Ltd.

Discussion Collectively, the current study indicates that T2DM patients who respond poorly to OADs can benefit from addition of a single insulin (glargine) injection to a daily gliclazide MR regimen. Specifically, patients in this analysis who were given this combination therapy achieved more effective glycaemic control than those who received twice-daily premixed insulin, as evidenced by more robust improvements in A1C and FPG. These data are consistent with the previous studies that compared the effectiveness of two commonly used regimens for initiating insulin therapy in patients with type 2 diabetes. A 24-week multinational clinical trial by Janka et al. compared switching from prior OADs treatment to twice-daily premixed human 70/30 insulin versus adding a once-daily injection of basal insulin glargine to prior OADs. The study demonstrated that glargine plus OAD was more efficacious than premixed insulin monotherapy in decreasing A1C from baseline to 7% or less [6]. Similar findings were observed in the subset of patients aged 65 years and older, and the use of insulin glargine combined with OAD treatment regimen should improve patient compliance [10]. On the contrary, Yki-Jarvinen et al. carried a meta-analysis of the published trials reporting on comparisons of the basal insulin plus OAD combination therapy versus the premixed insulin monotherapy, and the authors suggested that there was no difference between the two groups in the extent of A1C improvements [11]. The explanation for the discrepancy between our study and the meta-analysis can be because in a majority of randomized controlled trials included in the meta-analysis, the glycaemic targets were mostly not achieved. Thus, the inadequate titration of the treatment appears to be a likely explanation for the basal plus OAD group showing no superior glycaemic control. The other explanations include heterogeneity of the study populations, the use of different OADs, the various follow-up time, and the differences in race as race may potentially influence the effects of insulin therapy [12]. Interestingly, an up-to-date systematic review by Rys et al. demonstrated that insulin glargine added to OAD was associated with higher probability of reaching target A1C level. Insulin glargine added to OAD also showed significantly lower risk of symptomatic hypoglycaemia as compared with premixed insulin regimen [13]. Conclusively, the present study is consistent with previous literatures as the use of insulin glargine plus OAD has been shown to provide at least equivalent or even better glycaemic control compared with premixed insulin treatment options. An important feature of the previous studies of OADbased therapy efficacies is the major outcome measure of A1C improvement. While A1C level is a good estimator of Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr

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glycaemic control over a longer period of time, it is not sufficient for designing a management strategy that effectively decreases glycaemic variability, also an important component of poor glucose control in diabetes. For the current study, we considered the promotion of chronic diabetic complications demonstrated by Monnier et al. [14] in parallel models integrating chronic hyperglycaemia (the basal and postprandial hyperglycaemia) and glucose variability (postprandial hyperglycaemia and hypoglycaemic episodes). Although CGMS is a useful tool for assessing daily glucose fluctuations, few studies have considered using it when measuring treatment outcome. It provides 288 glucose values per day and offered clinicians the detailed change of glucose, especially in detecting hypoglycaemia. Recently, some clinical trials start to use CGMS when evaluating effects of OAD in clinical trials. McNally and colleagues used CGM to measure the frequency of hypoglycaemic events when using biphasic insulin aspart 30 compared with biphasic human insulin 30 [15]. Therefore, in the present study, we used CGMS to evaluate glycaemic variability in addition to A1C measurement in our study as outcomes. Sulphonylureas were introduced more than 60 years ago [16] and remain extensively used. Sulphonylureas reduce A1C levels by approximately 1.5% [17], but some reports have suggested that weight gain [17,18], increased risk of hypoglycaemia [19,20], and concerns for cardiovascular safety [21,22] are the major issues in its clinical application. However, sulphonylureas remain affordable, especially to use in countries with limited resources and competing healthcare problems. Also, the combination of sulfonylurea with insulin glargine enables treatment with a smaller dosage of insulin compared with insulin monotherapy. Our analysis suggested that the insulin glargine/gliclazide MR treatment is superior to the twice-daily premixed insulin treatment. This finding may be related to the hydrophilic nature of gliclazide MR, which facilitates its release to give a more sustained effect to help achieve full control of blood glucose within a 24-h period. Gliclazide MR was also used as the intensive glucose-lowering treatment medicine in the ADVANCE study. At the end of 5-year follow-up, the mean A1C was reduced from 7.5% at baseline to 6.5% in those on intensive gliclazide MRbased regimen and to 7.3% in those on standard glucose control. There was no significant weight gain in the intensive glucose control group, and severe hypoglycaemia was uncommon in the study [23]. In the current study, the combination regimen and the monotherapy regimen showed similar effects on the rate of hypoglycaemic events experienced by patients. Also, the patients in the combination group did experience less weight gain during the study period, although it was not significantly different from that of the premixed insulin Copyright © 2015 John Wiley & Sons, Ltd.

J. Zhou et al.

treatment group at the endpoint; however, this result may merely reflect the study’s limitations of small sample size and short observation time (12-week). To be noted, the major benefit of the insulin glargine plus gliclazide MR combination therapy is its requirement of a single daily insulin injection, making it more convenient for use in clinical practice. Given the chronic nature of diabetes, patient’s adherence to therapy is very important in glycaemic control. One of the barriers to achieving glycaemic control targets is the difficulty of managing multiple injections and the associated requirements for multiple daily glucose measurements [24]. The impact of medication adherence on glycaemic control in type 2 diabetes has been evaluated in a number of prospective and retrospective studies [25,26]. A retrospective study was conducted between 1991 and 2001 among 1560 patients with type 2 diabetes. The authors found that glycaemic control rates improved progressively in accord with higher rates of medication adherence. A1C levels were 0.34% lower with improvements in medication adherence (p = 0.009) at the end of 12-month care [27]. Similarly, Pladevall et al. performed a study in 677 patients diagnosed with diabetes, hypercholesterolaemia, and hypertension, and they found a 10% increase in non-adherence to metformin related to a 0.14% increase in A1C [28]. These findings highlight the importance of medication adherence for attaining glycaemic control. Therefore, in our study, the insulin glargine plus gliclazide MR treatment can lead to increased compliance compared with twice-daily insulin treatment because the former treatment is obviously more convenient for patients, thus leading to improved glycaemic control and hence decreased risk of the associated microvascular and macrovascular complications. As stated in the preceding text, some features of the current study’s design may have impacted the findings and should be taken into consideration when interpreting the results. In the present study, only a small number of patients were included. However, the study was designed as a pilot trial, and we calculated the sample size based on the feasibility of conducting a clinical trial. Repeating the study with larger cohorts would likely provide information on the results presented here. Second, we did not assess the subjects’ islet function, so we are unable to make any speculations about the underlying pathophysiology of the two therapies. Future studies are needed to address the aforementioned limitations. In conclusion, this study demonstrated that, for patients with T2DM who are inadequately controlled with OADs, a once-daily injection of insulin glargine plus gliclazide MR is a simple therapeutic approach that is more effective in improving glycaemic control than starting twice-daily injections of premixed insulin. Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr

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Acknowledgements

Conflicts of interest

This work was funded by the National Natural Science Foundation of China (81100590). We would like to thank all the involved clinicians, nurses, and technicians at all the participating centres for their dedication to the study.

The authors have no competing financial interests related to the publication of this study.

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Copyright © 2015 John Wiley & Sons, Ltd.

10. Janka HU, Plewe G, Busch K. Combination of oral antidiabetic agents with basal insulin versus premixed insulin alone in randomized elderly patients with type 2 diabetes mellitus. J Am Geriatr Soc 2007; 55(2): 182–188. 11. Yki-Jarvinen H, Kotronen A. Is there evidence to support use of premixed or prandial insulin regimens in insulinnaive or previously insulin-treated type 2 diabetic patients. Diabetes Care 2013; 36(Suppl 2): S205–S211. 12. Davidson JA, Lacaya LB, Jiang H, et al. Impact of race/ethnicity on the efficacy and safety of commonly used insulin regimens: a post hoc analysis of clinical trials in type 2 diabetes mellitus. Endocr Pract 2010; 16(5): 818–828. 13. Rys P, Wojciechowski P, Rogoz-Sitek A, et al. Systematic review and metaanalysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus. Acta Diabetol 2015; Jan 14. [Epub ahead of print] 14. Monnier L, Colette C, Owens D. The glycemic triumvirate and diabetic complications: is the whole greater than the sum of its component parts. Diabetes Res Clin Pract 2012; 95(3): 303–311. 15. McNally PG, Dean JD, Morris AD, Wilkinson PD, Compion G, Heller SR. Using continuous glucose monitoring to measure the frequency of low glucose values when using biphasic insulin aspart 30 compared with biphasic human insulin 30: a double-blind crossover study in individuals with type 2 diabetes. Diabetes Care 2007; 30(5): 1044–1048. 16. McGill JB. Pharmacotherapy in type 2 diabetes: a functional schema for drug classification. Curr Diabetes Rev 2012; 8(4): 257–267. 17. Mazzola N. Review of current and emerging therapies in type 2 diabetes mellitus. Am J Manag Care 2012; 18(1 Suppl): S17–S26. 18. Sehra D, Sehra S, Sehra ST. Sulfonylureas: do we need to introspect safety again? Expert Opin Drug Saf 2011; 10(6): 851–861.

19. Holstein A, Egberts EH. Risk of hypoglycaemia with oral antidiabetic agents in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2003; 111(7): 405–414. 20. Burge MR, Sood V, Sobhy TA, Rassam AG, Schade DS. Sulphonylurea-induced hypoglycaemia in type 2 diabetes mellitus: a review. Diabetes Obes Metab 1999; 1(4): 199–206. 21. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and metaanalysis. Diabet Med 2013; 30(10): 1160–1171. 22. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013; 15(10): 938–953. 23. Zoungas S, Chalmers J, Kengne AP, et al. The efficacy of lowering glycated haemoglobin with a gliclazide modified release-based intensive glucose lowering regimen in the ADVANCE trial. Diabetes Res Clin Pract 2010; 89(2): 126–133. 24. Cefalu WT. Evaluation of alternative strategies for optimizing glycemia: progress to date. Am J Med 2002; 113(Suppl 6A): 23S–35S. 25. Doggrell SA, Warot S. The association between the measurement of adherence to anti-diabetes medicine and the HbA1c. Int J Clin Pharm 2014; 36(3): 488–497. 26. 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. 27. Rhee MK, Slocum W, Ziemer DC, et al. Patient adherence improves glycemic control. Diabetes Educ 2005; 31(2): 240–250. 28. Pladevall M, Williams LK, Potts LA, Divine G, Xi H, Lafata JE. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care 2004; 27(12): 2800–2805.

Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr

gliclazide MR combination therapy is more effective than premixed insulin monotherapy in Chinese patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs.

The aim of this study is to compare the efficacy and safety of once-daily insulin glargine plus gliclazide modified release combination therapy versus...
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