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
patients with poor OAD-mediated glycaemic control during 12 weeks between basal insulin analogue plus OAD combination therapy and premixed insulin therapy.
Material and methods Study design This was a parallel-group, randomized, multicenter, treat-to-target clinical trial comparing the efﬁcacy and safety of insulin glargine plus gliclazide MR versus the premixed insulin injection (Novolin 30R) in 110 Chinese T2DM patients from eight hospitals, who had been treated with OADs but had achieved inadequate glycaemic control (FPG ≥7.0 mmol/L, 7.5% < A1C ≤10%). Subjects were randomized (1 : 1 ratio) for receipt of once-daily insulin glargine/gliclazide MR combination therapy or premixed insulin monotherapy group. A 1 : 1 randomization schedule stratiﬁed by a centre sequentially assigned treatment codes to eligible patients, using a central randomization service of the electronic case report form.
Inclusion and exclusion criteria Adult (35 to 65 years old) patients were recruited according to the T2DM diagnosis criteria by the American Diabetes Association, with body mass index between 19 to 32 kg/m2, and with previous treatment of a single OAD (monotherapy), including secretagogue agents, with the daily dosage of the secretagogue agent at no more than 50% of the maximum dose. All including patients were insulin naive. Patients were excluded according to the following criteria: use of insulin at any time prior to study enrolment; current use of any medication with known effects on OADs or with known effects on glucose tolerance (i.e. glucocorticoids); hepatic dysfunction (i.e. >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
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 <6.1 mmol/L using a titration algorithm. For the combination therapy group, an FPG level of ≥6.1 mmol/L prompted increase in the gliclazide MR dosage (up to a maximum dose of 90 mg/d); continued elevated FPG was then managed by increasing the dosage of insulin glargine (to a maximum dose of 30 U/d). The titration algorithm in dosage of insulin glargine was the same as that of premixed insulin. If the condition of elevated FPG remained still unresolved, the gliclazide MR was further increased to 120 mg/d. The premixed insulin dosage was given using the following titration algorithm based on FPG or predinner blood glucose values: glucose level ≥ 6.1–7.7 mmol/L, increase by 2 U/day; glucose level >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).
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 <0.4% and <0.6%, respectively . Measurement of plasma glucose was carried out using the glucose oxidase method.
Continuous glucose monitoring Each subject was required to undergo two rounds of 72-h CGM, which occurred on day 0 to day 3 at week 0 and at week 12 . A retrospective Medtronic CGM system (CGMS) sensor (Northridge, CA, USA) was inserted by a specialized nurse during day 0 between 8:00 and 9:00 AM. Subjects were released from the clinic to complete the 72-h CGM at home with the requirement of self-inputting at least four calibration readings per day. During the CGM monitoring period, patients were unable to read the blood glucose levels. On day 3, the participants returned to the clinic for the removal of the CGMS. The sensor detected one signal every 5 min, so that 288 signals were obtained for each 24-h CGM period. The 24-h mean blood glucose (24-h MBG) level was calculated as the average of the readings collected during a 24-h period on day 1 and day 2; and the participant’s overall 24-h MBG was calculated as the average value for 24-h MBG on days 1 and 2. The intraday glycaemic variability parameters included the standard deviation of blood glucose readings (SDBG) and the mean amplitude of glycaemic excursions (MAGE). The MAGE was calculated as the mean of differences between consecutive peaks and nadirs, with excursions <1 standard deviation excluded. We calculated each patient’s SDBG and MAGE during a 24-h period on day 1 and day 2, and the average value on days 1 and 2 was regarded as the overall value. The interday glycaemic variability parameter was calculated as the mean of daily differences using the absolute difference between paired CGM values obtained during day 1 and day 2. Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr
J. Zhou et al.
Outcomes The primary efﬁcacy measures were changes (from baseline to week 12) in A1C level, in FPG level, and in the proportions of patients achieving A1C ≤6.5% and ≤7%. The secondary efﬁcacy measures included changes in the CGM measurements of 24-h MBG, MAGE, SDBG, and mean of daily differences, as well as in patients’ weight. The primary safety measures were changes in the proportion of patients experiencing hypoglycaemic events and in the frequency of those events. A reported hypoglycaemic event was deﬁned as blood glucose ≤3.9 mmol/L; and a severe event was deﬁned as blood glucose level ≤2.8 mmol/L and/or when the person required intake of an oral carbohydrate, intravenous glucose, or glucagon administration. A minor hypoglycaemic event recorded by CGMS was deﬁned as blood glucose ≤3.9 mmol/L, and a major hypoglycaemic event by CGMS was deﬁned as blood glucose ≤2.8 mmol/L. The secondary safety measures included the adverse events experienced during the study.
Statistical analysis All statistical analyses were conducted according to the intent-to-treat concept and using the Statistical Package for the Social Sciences software suite (version 17.0; SPSS Inc., Chicago, IL, USA). Descriptive data were expressed
as mean ± standard deviation, unless otherwise indicated. The difference in mean absolute change in A1C between the two treatment groups after 12 weeks of treatment was analysed by analysis of covariance model. The model accounted for age, body mass index, diabetes duration, sex, and A1C at baseline as covariates and treatment regimen as ﬁxed effects. Percentages of subjects who achieved A1C targets at the end of the study were analysed by a logistic regression approach with treatment, age, body mass index, diabetes duration, sex, and A1C at baseline as explanatory variables. The difference in the proportion of patients experiencing hypoglycaemic events was analysed post hoc by a chisquare test. CGM parameters were assessed using the analysis software (version 3.0).
Results Characteristics of study subjects Of 110 patients who underwent screening, 105 were assigned randomly at baseline to the insulin glargine/ gliclazide MR combination therapy group (n = 52) or the premixed insulin monotherapy group (n = 53) (Figure 1). The demographic and baseline clinical characteristics of the two groups were similar (Table 1). After randomization, three patients in the combination therapy group were withdrawn from the study because of non-compliance with the protocol (n = 1), requirement for basal insulin
Figure 1. Enrolment and outcomes. MR, modiﬁed release
MR, modiﬁed release; BMI, body mass index; A1C, haemoglobin A1c; continuous glucose monitoring; 24-h MBG, 24-h mean blood glucose; SDBG, standard deviation of blood glucose; MAGE. mean amplitude of glycaemic excursions; MODD, mean of daily differences.
glargine dose >30 U/d (n = 1), and lack of therapy response (n = 1). In the monotherapy group, one patient withdrew participation (n = 1).
Figure 2. Comparison of the haemoglobin A1c (A1C) decrease following 12 weeks of treatment with once-daily insulin glargine plus gliclazide MR versus twice-daily premixed insulin. MR, modiﬁed release
Medicine and insulin dose The patients in the combination therapy group required an increase in insulin glargine dosage over the 12-week study period (from the starting dosage of 0.19 ± 0.02 to 0.27 ± 0.09 U/kg/d at the study end). Similarly, the patients in the premixed insulin monotherapy group also required an increase in insulin dosage (from the starting dose of 0.41 ± 0.10 U/kg/d to ending dose of 0.57 ± 0.20 U/kg/d). The mean daily dose of gliclazide MR was also increased over the study period (from 58.13 ± 9.60 mg/d at week 0 to 88.09 ± 27.56 mg/d at week 12). The majority of patients in the combination therapy group required 90 mg/d (65.23%) or 60 mg/d (23.91%) of gliclazide MR at week 12, with the remaining patients requiring a low dose (30 mg/d) or very high dose (120 or 150 mg/d).
Comparison of continuous glucose monitoring system parameters Over the 12-week treatment period, both treatment groups showed signiﬁcant decreases in the 24-h MBG level (from 10.64 ± 2.25 to 8.60 ± 1.68 mmol/L for the combination group, and from 10.11 ± 2.33 to 8.38 ± 1.70 mmol/L for the premixed insulin group; both, p < 0.001) (Figure 4). However, the extent of decrease induced by the two therapies was not signiﬁcantly different. Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr
J. Zhou et al.
Figure 3. Comparison of mean fasting plasma glucose (FPG) of two groups during the study visits. The mean FPG values at baseline and at each clinic visit are presented for the insulin glargine plus gliclazide modiﬁed release combination therapy group (black circles) and the premixed insulin monotherapy group (white squares). Note: The decrease from baseline to study end (week 12 of treatment) was signiﬁcantly better in the combination therapy group than in the monotherapy group. *p < 0.05, ** p < 0.01
Figure 4. Comparison of average continuous glucose monitoring tracings between the (A) insulin glargine plus gliclazide MR combination therapy group and the (B) premixed insulin monotherapy group. The red curve represents the baseline values, and the green curve represents the endpoint values
Adherence In the combination therapy group, the adherence rate of gliclazide MR was 100% during the study period, and the adherence rate of insulin glargine was 99.9% as one patient missed one insulin injection. In the Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr
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premixed insulin monotherapy group, a total of nine times insulin injections were missed; the adherence rate was 99.9%.
Hypoglycaemia First, no self-reported severe hypoglycaemic event was recorded in the combination group. Two episodes of severe hypoglycaemia were reported by two patients in the premixed insulin monotherapy group. Second, a total of 45 reported hypoglycaemic episodes were recorded in the combination group, and 60 episodes were recorded in the monotherapy group, but the difference did not reach statistical signiﬁcance. Also, the hypoglycaemic rate was not signiﬁcantly different from that of the combination therapy group (52.83% vs 35.42%). Third, according to the data from CGMS performed at the end of the study, the combination therapy group had fewer average major hypoglycaemic events than the monotherapy group (0.79 ± 0.39 vs 1.13 ± 0.52) as well as minor hypoglycaemic events (1.00 ± 0.71 vs 1.29 ± 0.63), but the differences were not signiﬁcant between the two groups (both, p > 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.
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 . 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 . 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 . 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 . 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 . 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
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 . 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 . 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 . 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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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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Diabetes Metab Res Rev 2015; 31: 725–733 DOI: 10.1002/dmrr
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