Volume 2, Issue 2 , Pages 110-113, August 2010
Safety and efficacy of switching to biphasic insulin aspart 30/70 (BIAsp 30) under the routine diabetic care in patients with type 2 diabetes: The IMPROVE™ observational study in the Gulf region
Article Outline
Abstract
The IMPROVE™ study was a 26-week, multinational, open-label, non-randomized study, carried out in 11 countries.
Aim
To evaluate the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes under routine clinical practice.
Study design
There were no prescribed procedures for this study except for the collection of data.
Result
Data obtained at baseline and Week 26 in patients from the Gulf region is presented. From the Gulf region, 1613 patients (61% males) were enrolled with a mean age of 50.5
years and a mean BMI of 30.4kg/m2. The majority of the patients (57.0%) were treated with OAD only, while 34.3% patients were previously treated with insulin ±OAD and 8.7% were treatment naive. After 26weeks of treatment, the mean HbA1c was reduced by 1.4% from 9.3% at baseline to 7.9% at Week 26. The mean FBG was reduced by 66.6mg/dL from 212.4mg/dL at baseline to 145.8mg/dL at Week 26. No major hypoglycaemic episodes were reported as SADRs during the study. The rate of major hypoglycaemic episodes was reduced from 0.13 episodes/patient year at baseline to 0.05 episodes/patient year at Week 26. A lower risk of minor hypoglycaemia was also observed. Body weight was reduced by 0.6kg from 85.4kg at baseline to 84.7kg at Week 26.
Conclusion
BIAsp 30 improved glycaemic control without increasing the risk of hypoglycaemic episodes and weight gain after 26weeks’ treatment in patients with type 2 diabetes from the Gulf region.
Keywords: Biphasic insulin aspart 30/70, Gulf region, Safety, Efficacy
1. Introduction
Type 2 diabetes is characterised by chronic hyperglycaemia caused by the combination of insulin resistance and a progressive decline in insulin secretion [1]. However, both fasting and postprandial blood glucose (PPBG) levels contribute to the HbA1c level which reflects the mean glucose control for the preceding 3months [2]. It is anticipated that postprandial hyperglycaemia is more closely associated with an increased risk of macro-vascular disease [3]. The Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) indicates that macro-vascular disease has a stronger association with postprandial hyperglycaemia than with fasting hyperglycaemia [4]. Therefore, it seems reasonable to target postprandial hyperglycaemia, in addition to fasting blood glucose (FBG) levels, to achieve maximum benefits. In this sense, the basal only therapy may be inadequate in glycaemic control (especially controlling post prandial hyperglycaemia) in some patients. Either a basal-bolus or a premixed insulin regimen is suggested at this point [5].
Biphasic insulin aspart 30/70 (BIAsp 30) (NovoMix®30) is an insulin analogue mixture which contains 30% unbound rapid-acting insulin aspart and 70% intermediate-acting protaminated insulin aspart. This premix formulation aims at targeting postprandial hyperglycaemia as well as providing a basal insulin supplementation [6]. The 1-2-3 study has demonstrated that initiation of once-daily BIAsp 30 in poorly controlled type 2 diabetes patients was effective in achieving glycaemic goals. With the increase of daily injections from one to two, and from two to three, more patients could safely achieve glycaemic goals [7]. The INITIATE™ study indicated that BIAsp 30 was more effective than insulin glargine in achieving targeted HbA1c levels in insulin-naive patients who had poorly controlled blood glucose levels in concomitant treatment with OADs. In this study, the HbA1c was reduced by 2.9% and 65% patients achieved HbA1c<7% with twice-daily BIAsp 30 [8]. In another treat-to-target study in insulin-naïve patients with type 2 diabetes poorly controlled with OADs (sulphonylureas with or without metformin, or metformin mono-therapy), starting with twice daily BIAsp 30 in combination with metformin reduced HbA1c to a greater extent than once daily insulin glargine and glimepiride. The treatment difference was −0.5% (95% CI: −0.8; −0.2) [9], [10]. The safety and efficacy were also confirmed by an earlier report on eight countries participating in the IMPROVE™ study and by the OnceMix study with once-daily BIAsp 30 treatment [11], [12].
Observational studies are considered to be a valuable supplement for randomized clinical trials (RCTs) as a tool to evaluate the safety and efficacy of drugs in a heterogeneous population under routine clinical practice [13], [14]. Therefore, IMPROVE™, a large, multi-national, observational study has been carried out to investigate the safety and effectiveness of BIAsp 30 in the treatment of type 2 diabetes under the routine clinical practice. The results from the Gulf region are reported in this paper.
2. Methods
IMPROVE™ was a 26-week, open-label, non-randomized, multi-centre observational study of patients with type 2 diabetes carried out in 11 countries (Canada, China, Greece, Gulf region, India, Iran, Italy, Japan, Poland, Russia and South Korea) [15], [16]. The results in patients with type 2 diabetes from the Gulf region, including Saudi Arabia, United Arab Emirates, Kuwait, Qatar and Oman are presented in this paper. Patients who initiated insulin therapy with, or switched existing insulin therapy to BIAsp 30 in routine care were eligible. There were no study-prescribed procedures for this study.
The study was conducted in accordance with the Declaration of Helsinki, and complied with local regulations governing observational studies with regards to health authority and ethics committee approval, as well as patient informed consent.
The primary endpoint was the incidence of major hypoglycaemic events reported as serious adverse drug reactions (SADRs). A major hypoglycaemic episode was defined as an episode with severe central nervous system symptoms consistent with hypoglycaemia, in which the patient was unable to treat himself/herself with/without measurement of blood glucose<50mg/dL (2.8mmol/L) or reversal of symptoms after either food intake or glucagon or intravenous glucose administration. A minor hypoglycaemic episode was defined as an episode with symptoms of hypoglycaemia with the confirmation of blood glucose measurement<56mg/dL (3.1mmol/L) and which was handled by the patient or any asymptomatic blood glucose measurement<56mg/dL (3.1mmol/L).
Data were collected at baseline (Visit 1), at the follow-up visit (Visit 2) at approximately 13weeks, and at the final visit (Visit 3) at approximately 26weeks. Results from baseline and Week 26 are presented in this report.
The summary of the baseline characteristics and safety data were based on Full Analysis Set (FAS), which consisted of all patients with a baseline visit, which had been prescribed BIAsp 30 at least once and did not use BIAsp 30 before the start of the study. The analysis of the efficacy outcome variables were based on Efficacy Analysis Set (EAS), which was defined as all patients from FAS who had the Week 26 visit, at least one measurement concerning FBG, PPG, most recent HbA1c, weight or hypoglycaemic episodes at baseline and Week 26, with the final visit within 18 to 34weeks from baseline.
Descriptive statistics were used to summarize HbA1c, body weight and the daily dose of BIAsp 30 at baseline and Week 26 and the absolute changes from baseline. Paired t-test was used to compare HbA1c, body weight and the daily dose of BIAsp 30 at baseline and Week 26. The test was performed only if values at both visits were present. The occurrence of hypoglycaemic episodes was evaluated as episodes per patient year. All testing used two-sided tests with the significant level set at α=0.05. All analysis was performed using SAS, Version 9.1 (SAS Institute, Cary, NC).
3. Results
3.1. Baseline demographics
An overview of patient disposition from the Gulf region is shown in Table 1. The FAS included 1613 patients, while there were 1136 (70.4%) patients in the EAS. A total of 477 patients (29.6%) in the FAS were excluded from the EAS, in which 224 (13.9%) had no final visits, 195 (12.1%) had the final visit outside the range of 18–34weeks from baseline, 47 (2.9%) had no measurement at baseline and Week 26 and 11 (0.7%) had missing baseline or final visit date. A total of 157 (9.7%) patients discontinued from the study due to “lost contact” (128 patients, 7.9%), “ADR” (nine patients, 0.6%) or “other reasons” (27 patients, 1.7%).
Table 1. Analysis sets.
| Number of patients N (%) | |
|---|---|
| Number of patients in FAS | 1613 |
| Number of patients in EAS | 1136 (70.4) |
| Number of patients in FAS excluded from EAS | 477 (29.6) |
| By reason of exclusion | |
| No final visit | 224 (13.9) |
| No measurement at baseline and Week 26a | 47 (2.9) |
| Final visit outside range 18–34 weeks from baseline | 195 (12.1) |
| Baseline or final visit dates are missing | 11 (0.7) |
| Number of patients | |
| Who completed the study | 1456 (90.3) |
| Who discontinued the study | 157 (9.7) |
| By reason of discontinuation | |
| Lost contact | 128 (7.9) |
| Adverse drug reaction | 9 (0.6) |
| Other reasons | 27 (1.7) |
aNot having at least one measurement concerning blood glucose, HbA1c, weight or hypoglycaemic episodes at baseline and final visit. |
The complete demographic characteristics of all patients from the Gulf region and the reasons for initiating a new therapy are summarised in Table 2. The patients had a mean age of 50.5±10.4years, with a higher proportion of males (male: female=60.8/39.2). The mean BMI was 30.4±5.3kg/m2 and the mean diabetes duration was 10.1±5.8years. They were treatment-naïve (8.7%) or previously treated with OADs only (57.0%) and/or insulin (34.3%). The most cited reason for starting a new therapy was to improve glycaemic control (to improve HbA1c: 83.6%, to improve FBG: 81.8%, to improve PPBG: 74.3%) (Table 2).
Table 2. Demography and reasons for initiating new therapy.
| FAS | |
|---|---|
| Age, years | |
| N | 1121 |
| Mean (SD) | 50.5 (10.4) |
| Gender, N (%) | |
| Female | 628 (39.2) |
| Male | 972 (60.8) |
| BMI, kg/m2 | |
| N | 1495 |
| Mean (SD) | 30.4 (5.3) |
| Duration of diabetes, years | |
| N | 1554 |
| Mean (SD) | 10.1 (5.8) |
| Reason(s) for starting a new therapy, % | |
| Easy start of insulin therapy | 46.2 |
| Easy intensification of insulin therapy | 38.0 |
| Improve HbA1c | 83.6 |
| Improve FBG | 81.8 |
| Improve PPBG | 74.3 |
| Reduce risk of hypoglycaemia | 25.1 |
| Patient dissatisfaction with previous therapy | 35.0 |
| Side effects from previous therapy | 17.1 |
| Change due to insulin pen | 28.6 |
| Allow for mealtime administration | 22.9 |
| Missing | 0.4 |
3.2. Safety
The primary endpoint was the incidence of major hypoglycaemic events reported as serious adverse drug reactions, during 26weeks of BIAsp 30 therapy. No major hypoglycaemic episodes were reported as SADRs during the study. In total, 1 SADR was reported in this study and it was moderate. The patient fully recovered from the SADR.
The rates of major and minor hypoglycaemic episodes are shown as episodes/patient year in Fig 1. The rate of major hypoglycaemic episodes was reduced from 0.13 episodes/patient year at baseline to 0.05 episodes/patient year at Week 26. The similar pattern was also observed for both diurnal (from 0.08 episodes/patient year at baseline to 0.04 episodes/patient year) and nocturnal hypoglycaemic episodes (from 0.05 episodes/patient year at baseline to 0.02 episodes/patient year). The rate of minor hypoglycaemic episodes decreased from 6.08 episodes/patient year at baseline to 3.83 episodes/patient year. Similarly, diurnal and nocturnal minor episodes also decreased from 4.43 episodes/patient year at baseline to 2.94 episodes/patient year (diurnal) and from 1.66 episodes/patient year at baseline to 0.89 episodes/patient year (nocturnal).
Fig. 1.
Number of hypoglycaemic episodes (episodes/patient years).
3.3. Efficacy
After 26week’s treatment with BIAsp 30, HbA1c was reduced by 1.4±2.3% from 9.3±2.8% at baseline to 7.9±1.7% at the end of the study (Table 3). The proportion of patients who achieved the target of HbA1c⩽6.5% was slightly reduced from 7.6% at baseline to 5.4% at Week 26, while the proportion of patients who achieved the target of HbA1c<7.0% was increased from 8.8% at baseline to 15.0% at Week 26. The mean FBG was reduced by 66.6±55.8mg/dL from 212.4±64.8mg/dL at baseline to 145.8±41.4mg/dL at Week 26. Decrease in PPBG at breakfast, lunch and dinner were also observed (Table 3).
Table 3. Efficacy parameters.
| Parameter (SD) | Baseline | Week 26 | Absolute change |
|---|---|---|---|
| Mean HbA1c, %Hb | 9.3 (2.8) | 7.9 (1.7) | −1.4 (2.3)⁎ |
| Mean FBG, mmol/L | 212.4 (64.8) | 145.8 (41.4) | −66.6 (55.8)⁎ |
| Mean PPG, mmol/L | |||
| At breakfast | 291.6 (81.0) | 158.4 (41.4) | −135.0 (82.8)⁎ |
| At lunch | 280.8 (77.4) | 165.6 (34.2) | −115.2 (79.2)⁎ |
| At dinner | 279.0 (86.4) | 163.8 (37.8) | −115.2 (91.8)⁎ |
| Body weight, kg | 85.4 (16.6) | 84.7 (15.3) | −0.6 (4.1)⁎ |
| BMI, kg/m2 | 30.5 (5.5) | 30.3 (5.2) | −0.2 (.1.5)⁎ |
⁎p |
3.4. Body weight and insulin dose
The mean daily dose of BIAsp 30 increased by 12.2 U (0.15 U/kg) from 46.8 U (0.56 U/kg) at baseline to 59.0 U (0.71 U/kg) at Week 26. Body weight was reduced by 0.6±4.1kg from 85.4±16.6kg at baseline to 84.7±15.3kg at Week 26. Accordingly, BMI was reduced by 0.22±1.46kg/m2 from 30.49±5.51kg/m2 at baseline to 30.28±5.17kg/m2 at Week 26.
4. Discussion
Although there is no published data on the prevalence of type 2 diabetes in the Gulf region, it seems that the population has the highest rate in the world, which is reaching 35% in some areas [17]. It is believed that the increases in obesity and metabolic syndrome, induced by oil wealth and the subsequent alteration of lifestyle, lead to a type 2 diabetes pandemic of as high as 1 in 2 people in Gulf, which has a serious impact on general health and absolute life expectancy [18]. The grim situation, as also demonstrated by the baseline data from the IMPROVE study [15], warrants extensive studies on the current status and treatments of type 2 diabetes from the Gulf region, which are crucial to the overall management strategy.
The IMPROVE™ study was a 26-week, large, multi-centre observational study conducted in 11 countries in patients with type 2 diabetes. The aim of this study was to investigate the clinical profile of BIAsp 30 under routine clinical practice in the partaking countries. Safety and efficacy assessments were performed at baseline, at Week 13 and at Week 26. The results from the Gulf region of the IMPROVE study are presented in this paper. The present paper demonstrates that treatment with BIAsp 30 was a safe (with a low risk of hypoglycaemic episodes) and effective therapy (with an improvement in glycaemic control) in patients with type 2 diabetes from the Gulf countries.
The incidence of major hypoglycaemic episodes assessed as SADRs was the primary endpoint. No major hypoglycaemic episode was reported as SADRs during the study. In Gulf countries, the rates of both major and minor hypoglycaemic episodes as episodes/patient year were reduced from baseline to the final visit at Week 26 (−62% and −37%, respectively), while a lower risk of major episodes and no difference in minor episodes were observed in the global IMPROVE™ study [11].
After 26weeks of treatment with BIAsp 30, an improvement in glycaemic control was shown. The HbA1c in patients from the Gulf region was reduced from 9.3% at baseline to 7.9% at Week 26, which was slightly less compared to the decrease in the global IMPROVE™ study (9.3% at baseline to 7.1% at Week 26). The difference might be due to the higher percentage of patients with no or OAD-only pre-treatment in the global cohort (81.6% in the global cohort versus 65.7% in patients from the Gulf region). At baseline, a poor glycaemic control (HbA1c: 9.3%) and high rates of microvascular complications (63.8%) and macro-vascular complications (43.4%) were observed, which warranted the need of an earlier initiation of insulin therapy. Although the HbA1c level has been reduced by 1.4% from the baseline after 26weeks of treatment with BIAsp 30, the proportion of patients who achieved the target of HbA1c<7.0% or ⩽6.5% was low. The 1–2–3 study demonstrated that the initiation of once daily treatment with BIAsp 30, using an intense titration schedule enabled 21% patients to achieve HbA1c⩽6.5% (41% achieved HbA1c<7.0%). Additional patients safely achieved these goals when the number of daily injections was increased from one to two, and then if not meeting those HbA1c targets, from two to three daily injections. With three daily injections of BIAsp 30, these glycaemic goals were achieved in 60% and 77% patients respectively [7]. In contrast, our study was an observational study without set titration schedule. With physicians focusing more on dose optimisation and titration the HbA1c level at Week 26 (7.9%) could be further reduced, and more patients could achieve the targets of glycaemic control with intensified titrations as also confirmed in other randomized clinical trials[8], [9], [10]. The proportion of patients who achieved the target of HbA1c⩽6.5% was slightly reduced from 7.6% at baseline to 5.4% at Week 26, which could be explained by the random errors and fluctuations that might occur, given the small number of patients involved. Furthermore, the decrease in both FBG and PPG indicated that BIAsp 30 provides basal insulin coverage as well as postprandial coverage. This was consistent with the finding in clinical trials and the global IMPROVE™ study [6], [11], [15]. No clinical relevant change in body weight was found after 26weeks of treatment with BIAsp 30.
Overall, the findings from the Gulf region were comparable to those from the IMPROVE™ global study. The study was limited by the potential patient recall bias.
In conclusion, the treatment with BIAsp 30 improved glycaemic control measured as mean HbA1c without increasing the risk of hypoglycaemic episodes and weight gain in poorly controlled patients with type 2 diabetes in various pre-study treatments, in the Gulf countries. Our study provided valuable information of the treatment of type 2 diabetes under ‘real-life’ clinical practice as complementary data for RCTs. The low proportion of patients achieving glycaemic control targets observed in this study reinforces the importance of reminding physicians of dose optimisation/titration and intensification. It is helpful for the better understanding and management of the disease in the Gulf region, which has far-reaching benefits across all socioeconomic classes, given the rapid increase of the prevalence of type 2 diabetes in these countries.
Acknowledgements
Special thanks are due to all the patients and investigators from the Gulf region for their participation in this study. The IMPROVE™ study was sponsored by Novo Nordisk A/S, Denmark. Medical writing support was provided by Chen L, and statistical analysis support was provided by Hu H, Novo Nordisk, and International Operations Clinical Development Center.
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PII: S1877-5934(10)00023-8
doi:10.1016/j.ijdm.2010.05.001
© 2010 Published by Elsevier Inc.
Volume 2, Issue 2 , Pages 110-113, August 2010
