Starting or switching to biphasic insulin aspart 30 (BIAsp 30) in type 2 diabetes: A multicenter, observational, primary care study conducted in Finland☆

Article Outline

• Abstract
• 1. Introduction
• 2. Patients and methods
  • 2.1. Study design
  • 2.2. Patient population
  • 2.3. Treatment regimen
  • 2.4. Assessments and outcome measures
  • 2.5. Statistical analyses
• 3. Results
  • 3.1. Patients
  • 3.2. Study treatment
  • 3.3. SADRs and major hypoglycaemia
  • 3.4. Adverse drug reactions
  • 3.5. Minor and nocturnal hypoglycaemic events
  • 3.6. HbA1c measures
  • 3.7. FPG
  • 3.8. Body weight
• 4. Discussion
• Conflicts of interest
• Acknowledgments
• References
• Copyright

Abstract 

Aims

Assess safety and glycaemic control in patients initiating insulin with, or switching from basal insulin to, biphasic insulin aspart 30/70 (BIAsp 30) in primary care in Finland.

Methods

A non-randomised, non-interventional, open-label, 26-week study of type 2 diabetes (T2D) patients prescribed BIAsp 30 by their physician, who determined starting dose, titration and injection frequency.

Results

496 patients provided safety data (insulin-naïve n=197; prior insulin n=299 [84.9% received NPH insulin]). Three patients (0.6%) reported four SADRs (three hypoglycaemia, one hypoglycaemia with unconsciousness). HbA1c was significantly (p<0.0001) reduced after 26 weeks’ BIAsp 30 therapy (final dose): insulin-naïve −1.4% (44.4 IU); prior insulin −1.1% (77.4 IU). HbA1c<7.0% was achieved by 10% of insulin-naïve patients at baseline and 51% at 26-week follow-up. In the prior insulin group, 7% and 30% of patients had HbA1c<7.0% at baseline and 26 weeks, respectively. Minor hypoglycaemia increased significantly from baseline to study end: insulin-naïve 0.66–6.45 events/patient/year (p<0.0001); prior insulin 5.11–8.58 events/patient/year (p<0.05). Weight increased by 1.0kg (insulin-naïve) and 1.3kg (previous insulin).

Conclusion

BIAsp 30, initiated and titrated in T2D patients in primary care in Finland, showed a good safety profile and significantly improved glycaemic control.

Keywords: Biphasic insulin aspart, Glycaemic control, Observational study, Primary care, Safety, Type 2 diabetes

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1. Introduction 

Several studies have shown that intensive therapy that achieves good glycaemic control reduces micro- and macrovascular complications associated with type 2 diabetes [1], [2]; thus, the primary treatment goal is the attainment of near-normal glycaemia, as far as is practical. Conventional treatment of patients with type 2 diabetes usually begins with lifestyle changes (i.e., diet and physical activity), often in parallel with oral antidiabetic drug (OAD) monotherapy. After a mean of 1.5 years, this initial approach fails in over a third of patients [3], necessitating initiation of a multidrug regimen, which often includes insulin.

When initiating insulin treatment in type 2 diabetes, the European Association for the Study of Diabetes/American Diabetes Association (EASD/ADA) consensus statement recommends one injection of basal insulin at bedtime in addition to OADs [4]; this is also the most common initial insulin regimen in Finland. Following the initiation of insulin, many patients achieve better metabolic control and reduced glycated hemoglobin (HbA1c) measurements; however, it often remains a challenge to reach the HbA1c treatment target of <7.0% recommended by the Finnish Current Care guidelines [5] and the ADA standards [6]. A nationwide survey reported that, among people with type 2 diabetes in Finland, only 17% of those on an insulin-only regimen and 11% of those on an insulin plus OAD regimen have HbA1c measurements <7% [7]. The reasons for not reaching treatment targets in insulin-treated type 2 diabetes are multifactorial and can include issues such as insecurity about insulin treatment, fear of side effects (e.g., hypoglycaemia and weight gain), delay in initiating insulin treatment and ignoring postprandial glucose (PPG) increase. As such, diabetes treatment guidelines often focus on modulating both fasting plasma glucose (FPG) and PPG to achieve optimal glycaemic control [8], [9].

In type 2 diabetes, increased blood glucose concentrations at mealtimes result from the combination of a delayed and weakened beta-cell response, together with reduced insulin sensitivity. Elevated glucose concentrations are a risk factor for cardiovascular disease [10], [11], [12]; therefore, optimal glycaemic control involves targeting both FPG and PPG to achieve HbA1c measurements that substantially reduce the risk of diabetes complications [13], [14].

Coverage of FPG and PPG can be achieved using a premixed insulin formulation containing both rapid-acting and basal insulin. Indeed, randomised controlled trials (RCTs) have shown that initiating insulin therapy with a premixed insulin analogue (biphasic insulin aspart 30 [BIAsp 30]: 30% insulin aspart, 70% protaminated aspart) more effectively achieved HbA1c targets in patients with type 2 diabetes experiencing suboptimal glycaemic control with OADs than once-daily use of the basal insulin, insulin glargine [15], [16], [17]. The effectiveness of BIAsp 30 in restoring glycaemic control was especially pronounced in patients with HbA1c measurements >8.5% [15]. In a separate study (the 1-2-3 Study), 21% of patients with type 2 diabetes, with or without previous basal insulin treatment, achieved target HbA1c measurements of ≤6.5%, and 41% reached HbA1c levels of <7.0% when BIAsp 30 once daily was added to OADs [18]. Additionally, in the 1-2-3 Study, patients who did not achieve target HbA1c measurements with BIAsp 30 once daily progressed to twice-daily treatment or, if needed, three-times daily treatment. By the end of the 48-week study period, 77% of patients achieved a target HbA1c measurement of <7.0%, and 60% of patients had an HbA1c measurement ≤6.5% [18]. Thus, by initiating insulin treatment with BIAsp 30, or switching to BIAsp 30 from basal-only insulin therapy, patients with type 2 diabetes may achieve improved glycaemic control compared with basal insulin, as both the prandial and basal insulin requirements are addressed by the premixed insulin treatment regimen.

Data from RCTs and observational studies for BIAsp 30 use in secondary care have been published. However, it is important to continue to monitor serious adverse drug reactions (SADRs) once a phase III program is complete, which is best achieved with observational studies in a clinical practice setting. The primary objective of this observational study was to evaluate the incidence of SADRs over 26 weeks when initiating, or switching to, insulin therapy with BIAsp 30 in patients with type 2 diabetes in a primary care setting in Finland. In addition, the study aimed to determine the frequency of hypoglycaemic events and glycaemic control with BIAsp 30.

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2. Patients and methods 

2.1. Study design 

This was an observational, non-interventional, non-randomised, open-label, prospective, 26-week study conducted in 81 primary care centres in Finland. This study was not part of a larger global observational study. The primary objective was to evaluate the incidence of SADRs occurring in patients with type 2 diabetes when initiating, or switching to, insulin therapy with BIAsp 30 in primary care.

An active comparator was not included as this was an observational study conducted in a real-life setting and patients acted as their own controls prior to and following treatment with BIAsp 30.

This study was conducted in accordance with local Independent Ethics Committee/Institutional Review Board approval, the International Conference on Harmonisation and Good Clinical Practice guidelines, and the Declaration of Helsinki. Patients were informed of the potential risks/benefits relating to participation in the study and provided written consent prior to enrolment.

2.2. Patient population 

Prescription of BIAsp 30 was at the discretion of the treating physician and was initiated as part of normal clinical evaluation. Following the decision to initiate BIAsp 30 therapy, any patient with type 2 diabetes who was insulin-naïve or previously treated with basal-only insulin therapy and who required improved metabolic control, as judged by the treating primary care physician, was able to participate. Physicians were asked to pay particular attention to drug interactions listed on the product label.

Patients were excluded from the study if they were unable to comply with protocol requirements (e.g., could not return for the final visit). Women who were pregnant, intended to become pregnant or who were breastfeeding were also excluded from the study.

2.3. Treatment regimen 

There were no study-prescribed procedures. The treating primary care physician determined the starting dose and frequency of BIAsp 30 administration, as well as any dose or frequency changes that were subsequently required. Biphasic insulin aspart 30 was commercially available, was prescribed according to normal clinical practice and was administered by subcutaneous injection.

2.4. Assessments and outcome measures 

The primary endpoint was the frequency of SADRs (defined as an event leading to death, a life-threatening experience, or hospitalisation or significant disability/incapacity, including major hypoglycaemic events) reported during 26 weeks of BIAsp 30 treatment. A major hypoglycaemic event was the inability of the patient to treat the episode him/herself and requiring food, glucagon or intravenous glucose administration by another person.

Secondary endpoints included the frequency of hypoglycaemic events in the 4 weeks preceding each visit and change in FPG, HbA1c and body weight over 26 weeks. Hypoglycaemia was defined as ‘minor’ if plasma glucose measured <3.1mmol/L and events without a plasma glucose measure or a plasma glucose measure ≥3.1mmol/L were considered ‘symptoms only’. Nocturnal hypoglycaemia was defined as events occurring after bedtime and before getting up in the morning. Physicians examined patients at three scheduled clinical visits at week 0 (baseline, prior to initiating BIAsp 30 treatment) and at approximately weeks 12 (interim visit) and 26 (final visit). A post hoc analysis was carried out to calculate the incidence of SADRs, including all reported major hypoglycaemic events, to address potential underreporting of SADRs.

At baseline, physicians collected demographic data and detailed medical histories from patients’ records, diaries or recollection, including the three most recent FPG values, HbA1c value, number of hypoglycaemic events (daytime/night time/major) over the previous 4 weeks, date of initiating OAD treatment, current diabetes medications and weight. At weeks 12 and 26, physicians collected the following information on case report forms: all SADRs, the three most recent FPG values and the number of hypoglycaemic events (daytime/night time/major) over the previous 4 weeks (from patients’ records, diary or recollection), current diabetes medications, and date and value of the most recent HbA1c assessment.

2.5. Statistical analyses 

The sample size was based on the primary endpoint. A sample size of 1000 patients was calculated to provide 90% power to detect an SADR in this study, if the true incidence was at least 0.25%. Assuming a dropout rate of 15%, the total number of patients that needed to be enrolled in the study was estimated to be 1200.

The primary endpoint was analysed for the safety population, which included all enrolled patients who received at least one dose of BIAsp 30 and provided safety data to the physician (either by telephone or at the final visit). In the case of <10 events (SADRs), only listings were to be produced, as well as a table with overall incidence and confidence intervals and an overall summary of adverse events by intensity. Thus, analysis of the primary endpoint was carried out using descriptive statistics only. The 95% confidence limit for the incidence of SADRs was estimated. To test for differences between subgroups (patients who were insulin-naïve and patients treated with insulin prior to initiation of BIAsp 30), Fisher's exact test was used both on the number of patients with SADRs and on the number of SADR events.

The secondary safety endpoint was the number of all hypoglycaemic events in the 4 weeks preceding visits, which was analysed for the safety population. HbA1c and mean FPG values were analysed for the efficacy intent-to-treat population (all enrolled patients who received at least one dose of BIAsp 30 and provided efficacy data) and results were summarised at baseline, 12 and 26 weeks. Changes from baseline were summarised for 12 and 26 weeks and tested for statistical significance using paired t-tests. The mean of the three most recent FPG values over the previous 4 weeks was calculated for each timepoint.

For the efficacy endpoints, two-tailed Wilcoxon signed rank tests were carried out at the 5% level and (two-sided) 95% confidence limits were presented for within-group changes. Non-parametric methods were chosen because the data were not normally distributed. To adjust for multiple testing, Bonferroni correction was used. There was no imputation for missing data. For the two subgroups (patients who were insulin-naïve and patients previously treated with insulin prior to initiation of BIAsp 30), efficacy endpoints were analysed using Fisher's exact test.

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3. Results 

3.1. Patients 

A total of 557 patients were recruited (one additional patient did not provide data on prior insulin treatment); of these, 503 completed the study between 2 January 2007 and 5 September 2008. Recruitment did not reach the specified target because many sites did not succeed in enrolling the required numbers of patients; however, to avoid interfering with the real-life setting of the study, no specific recruitment programs were utilised. Overall, 496 patients were included in the safety population (197 were insulin-naïve and 299 had previously used insulin). Patient flow throughout the study is shown in Fig. 1. Briefly, 58 patients withdrew or were excluded from the study (adverse events n=5; lost to follow-up n=29; other n=21; excluded n=3).

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• Fig. 1. 

  Patient flow. (a) One patient did not provide information on prior therapy so was not counted here, but was included in the overall efficacy and safety populations (total recruited: n=558). Patients who did not provide efficacy or safety data were excluded from the relevant study populations.

Patient demographics and clinical characteristics at baseline, stratified by pre-study treatment and for the overall population, are shown in Table 1. There were no notable differences between the insulin-naïve and prior insulin use groups.

Table 1. Patient demographics and clinical characteristics at baseline stratified by pre-study treatment and in the total population.

SD, standard deviation.

Duration of diabetes is a relevant confounding baseline factor in observational studies that define cohorts according to previous treatment. As perhaps would be expected, patients who were insulin-naïve when entering this study appeared to have a shorter mean diabetes duration than those who had previously received insulin; however, statistical comparisons between the groups stratified according to previous treatment were not carried out for baseline data as such comparisons were not part of the analysis plan due to the observational nature of the study.

3.2. Study treatment 

Among patients with previous insulin use, 84.9% received NPH insulin, 10.8% received insulin glargine, 1.6% received BIAsp 30, 1.0% received insulin aspart, 0.7% received insulin detemir and 0.3% received regular human insulin. Data for current insulin therapy at baseline were missing for two (0.7%) patients. Note that, due to the observational nature of this study, e.g., less stringent monitoring compared with an RCT, some patients were included who did not strictly meet the inclusion criterion regarding previous basal insulin treatment; however, the majority of patients with previous insulin use were switched from basal treatment at baseline. Biguanides, sulphonylureas and combination treatment with both were the most common OAD treatments at baseline in the insulin-naïve and prior insulin use groups (Table 2). Following BIAsp 30 initiation, sulphonylurea use declined and biguanide use increased (Table 2).

Table 2. OAD treatment at baseline and follow-up.

OAD, oral antidiabetic agent. Patients could be receiving more than one OAD therapy.

In the insulin-naïve group, mean (SD) BIAsp 30 dose was 0.15 (0.08)IU/kg at baseline (day 1) and 0.48 (0.27) at week 26 (p<0.001). For the group with prior insulin use, mean (SD) total daily BIAsp 30 dose at day 1 was 0.50 (0.30)IU/kg and was 0.82 (0.47)IU/kg at week 26 (p<0.01). At study end, 8.8% of patients were treated with BIAsp 30 once daily, 75.1% twice daily and 16.1% three-times daily.

3.3. SADRs and major hypoglycaemia 

Overall, three patients reported four SADRs: one insulin-naïve patient had one SADR and two patients with prior insulin use had three SADRs. The most common SADR was hypoglycaemia, which was reported by three patients. One patient with prior insulin use reported one SADR of hypoglycaemia with unconsciousness. There were no significant differences in reported SADRs between the two groups. Three SADRs were classified as severe and one as moderate. For all of these SADRs, the relationship with study treatment was assessed as ‘probable’.

The overall study population was exposed to BIAsp 30 for 268 person-years, which translates to an incidence of SADRs of 14.92 per 1000 person-years. In the insulin-naïve and prior-insulin-use groups, the incidence of SADR events was 9.42 and 18.60 per 1000 person-years, respectively.

During the study period, 19 major hypoglycaemic events were reported altogether: five in the insulin-naïve group and 14 in the prior insulin use group. One major hypoglycaemic event in the insulin-naïve group and seven in the prior insulin use group were nocturnal events. In the subgroups at study end, the rate of major hypoglycaemia events per patient-year did not significantly change in insulin-naïve patients (baseline: 0.13 events/patient-year, study end: 0.20 events/patient-year; p=not significant [NS]) or patients with prior insulin use (baseline: 0.17 events/patient-year, study end: 0.13 events/patient-year; p=NS).

Some of the 19 major hypoglycaemic events were not classified as SADRs because they did not fulfil the criteria (e.g., they were not fatal, life-threatening, did not require hospitalisation or did not cause significant disability/incapacity). Therefore, a post hoc analysis was carried out to provide additional information based on including all 19 major hypoglycaemic events as SADRs. This analysis of SADRs, including all 19 major hypoglycaemic events, determined the incidence of SADRs to be 71.03 events per 1000 person-years, 47.09 events per 1000 person-years and 86.78 events per 1000 person-years in the overall population, insulin-naïve and prior insulin use groups, respectively.

3.4. Adverse drug reactions 

Six adverse drug reactions (ADRs) were reported by six patients and all were considered by the investigator to be possibly related to study treatment. The most common ADR, reported by three patients, was hypoglycaemia. The following ADRs were each reported by one patient: asthenia, malaise and dyspnoea. The severity of two ADRs was classified as moderate and four as mild.

3.5. Minor and nocturnal hypoglycaemic events 

Of the total hypoglycaemic events, most were minor; 752 minor hypoglycaemic events were reported. The frequency of minor hypoglycaemic events in insulin-naïve patients increased from 0.66 events/patient-year at baseline to 6.45 events/patient-year at study end (p<0.0001) (Fig. 2a). The frequency of daytime minor hypoglycaemic events increased from 0.59 to 6.20 events/patient-year (p<0.0001). For nocturnal minor hypoglycaemic events, the frequency remained very low in the insulin-naïve group during BIAsp 30 treatment; however, the difference from baseline was statistically significant (0.07 vs. 1.25 events/patient-year; p<0.05) (Fig. 2b).

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• Fig. 2. 

  (a) Rates of minor hypoglycaemia at baseline, week 12 and week 26 (study end) stratified by pre-study treatment; (b) rates of nocturnal hypoglycaemia at baseline, week 12 and week 26 (study end) stratified by pre-study treatment. *p<0.05; **p<0.0001 vs. baseline.

For patients with prior insulin use, a significant increase from baseline to study end was noted for all minor hypoglycaemic events (5.11 vs. 8.58 events/patient-year; p<0.05; Fig. 2a) and for daytime minor hypoglycaemic events (2.90 vs. 6.01 events/patient-year; p<0.01). However, the frequency of nocturnal minor hypoglycaemic events did not significantly increase following a switch to BIAsp 30 (baseline: 2.21 events/patient-year, study end: 2.56 events/patient-year; p=NS; Fig. 2b).

3.6. HbA1c measures 

Mean (SD) HbA1c measurement prior to starting BIAsp 30 therapy was 8.5% (1.5%) in the insulin-naïve group and 8.6% (1.4%) in the group with prior insulin use; levels were reduced to mean (SD) 7.1% (1.2%) and 7.5% (1.0%), respectively, at study end (Fig. 3). Overall, during 26weeks of BIAsp 30 therapy, the total mean (SD) reductions in mean HbA1c levels of 1.4% (1.6%) in insulin-naïve patients and 1.1% (1.3%) in prior insulin users was statistically significant (both p<0.0001) and clinically relevant. In total, 186 (38%) of patients achieved HbA1c<7.0% at week 26, compared with 40 (8%) at baseline. HbA1c<7.0% was achieved by 20 (10%) of insulin-naïve patients at baseline and 100 (51%) at 26-week follow-up. In the prior-insulin use group, 20 (7%) and 86 (30%) of patients had HbA1c<7.0% at baseline and 26 weeks, respectively.

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• Fig. 3. 

  HbA1c levels at baseline and after 12 and 26 weeks (final visit) of treatment with BIAsp 30 stratified by pre-study treatment. Error bars represent standard errors of the mean. *p<0.0001 vs. baseline. BIAsp, biphasic insulin aspart.

3.7. FPG 

Following 26 weeks of BIAsp 30 therapy, mean [SD] FPG was significantly lower compared with baseline in insulin-naïve patients (−2.3 [2.7]mmol/L; p<0.0001); a non-significant mean change in FPG was reported for patients with prior insulin use (+0.01 [2.4]mmol/L; p=NS) (Fig. 4).

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• Fig. 4. 

  Fasting plasma glucose levels at baseline and after 12 and 26 weeks (final visit) of treatment with BIAsp 30 stratified by pre-study treatment. Error bars represent standard errors of the mean. *p<0.0001 vs. baseline. BIAsp, biphasic insulin aspart.

3.8. Body weight 

During 26 weeks of BIAsp 30 therapy, mean [SD] body weight increased moderately, but significantly, in both the insulin-naïve group (+1.0 [4.8]kg; p<0.01 vs. baseline) and the group with prior insulin use (+1.3 [4.3]kg; p<0.0001 vs. baseline).

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4. Discussion 

This observational study conducted in Finland examined safety and glycaemic control in patients with type 2 diabetes who initiated insulin therapy with, or switched to, BIAsp 30, as directed by their primary care physician. Overall, the results presented here indicate that BIAsp 30 is associated with a low rate of observed SADRs; these data are generally in keeping with those from RCTs [16], [17], [19], [20] and other observational studies [21], [22], [23], [24] of this premix insulin in type 2 diabetes.

Hypoglycaemia is a consideration when selecting an insulin regimen. The primary endpoint in our study was the frequency of SADRs, including major hypoglycaemic events, reported during 26 weeks of BIAsp 30 treatment. The frequency of major hypoglycaemic events was low during BIAsp 30 therapy and did not change from baseline in insulin-naïve patients or in prior insulin users; these findings compare favourably with RCT data. There were five major hypoglycaemic episodes in the insulin-naïve group and 14 in the prior-insulin use group, which may reflect the difference in diabetes duration in the prior insulin versus the insulin-naïve groups (8.1 vs. 13.5 years, respectively), as diabetes duration has been shown to be an independent risk factor for severe hypoglycaemia [25]. Increasing diabetes duration and duration of insulin therapy has also been shown to be associated with increasing frequency of hypoglycaemia [26]. In the 26-week multinational, multicenter, treat-to-target PREFER study, patients with type 2 diabetes discontinued OADs and were randomised to receive analogue basal–bolus therapy (insulin detemir once daily and insulin aspart at mealtimes) or BIAsp 30 twice daily; there were no major hypoglycaemic events in the BIAsp 30 group during this study [20]. Almost identical SADR results to those in our study have been reported from a similarly sized observational study conducted in Denmark in either a hospital or a primary care setting that initiated or switched patients with type 2 diabetes onto BIAsp 30 treatment (four patients reported an SADR, two [1% of the cohort] in the insulin-naïve group and two [1%] in the prior insulin users group) [21].

Overall, in our study, the frequency of hypoglycaemic events per patient-year at week 26 was 6.45 and 8.58 for insulin-naïve patients and prior insulin users, respectively. Rates of minor hypoglycaemia were not published per patient-year for the PREFER study; however, Breum et al. [21] reported hypoglycaemia rates of 5.0 and 6.6 events per patient-year for insulin-naïve patients and prior insulin users, respectively. The difference in the incidence of minor hypoglycaemia may be explained by higher insulin doses in the present study compared with the Danish cohort; specifically, the mean insulin dose in our study was 19% higher in insulin-naïve patients and 33% higher in prior insulin users. The frequency of minor hypoglycaemic events increased significantly in insulin-naïve patients, which is not surprising considering the low baseline rate associated with previous OAD therapy coupled with significantly improved HbA1c levels. There was also an increase in minor hypoglycaemia rates at week 26 in patients with prior insulin use, probably reflecting the addition of a prandial insulin component, but, importantly from the patients’ perspective, rates of nocturnal hypoglycaemia were not increased in either group. Approximately half of the patients in this study were receiving treatment with sulphonylureas at baseline, which may themselves be associated with hypoglycaemia [27]. However, since the majority of patients discontinued sulphonylureas following initiation of BIAsp 30 (only 8% and 12% of patients in the insulin-naïve and prior insulin groups, respectively, were still receiving sulphonylureas at week 26), the impact of sulphonylureas on hypoglycaemia in this study is likely to be limited. While minor hypoglycaemia may be considered an expected consequence of effective glycaemic control, it is important to note that the frequency of major hypoglycaemia with BIAsp 30 treatment was not statistically different at study end versus baseline in either the insulin-naïve group or the group that had previously received insulin.

According to the Finnish Current Care guidelines [5], the overall glycaemic target for patients receiving insulin is HbA1c<7.0%, but a less stringent target of HbA1c<7.5% should be individually applied to, for example, elderly or obese patients, or professional drivers. The results of the present study suggest that treatment with BIAsp 30 may help many patients with type 2 diabetes meet these targets. For patients previously treated with insulin who presented with markedly longer duration of diabetes compared with the insulin-naïve cohort (13.5 vs. 8.1 years), and thus more advanced disease, a significant reduction in HbA1c levels (−1.1%) was demonstrated following treatment with BIAsp 30, resulting in a mean value of 7.5% at study end. The improvement in HbA1c levels observed in patients previously treated with insulin is consistent with previous experience from the PREFER [20] and Breum et al. [21] studies. Additionally, the magnitude of change observed in HbA1c levels in insulin-naïve patients in our study, where HbA1c was significantly (p<0.0001) reduced by −1.4% from baseline to a mean of 7.1% at study end, is supported by the data from the Breum et al. study [21]. These results are also in agreement with those from the IMPROVE study, which demonstrated greater reductions in HbA1c in patients with shorter diabetes duration [24]. Therefore, although significant improvements were seen following BIAsp 30 treatment in HbA1c levels in both cohorts, as perhaps may be expected, the most substantial reduction in this parameter was observed in insulin-naïve patients.

After 26 weeks of BIAsp 30 treatment, mean FPG was significantly reduced from baseline in insulin-naïve patients (−2.3mmol/L; p<0.0001). In prior insulin users, FPG levels were similar at baseline and at week 26, despite a mean 1.1% reduction in HbA1c in this cohort. Notably, almost all prior insulin users (96%) were on a basal insulin regimen before switching to BIAsp 30. Thus, because a significant change in FPG was not observed following a switch from basal insulin to BIAsp 30, it may be hypothesised that the significant improvement in glycaemic control resulted from the ability of the rapidly acting component of the biphasic insulin mixture to reduce postprandial glycaemic excursions without compromising FPG. At baseline, patients already using insulin reported a mean dose of 50.9IU compared with a mean daily dose of BIAsp 30 of 77.4IU (23.2IU insulin aspart; 54.2IU protaminated insulin aspart) at study end. Therefore, the mean increase in basal insulin dose from baseline was 3.3IU; this small increase is not considered sufficient to explain the 1.1% reduction in HbA1c observed in prior insulin users. Moreover, as the increase in dose in the prior insulin use group corresponded to the prandial component of BIAsp 30 treatment, there was no relevant change in basal insulin supply. Overall, 26 weeks of BIAsp 30 treatment resulted in statistically significant and clinically meaningful improvements in glycaemic control.

As glycaemic control improves following the initiation of insulin therapy, an increase in weight is often observed. Indeed, in the randomised PREFER study, where insulin was titrated toward a target dose, body weight increased by a mean (SD) of 2.1 (4.0)kg in the BIAsp 30 treatment group [20]. Two other randomised studies investigating BIAsp 30 using a targeted dosing schedule in patients with type 2 diabetes reported weight increases of 4.6 and 5.0kg at study end (weeks 26 and 32, respectively) [18], [28]. In contrast, in our observational study, only a slight increase in mean body weight was observed during 26 weeks of BIAsp 30 treatment (+1.0kg, insulin-naïve patients; +1.3kg, prior insulin users), which is considered modest in relation to mean improvements in HbA1c levels of −1.1 and −1.4%, respectively. This may reflect the fact that over 90% of patients in the study combined BIAsp 30 with metformin, as it has been shown that adding metformin to insulin treatment resulted in weight, glycaemic control and insulin requirement benefits compared with insulin alone [29]. Overall, our study shows that, in a real-life setting where individual dose adjustments are carried out at the discretion of the treating physician rather than according to stringent titration algorithms, patients with type 2 diabetes are able to achieve significant improvements in glycaemic control without excessive weight gain.

Observational studies, designed to reflect clinical practice, contribute to the already existing data gathered from previous clinical trials. However, as with other non-interventional trials, the observational data reported here also have certain limitations. For example, the unselected population means groups may not be accurately matched or controlled; however, the wide inclusion criteria permitted in observational studies allows enrolment of a broad range of available patients, and thus, in addition to randomised, controlled data, further informs clinical practice. Additionally, data generated from a heterogeneous patient population can be more difficult to interpret. As the principle of observational studies is not to interfere with the normal course of medicine (including changes to existing treatment), no additional study-related measurements were made, thus minimising any ‘study effect’, but reducing the efficiency of data collection. In our study, recording of hypoglycaemia was achieved by retrospective recall/diaries, which may have underestimated the incidence at baseline compared with the incidence following change of therapy. In addition, the target sample size was not achieved; however, while 1000 patients would have provided 95% power to detect a single SADR if the true incidence was ≥0.25%, four SADRs were reported, suggesting that the study was not underpowered. Despite these limitations, observational studies offer useful insight into the safety and efficacy of BIAsp 30 in addition to existing randomised, controlled data.

In summary, in an unselected sample of almost 500 Finnish patients with type 2 diabetes no longer controlled by their current treatment regimen, a low frequency of serious adverse drug reactions was confirmed for BIAsp 30 treatment. Only three patients reported a total of four SADRs, which were all related to hypoglycaemia. Switching to BIAsp 30 significantly improved glycaemic control in patients with type 2 diabetes, both in insulin-naïve patients for whom OAD therapy was no longer controlling their disease, and in patients for whom basal insulin treatment was providing suboptimal glycaemic control. Patients with type 2 diabetes who were insulin-naive experienced improvement in glycaemic control with a modest increase in rates of hypoglycaemia. For patients with type 2 diabetes who had previously received insulin treatment, glycaemic control did not occur at the cost of a clinically relevant increase in hypoglycaemia. Weight gain was clinically modest in both groups. Taken together, these data suggest that earlier intervention with BIAsp 30 may provide better diabetes control with a lower total insulin dose and fewer adverse side effects such as hypoglycaemia and weight gain, compared with later intervention. This finding is supported by studies such as Valensi et al. [24], which demonstrated greater HBA1c reduction following BIAsp 30 treatment in patients with a shorter duration of diabetes. In addition, insulin initiation with three-times daily premix insulin analogues plus metformin has been demonstrated to provide improved glycaemic control with reduced hypoglycaemic episodes and no weight gain over a mean treatment period of almost 3 years [30].

In conclusion, BIAsp 30 therapy in patients with type 2 diabetes was associated with a low rate of SADRs and major hypoglycaemia and was effective in a primary care setting in Finland.

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Conflicts of interest 

The authors have a competing interest to declare. JM has received speaker fees from Novo Nordisk, Eli Lilly, Novartis and Roche, and research funding from Novo Nordisk, Sanofi-Aventis, AstraZeneca and Bristol Meyer Squibb. CS and KA have no conflicts of interest relating to this study. TS is employed by Novo Nordisk Pharma Oy.

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Acknowledgments 

This study (BIAsp-1917) was funded by Novo Nordisk Pharma Oy, Finland. Editorial assistance was provided by Kim Croskery and Helen Marshall of Watermeadow Medical, UK, funded by Novo Nordisk A/S, Denmark.

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References 

1. Malmberg K for the DIGAMI (Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512–1515
   • View In Article
   • MEDLINE
   • CrossRef
2. UK Prospective Diabetes Study Group (UKPDS Group). Intensive blood–glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–853
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (708 KB)
   • CrossRef
3. Riedel AA, Heien H, Wogen J, Plauschinat CA. Loss of glycemic control in patients with type 2 diabetes mellitus who were receiving initial metformin, sulfonylurea, or thiazolidinedione monotherapy. Pharmacotherapy. 2007;27:1102–1110
   • View In Article
   • CrossRef
4. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203
   • View In Article
   • CrossRef
5. Duodecim . Finnish current care guideline: the treatment of diabetes. Duodecim. 2007;123:1490–1520
   • View In Article
6. American Diabetes Association (ADA) . Standards of medical care in diabetes––2009. Diabetes Care. 2009;32(Suppl 1):S13–S61
   • View In Article
   • CrossRef
7. Valle T, Tuomilehto J. People with diabetes and metabolic control in Finland in the years 2000–2001. DHEKO Report; 2004. p. 1.
   • View In Article
8. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, et al. European guidelines on cardiovascular disease prevention in clinical practice: third joint task force of European and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of eight societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2003;10:S1–S10
   • View In Article
   • MEDLINE
   • CrossRef
9. El-Kebbi IM, Ziemer DC, Cook CB, Gallina DL, Barnes CS, Phillips LS. Utility of casual postprandial glucose levels in type 2 diabetes management. Diabetes Care. 2004;27:335–339
   • View In Article
   • MEDLINE
   • CrossRef
10. DECODE Study Group, European Diabetes Epidemiology Group. Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases?. Diabetes Care. 2003;26:688–696
    • View In Article
    • MEDLINE
    • CrossRef
11. Meigs JB, Nathan DM, D’Agostino RB, Wilson PW Framingham Offspring Study. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care. 2002;25:1845–1850
    • View In Article
    • MEDLINE
    • CrossRef
12. Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999;22:920–924
    • View In Article
    • MEDLINE
    • CrossRef
13. Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care. 1997;20:1822–1826
    • View In Article
    • MEDLINE
14. Monnier L, Colette C, Lapinski H. Global assessment for quality and safety of control in type 2 diabetic patients. Eur J Clin Invest. 2004;34:37–42
    • View In Article
    • MEDLINE
    • CrossRef
15. Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, et al. Initiating insulin therapy in type 2 diabetes. Diabetes Care. 2005;28:260–265
    • View In Article
    • MEDLINE
    • CrossRef
16. Kann PH, Wascher T, Zackova V, Moeller J, Medding J, Szocs A, et al. Starting insulin therapy in type 2 diabetes: twice-daily biphasic insulin aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride. Exp Clin Endocrinol Diabetes. 2006;114:527–532
    • View In Article
    • MEDLINE
    • CrossRef
17. Strojek K, Bebakar WM, Khutsoane DT, Pesic M, Smahelová A, Thomsen HF, et al. Once-daily initiation with biphasic insulin aspart 30 versus insulin glargine in patients with type 2 diabetes inadequately controlled with oral drugs: an open-label, multinational RCT. Curr Med Res Opin. 2009;25:2887–2894
    • View In Article
    • CrossRef
18. Garber AJ, Wahlen J, Wahl T, Bressler P, Braceras R, Allen E, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes Obes Metab. 2006;8:58–66
    • View In Article
    • MEDLINE
    • CrossRef
19. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul , et al. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med. 2007;357:1716–1730
    • View In Article
    • CrossRef
20. Liebl A, Prager R, Binz K, Kaiser M, Bergenstal R, Gallwitz B. Comparison of insulin analogue regimens in people with type 2 diabetes mellitus in the PREFER study: a randomized controlled trial. Diabetes Obes Metab. 2009;11:45–52
    • View In Article
    • CrossRef
21. Breum L, Almdal T, Eiken P, Lund P, Christiansen E, on behalf of the Danish BIAsp Study Group . Initiating or switching to biphasic insulin aspart 30/70 therapy in subjects with type 2 diabetes mellitus. An observational study. Rev Diabet Stud. 2008;5:154–162
    • View In Article
22. Khutsoane D, Sharma SK, Almustafa M, Jang HC, Azar ST, Danciulescu R, et al. Biphasic insulin aspart 30 treatment improves glycaemic control in patients with type 2 diabetes in a clinical practice setting: experience from the PRESENT study. Diabetes Obes Metab. 2008;10:212–222
    • View In Article
    • CrossRef
23. Shestakova M, Sharma SK, Almustafa M, Min KW, Ayad N, Azar ST, et al. Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study. Curr Med Res Opin. 2007;23:3209–3214
    • View In Article
    • CrossRef
24. Valensi P, Benroubi M, Borzi V, Gumprecht J, Kawamori R, Shaban J, et al. Initiating insulin therapy with, or switching existing insulin therapy to, biphasic insulin aspart 30/70 (NovoMix 30) in routine care: safety and effectiveness in patients with type 2 diabetes in the IMPROVE observational study. Int J Clin Pract. 2009;63:522–531
    • View In Article
    • CrossRef
25. Davis TM, Brown SG, Jacobs IG, Bulsara M, Bruce DG, Davis WA. Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study. J Clin Endocrinol Metab. 2010;95:2240–2247
    • View In Article
    • CrossRef
26. Henderson JN, Allen KV, Deary IJ, Frier BM. Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med. 2003;20:1016–1021
    • View In Article
    • MEDLINE
    • CrossRef
27. Derosa G, Maffioli P. Effects of thiazolidinediones and sulfonylureas in patients with diabetes. Diabetes Technol Ther. 2010;12:491–501
    • View In Article
    • CrossRef
28. Raskin P, Matfin G, Schwartz SL, Chaykin L, Chu PL, Braceras R, et al. Addition of biphasic insulin aspart 30 to optimized metformin and pioglitazone treatment of type 2 diabetes mellitus: The ACTION Study (Achieving Control Through Insulin Plus Oral ageNts). Diabetes Obes Metab. 2007;11:27–32
    • View In Article
    • CrossRef
29. Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169:616–625
    • View In Article
    • CrossRef
30. Levit S, Toledano Y, Wainstein J. Improved glycaemic control with reduced hypoglycaemic episodes and without weight gain using long-term modern premixed insulins in type 2 diabetes. Int J Clin Pract. 2011;65:165–171
    • View In Article