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Switching from biphasic human insulin 30 to biphasic insulin aspart 30 in type 2 diabetes is associated with improved glycaemic control and a positive safety profile: Results from the A1chieve study

Nabil K. El Naggar, Pradana Soewondo, Mohammad E. Khamseh, Jian-Wen Chen and Jihad Haddad

Diabetes Research and Clinical Practice, 3, 98, pages 408 - 413

Published online Dec-2012


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4. Discussion

Switching from BHI 30 to BIAsp 30 was associated with significant improvements in HbA1c, FPG and PPG combined with a reduction in the rates of major and minor hypoglycaemia. The numbers of reported SADRs and SAEs were low. Overall, there was a negligible increase in mean bodyweight over the 24 weeks. Insulin dose increased slightly from baseline to Week 24. Switching to BIAsp 30 was also associated with improved self-reported QoL.

Observational studies can provide important clues about how drugs perform under conditions of real-life clinical practice. The results presented here confirm that switching from BHI 30 to BIAsp 30 is associated with significant reductions in PPG in a real-life setting. This supports results from RCTs that have consistently shown significantly better PPG reductions for BIAsp 30 compared with BHI [9], [10], and [11] x P.T. McSorley, P.M. Bell, L.V. Jacobsen, A. Kristensen, A. Lindholm. Twice-daily biphasic insulin aspart 30 versus biphasic human insulin 30: a doubleblind crossover study in adults with type 2 diabetes mellitus. Clin. Ther.. 2002;24:530-539 Crossref. x B.O. Boehm, P.D. Home, C. Behrend, N.M. Kamp, A. Lindholm. Premixed insulin aspart 30 vs. premixed human insulin 30/70 twice daily: a randomized trial in Type 1 and Type 2 diabetic patients. Diabet. Med.. 2002;19:393-399 Crossref. x K. Hermansen, M. Colombo, H. Storgaard, A. OStergaard, K. Kolendorf, S. Madsbad. Improved postprandial glycemic control with biphasic insulin aspart relative to biphasic insulin lispro and biphasic human insulin in patients with type 2 diabetes. Diabetes Care. 2002;25:883-888 Crossref. . This improvement in PPG may reflect the earlier and higher peak postprandial insulin concentrations achieved by BIAsp 30 compared with BHI 30 [12] x P.G. McNally, J.D. Dean, A.D. Morris, P.D. Wilkinson, G. Compion, S.R. Heller. 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;30:1044-1048 Crossref. .

It is important to address PPG control in order to achieve HbA1c targets [1] and [2] x L. Monnier, C. Colette. Targeting prandial hyperglycemia: how important is it and how best to do this?. Curr. Diab. Rep.. 2008;8:368-374 Crossref. x H.J. Woerle, C. Neumann, S. Zschau, S. Tenner, A. Irsigler, J. Schirra, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes Importance of postprandial glycemia to achieve target HbA1c levels. Diabetes Res. Clin. Pract.. 2007;77(2):280-285 Crossref. . In addition, lowering PPG is associated with reduced cardiovascular risk [3] x A. Ceriello, J. Davidson, M. Hanefeld, L. Leiter, L. Monnier, D. Owens, et al. Postprandial hyperglycaemia and cardiovascular complications of diabetes: an update. Nutr. Metab. Cardiovasc. Dis.. 2006;16:453-456 Crossref. . Failure to control PPG has been independently associated with macrovascular disease, retinopathy, cancer, impaired cognitive function in the elderly, increased carotid intima-media thickness, decreased myocardial blood volume and myocardial blood flow and oxidative stress, inflammation and endothelial dysfunction in individuals with diabetes [4] x International Diabetes Federation. Guideline For Management Of Postmeal Glucose In Diabetes 2011. International Diabetes Federation 2012. Accessed: August 22. Available from: URL: http://www.idf.org/2011-guidelinemanagement- postmeal-glucose-diabetes. . Baseline data from this study show that post-breakfast PPG was in the range of 12.9–15.1 mmol/l depending on region, well above the IDF recommended PPG target of <9 mmol/l [4] x International Diabetes Federation. Guideline For Management Of Postmeal Glucose In Diabetes 2011. International Diabetes Federation 2012. Accessed: August 22. Available from: URL: http://www.idf.org/2011-guidelinemanagement- postmeal-glucose-diabetes. . However, following 24 weeks of BIAsp 30 treatment, mean PPG was 9.9 mmol/l, a 4.3 mmol/l improvement, although still above the IDF target.

In this study BIAsp 30 was also associated with significant improvements in FPG versus BHI although this finding has not been demonstrated by clinical trials [5] and [13] x J.A. Davidson, A. Liebl, J.S. Christiansen, G. Fulcher, R.J. Ligthelm, P. Brown, et al. Risk for nocturnal hypoglycemia with biphasic insulin aspart 30 compared with biphasic human insulin 30 in adults with type 2 diabetes mellitus: a metaanalysis. Clin. Ther.. 2009;31:1641-1651 Crossref. x Qayyum R, Wilson LM, Bolen S, Maruthur N, Marinopoulos SS, Feldman L, et al. Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes. Rockville (MD): Agency for Healthcare Research and Quality (US). Available from: http://www.ncbi.nlm.nih.gov/books/NBK43174/. . Similarly, clinical trials have failed to demonstrate improved HbA1c reductions with BIAsp 30 over BHI [5], [13], and [14] x J.A. Davidson, A. Liebl, J.S. Christiansen, G. Fulcher, R.J. Ligthelm, P. Brown, et al. Risk for nocturnal hypoglycemia with biphasic insulin aspart 30 compared with biphasic human insulin 30 in adults with type 2 diabetes mellitus: a metaanalysis. Clin. Ther.. 2009;31:1641-1651 Crossref. x Qayyum R, Wilson LM, Bolen S, Maruthur N, Marinopoulos SS, Feldman L, et al. Comparative Effectiveness, Safety, and Indications of Insulin Analogues in Premixed Formulations for Adults With Type 2 Diabetes. Rockville (MD): Agency for Healthcare Research and Quality (US). Available from: http://www.ncbi.nlm.nih.gov/books/NBK43174/. x B.O. Boehm, J.A. Vaz, L. Brondsted, P.D. Home. Long-term efficacy and safety of biphasic insulin aspart in patients with type 2 diabetes. Eur. J. Intern. Med.. 2004;15:496-502 Crossref. . The data from clinical trials are in contrast to the impressive HbA1c improvements observed in this study of between 1.2 and 1.9%. It is possible that A1chieve® provided a stimulus for improved diabetes management or the adoption of positive lifestyle changes. This hypothesis was supported by the overall A1chieve® data, which showed minimal body weight gain in association with improved HbA1c, as well as improved blood pressure and lipid profile [8] x P. Home, N.E. Naggar, M. Khamseh, G. Gonzalez-Galvez, C. Shen, P. Chakkarwar, et al. An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: the A1chieve study. Diabetes Res. Clin. Pract.. 2011;94:352-363 Abstract, Full-text, PDF, Crossref. . It should be noted that there was an increase in the daily insulin dose from baseline to the end of study that may explain the improvements in glycaemic control.

The rate of major and minor hypoglycaemic episodes was reduced from baseline to week 24 in this study. Significant reductions in major and nocturnal hypoglycaemia were also observed in a meta-analysis of trials comparing BIAsp 30 and BHI [5] x J.A. Davidson, A. Liebl, J.S. Christiansen, G. Fulcher, R.J. Ligthelm, P. Brown, et al. Risk for nocturnal hypoglycemia with biphasic insulin aspart 30 compared with biphasic human insulin 30 in adults with type 2 diabetes mellitus: a metaanalysis. Clin. Ther.. 2009;31:1641-1651 Crossref. . A crossover study by McNally et al 2007 employed continuous glucose monitoring to examine the frequency of low interstitial glucose values in individuals treated with BIAsp 30 or BHI 30 [12] x P.G. McNally, J.D. Dean, A.D. Morris, P.D. Wilkinson, G. Compion, S.R. Heller. 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;30:1044-1048 Crossref. . The study demonstrated an increased frequency of nocturnal low glucose values with BHI 30 versus BIAsp 30 and this was associated with higher rates of self-reported nocturnal hypoglycaemia with BHI 30.

The A1chieve® study has a number of limitations that should be considered when assessing these results. It is a multinational noninterventional study and as such it is subject to the heterogeneity of healthcare systems in individual countries. Non-interventional studies do not have tightly controlled populations or control groups, which reduces the certainty with which outcomes can be ascribed to treatment. The incidence of hypoglycaemia at baseline was based on participants’ recall of the past 4 weeks prior to the study visit. Therefore, there was some potential for recall bias, which might have resulted in an underestimate of the real incidence of minor hypoglycaemic episodes. However, data from this noninterventional study forms part of the evidence base alongside that from a comprehensive programme of controlled clinical trials.

A number of limitations of the A1chieve® study design identified above, such as the lack of tightly controlled populations and the possible heterogeneity of diabetes care in different regions, mean that the study closely reflects ‘real-life’ clinical practice. The lack of strict inclusion/exclusion criteria meant that individuals who may have been excluded from more strictly controlled clinical trials were included in A1chieve® study. Hence, it is likely that the enrolled population in A1chieve® study closely reflected the wider population of individuals with diabetes in the regions studied. In addition, all clinical decisions were made by the treating physician, so although as a result, treatment heterogeneity was introduced into the study, the findings accurately reflect ‘real-life clinical practice’. In addition, the fact that switching from BHI 30 to BIAsp 30 improved clinical outcomes in all regions despite potential differences in treatment approach suggests that the clinical effects observed could be achievable within a range of healthcare systems.

This study demonstrated that switching to BIAsp 30 treatment in individuals with T2D previously treated with BHI 30 was associated with improvements in glycaemic control and a reduction in major and minor hypoglycaemic episodes. Low numbers of SADRs or SAEs were experienced by patients treated with BIAsp 30.

References

Label Authors Title Source Year
[3]

References in context

  • PPG has also been identified as an independent risk factor for diabetic complications such as cardiovascular disease [3].
    Go to context

  • In addition, lowering PPG is associated with reduced cardiovascular risk [3].
    Go to context

A. Ceriello, J. Davidson, M. Hanefeld, L. Leiter, L. Monnier, D. Owens, et al. Postprandial hyperglycaemia and cardiovascular complications of diabetes: an update Crossref. Nutr. Metab. Cardiovasc. Dis.. 2006;16:453-456 2006
[4]

References in context

  • Therefore, clinical guidelines such as those published by the International Diabetes Federation recommend targeting both FPG and PPG at all HbA1c levels in order to achieve glycaemic targets, and to minimise the development of diabetic complications [4].
    Go to context

  • Baseline data from this study show that post-breakfast PPG was in the range of 12.9–15.1 mmol/l depending on region, well above the IDF recommended PPG target of <9 mmol/l [4].
    Go to context

  • Baseline data from this study show that post-breakfast PPG was in the range of 12.9–15.1 mmol/l depending on region, well above the IDF recommended PPG target of <9 mmol/l [4].
    Go to context

International Diabetes Federation. Guideline For Management Of Postmeal Glucose In Diabetes 2011. International Diabetes Federation 2012. Accessed: August 22. Available from: URL: http://www.idf.org/2011-guidelinemanagement- postmeal-glucose-diabetes.
[5]

References in context

  • Biphasic insulin aspart 30 (BIAsp 30; NovoMix® 30, Novo Nordisk) has been shown to provide better control of PPG than BHI 30 in a meta-analysis including data from nine randomised controlled trials (RCTs) in patients with Type 2 diabetes mellitus (T2D) [5].
    Go to context

  • Significant reductions in major and nocturnal hypoglycaemia were also observed in a meta-analysis of trials comparing BIAsp 30 and BHI [5].
    Go to context

J.A. Davidson, A. Liebl, J.S. Christiansen, G. Fulcher, R.J. Ligthelm, P. Brown, et al. Risk for nocturnal hypoglycemia with biphasic insulin aspart 30 compared with biphasic human insulin 30 in adults with type 2 diabetes mellitus: a metaanalysis Crossref. Clin. Ther.. 2009;31:1641-1651 2009
[8]

References in context

  • It is important to select insulin therapy according to individual needs and the A1chieve® study is the first observational study that included individuals who were switched to BIAsp 30, insulin detemir (Levemir®, Novo Nordisk) or insulin aspart (NovoRapid®, Novo Nordisk) alone or in combination as part of their routine clinical care [8].
    Go to context

  • The A1chieve® study was an international prospective, obser vational, multicentre, open label, non-interventional, 24-week study in people with T2D who were treatment naïve or who had been using anti-diabetic medication other than Novo Nordisk insulin analogues being evaluated and who had started treatment with BIAsp 30, insulin detemir or insulin aspart (alone or in combination) in routine clinical practice [8].
    Go to context

  • This hypothesis was supported by the overall A1chieve® data, which showed minimal body weight gain in association with improved HbA1c, as well as improved blood pressure and lipid profile [8].
    Go to context

P. Home, N.E. Naggar, M. Khamseh, G. Gonzalez-Galvez, C. Shen, P. Chakkarwar, et al. An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: the A1chieve study Abstract, Full-text, PDF, Crossref. Diabetes Res. Clin. Pract.. 2011;94:352-363 2011
[12]

References in context

  • This improvement in PPG may reflect the earlier and higher peak postprandial insulin concentrations achieved by BIAsp 30 compared with BHI 30 [12].
    Go to context

  • A crossover study by McNally et al 2007 employed continuous glucose monitoring to examine the frequency of low interstitial glucose values in individuals treated with BIAsp 30 or BHI 30 [12].
    Go to context

P.G. McNally, J.D. Dean, A.D. Morris, P.D. Wilkinson, G. Compion, S.R. Heller 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 Crossref. Diabetes Care. 2007;30:1044-1048 2007

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