Back to list

Insulin detemir in the management of type 2 diabetes in non-Western countries: Safety and effectiveness data from the A1chieve observational study

Alexey Zilov, Nabil El Naggar, Siddharth Shah, Chunduo Shen and Jihad Haddad

Diabetes Research and Clinical Practice, 3, 101, pages 317 - 325

Received 24 December 2012, Revised 16 May 2013, Accepted 6 June 2013, Published online Oct-2013


Article view:

5. Discussion

Clinically and statistically significant improvements in HbA1c, FPG, and PPG were observed in people with T2D either starting insulin therapy with or changing to insulin detemir as part of the A1chieve study. These improvements in glycaemic profile were reported consistently across all participating regions and irrespective of prior treatment regimen. The improvements in glycaemic control were accompanied by reduced rates of major hypoglycaemia, low rates of SADRs, improved patient perception of HRQoL, and the absence of clinically significant increase in body weight. Using Table 1 and Table 2, these findings can be directly compared against those from the entire A1chieve study population.

The majority of people starting insulin detemir were insulin-naïve at baseline and reported greater improvements in HbA1c (−2.1% [23 mmol/mol]) than participants changing insulin therapy (−1.6% [17 mmol/mol]), despite similar baseline values. This is consistent with data previously reported for insulin detemir from observational studies and RCTs of basal-only insulin replacement in insulin-naïve people with T2D. Comparable results were also seen with regards to the change in number of hypoglycaemic events and modest weight loss [12], [14], [15], [18], [20], [23], and [24] x J.L. Selam, C. Koenen, W. Weng, L. Meneghini. Improving glycemic control with insulin detemir using the 303 Algorithm in insulin naïve patients with type 2 diabetes: a subgroup analysis of the US PREDICTIVE 303 study. Curr Med Res Opin. 2008;24:11-20 x Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care 2006;29:1269-74. Erratum in: Diabetes Care 2007;30:1035. x Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-81. Erratum in: Clin Ther 2006;28:1967. x J. Rosenstock, M. Davies, P.D. Home, J. Larsen, C. Koenen, G. Schernthaner. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia. 2008;51:408-416 Crossref. x A. Dornhorst, H.J. Lüddeke, S. Sreenan, P. Kozlovski, J.B. Hansen, B.J. Looij, et al. PREDICTIVE Study Group. Insulin detemir improves glycaemic control without weight gain in insulinnaïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study. Int J Clin Pract. 2008;62:659-665 Crossref. x L. Meneghini, C. Koenen, W. Weng, J.L. Selam. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes – results of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab. 2007;9:902-913 Crossref. x L.F. Meneghini, A. Dornhorst, S. Sreenan. PREDICTIVE Study Group. Once-daily insulin detemir in a cohort of insulin-naïve patients with type 2 diabetes: a sub-analysis from the PREDICTIVE study. Curr Med Res Opi. 2009;25:1029-1035 Crossref. . Improvements in FPG and PPG were also greater in the insulin-naïve subgroup; however, mean baseline values were higher than those reported for insulin-experienced people.

In insulin-experienced people, mean HbA1c was reduced by 1.6% [17 mmol/mol], a similar change to data previously reported for patients switching to detemir [19] and [20] x L.F. Meneghini, K.H. Rosenberg, C. Koenen, M.J. Merilainen, H.J. Lüddeke. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418-427 Crossref. x A. Dornhorst, H.J. Lüddeke, S. Sreenan, P. Kozlovski, J.B. Hansen, B.J. Looij, et al. PREDICTIVE Study Group. Insulin detemir improves glycaemic control without weight gain in insulinnaïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study. Int J Clin Pract. 2008;62:659-665 Crossref. . This may be a result of the very poor level of glycaemic control at baseline, not only in this treatment cohort but for the entire A1chieve study population, for whom a reduction of 1.8% [19 mmol/mol] was reported [7] 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. . Significant improvements in all measures of glycaemic control were seen regardless of prior insulin regimen, human or analogue, which supports previous findings from a clinical practice [19] x L.F. Meneghini, K.H. Rosenberg, C. Koenen, M.J. Merilainen, H.J. Lüddeke. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418-427 Crossref. . The proportion of patients reaching HbA1c < 7.0% [53 mmol/mol] with insulin detemir ± OGLDs was ∼30%, irrespective of prestudy therapy; similar to that reported for the entire A1chieve study cohort (31.8%) [7] 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. and for basal insulin analogue therapy in RCTs [25] and [26] x R.R. Holman, S.K. Paul, M.A. Bethel, D.R. Matthews, H.A. Neil. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589 Crossref. x P. Raskin, E. Allen, P. Hollander, A. Lewin, R.A. Gabbay, P. Hu, et al. INITIATE Study Group. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260-265 Crossref. . Likewise, overall mean reductions in FPG and PPG reported at the end of the study (−3.9 ± 3.3 and −5.1 ± 4.3 mmol/L, respectively) are comparable to those seen for the entire A1chieve cohort (−3.8 ± 3.5 mmol/L; p < 0.001 and −5.4 ± 4.5 mmol/L; p < 0.001, respectively) [7] 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. , suggesting that statistically significant improvements in blood glucose control are universal with insulin analogue therapy, irrespective of prior insulin regimen.

Regionally, both the poor level of glycaemic control at baseline and the magnitude of improvement were remarkably consistent. The proportion of patients attaining HbA1c < 7.0% [<53 mmol/mol] varied considerably (Supplementary Table 1.1). China reported the lowest baseline HbA1c of 8.4 ± 1.7% [68 mmol/mol] but too few patients started a regimen with insulin detemir in the region (n = 137) to be considered in the regional comparison. This low number was due to the fact that insulin detemir was not available in China during patient recruitment, and only gained marketing approval towards the end of the study. This exclusion from the regional comparison is unfortunate as, in the entire A1chieve study population, patients in China reported the largest reduction in HbA1c (2.5% [28 mmol/mol]) [7] 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. and it would have been interesting to see if this trend was consistent in patients initiated on insulin detemir

Insulin-experienced people reported significant reductions in the rate of overall, major, minor, and nocturnal hypoglycaemic events, while insulin-naïve patients, not unexpectedly, reported a reduction in the rate of major events only. The incidences of overall, minor, and nocturnal hypoglycaemic events were highest in Latin America and Russia at baseline, yet, despite similar improvements in glycaemic control and a comparative daily insulin dose after 24 weeks of treatment with insulin detemir, reductions in the event rates and the percentage of people experiencing hypoglycaemic events was markedly different between the two regions. There are a number of non-drug hypoglycaemiaprecipitating factors that may influence this reported outcome, such as manual work, alcohol consumption, nutritional differences, patient age, and degree of insulin resistance. However, despite regional differences, a reduction in the incidence of hypoglycaemic events was observed, which, for such a heterogeneous population, may result from studyrelated improvement in self-management, although the observation is consistent with previous publications [7], [14], [15], [16], [17], [19], [20], and [23] 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. x Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care 2006;29:1269-74. Erratum in: Diabetes Care 2007;30:1035. x Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-81. Erratum in: Clin Ther 2006;28:1967. x L. Blonde, M. Merilainen, V. Karwe, P. Raskin. TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE study. Diabetes Obes Metab. 2009;11:623-631 Crossref. x C. Fajardo Montañana, C. Hernández Herrero, M. Rivas Fernández. Less weight gain and hypoglycaemia with once-daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients: the PREDICTIVE BMI clinical trial. Diabet Med. 2008;25:916-923 x L.F. Meneghini, K.H. Rosenberg, C. Koenen, M.J. Merilainen, H.J. Lüddeke. Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418-427 Crossref. x A. Dornhorst, H.J. Lüddeke, S. Sreenan, P. Kozlovski, J.B. Hansen, B.J. Looij, et al. PREDICTIVE Study Group. Insulin detemir improves glycaemic control without weight gain in insulinnaïve patients with type 2 diabetes: subgroup analysis from the PREDICTIVE study. Int J Clin Pract. 2008;62:659-665 Crossref. x L. Meneghini, C. Koenen, W. Weng, J.L. Selam. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in patients with type 2 diabetes – results of the randomized, controlled PREDICTIVE 303 study. Diabetes Obes Metab. 2007;9:902-913 Crossref. .

A modest reduction in body weight was observed in both pre-study therapy subgroups, in contrast to the weight gain that is usually associated with insulin initiation. This evidence supports previously published data associating insulin detemir with minimal weight change [14], [15], [17], [18], and [27] x Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care 2006;29:1269-74. Erratum in: Diabetes Care 2007;30:1035. x Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther 2006;28:1569-81. Erratum in: Clin Ther 2006;28:1967. x C. Fajardo Montañana, C. Hernández Herrero, M. Rivas Fernández. Less weight gain and hypoglycaemia with once-daily insulin detemir than NPH insulin in intensification of insulin therapy in overweight Type 2 diabetes patients: the PREDICTIVE BMI clinical trial. Diabet Med. 2008;25:916-923 x J. Rosenstock, M. Davies, P.D. Home, J. Larsen, C. Koenen, G. Schernthaner. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia. 2008;51:408-416 Crossref. x P. Hollander, J. Cooper, J. Bregnhøj, C.B. Pedersen. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther. 2008;30:1976-1987 Crossref. . Changes in weight reported by region were minimal, with greater significant reductions being observed where reductions in HbA1c were greater, rather than a higher baseline weight. As the majority of the people from all regions were insulin-naïve at baseline, weight change ranging between −1.1 and +0.5 kg is modest considering the geographical and lifestyle differences. Interestingly, in the entire A1chieve study population, although no clinically significant weight change was reported, a larger range was seen (−0.8 and +0.9 kg) [7] 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. . Changes in SBP and blood lipid profiles were also favourable for both the insulin-naïve and insulinexperienced subgroups, which reflects the results seen for the entire A1chieve study cohort [7] 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. .

The A1chieve study, by nature of its design, has a number of limitations that must be considered when interpreting the data [7] 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. . Results can be difficult to conclude due to the heterogeneity of the population and healthcare systems encompassed by the geographical reach of the study. The lack of a control group reduces certainty that results are attributable to the insulin treatment alone. The consulting physicians may have initiated confounding interventions at the same time as the decision to start treatment with the study insulin, and the level of education in diabetes management provided, especially for the 73% of patients included in this analysis who were previously insulin-naïve, may have influenced the outcomes for the duration of the study follow-up period. Additionally, the duration of the study was relatively short, thus the observed beneficial findings may, in part, be due to an ‘entry into study’ effect that may not be sustainable in the long term. A small percentage of people were switched from basal–bolus treatment to basal insulin, which may not have been the ideal course of treatment optimisation. Certain endpoints were dependant on patient recall diaries and records, which may subject the data to recall bias. Despite limitations that are inherent in any observational study design, observational studies can help to assess treatment effects in diverse patient groups in different clinical environments and broaden the clinical evidence base provided by RCTs.

References

Label Authors Title Source Year
[7]

References in context

  • Health-related quality of life (HRQoL) was measured using the EQ-5D questionnaire [22] at baseline and after 24 weeks of therapy.
    Go to context

  • The proportion of patients reaching HbA1c<7.0% [53 mmol/mol] with insulin detemir ± OGLDs was ∼30%, irrespective of prestudy therapy; similar to that reported for the entire A1chieve study cohort (31.8%) [7] and for basal insulin analogue therapy in RCTs [25,26].
    Go to context

  • The proportion of patients reaching HbA1c<7.0% [53 mmol/mol] with insulin detemir ± OGLDs was ∼30%, irrespective of prestudy therapy; similar to that reported for the entire A1chieve study cohort (31.8%) [7] and for basal insulin analogue therapy in RCTs [25,26].
    Go to context

  • The proportion of patients reaching HbA1c<7.0% [53 mmol/mol] with insulin detemir ± OGLDs was ∼30%, irrespective of prestudy therapy; similar to that reported for the entire A1chieve study cohort (31.8%) [7] and for basal insulin analogue therapy in RCTs [25,26].
    Go to context

  • Regionally, both the poor level of glycaemic control at baseline and the magnitude of improvement were remarkably consistent.
    Go to context

  • Interestingly, in the entire A1chieve study population, although no clinically significant weight change was reported, a larger range was seen (−0.8 and +0.9kg) [7].
    Go to context

  • Interestingly, in the entire A1chieve study population, although no clinically significant weight change was reported, a larger range was seen (−0.8 and +0.9kg) [7].
    Go to context

  • The A1chieve study, by nature of its design, has a number of limitations that must be considered when interpreting the data [7].
    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
[19]

References in context

  • Table entry: −1.8 (1.7) [19]
    Go to context

  • Significant improvements in all measures of glycaemic control were seen regardless of prior insulin regimen, human or analogue, which supports previous findings from a clinical practice [19].
    Go to context

L.F. Meneghini, K.H. Rosenberg, C. Koenen, M.J. Merilainen, H.J. Lüddeke Insulin detemir improves glycaemic control with less hypoglycaemia and no weight gain in patients with type 2 diabetes who were insulin naive or treated with NPH or insulin glargine: clinical practice experience from a German subgroup of the PREDICTIVE study Crossref. Diabetes Obes Metab. 2007;9:418-427 2007

Back to list