An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: The A1chieve study
Diabetes Research and Clinical Practice, Issue 3, Volume 94, pages 352 - 363
Received 20 September 2011, Revised 10 October 2011, Accepted 13 October 2011, Published online Nov-2011
The overall results from the A1chieve non-interventional observational study find that beginning therapy with the insulin analogues detemir, aspart and biphasic aspart 30 under routine clinical practice was associated with marked improvements in average blood glucose levels (as measured by HbA1c), without evident tolerability or safety issues in the short term. Indeed, given that increase in hypoglycaemia was not a problem, and body weight was essentially unchanged, improvements in HbA1c of 22 mmol/mol (2.0%) or more are remarkable, and larger than would be expected from data from most RCTs , , , , , , and  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. Diabetic Med. 2008;25:916-923 x A. Philis-Tsimikas, G. Charpentier, P. Clauson, G.M. Ravn, V.L. Roberts, B. Thorsteinsson. 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;28:1569-1581 [Erratum in: Clin Ther 2006;28:1967] x K. Hermansen, M. Davies, T. Derezinski, G. Martinez Ravn, P. Clauson, P. Home. 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;29:1269-1274 [Erratum in: Diabetes Care 2007;30:1035] x A. Liebl, R. Prager, K. Binz, M. Kaiser, R. Bergenstal, B. Gallwitz. Comparison of insulin analog regimens in people with type 2 diabetes mellitus in the PREFER Study: a randomized controlled trial. Diabetes Obes Metab. 2009;11:45-52 x L. Meneghini, H. Mersebach, S. Kumar, A.L. Svendsen, K. Hermansen. A comparison of two intensification regimens with rapid-acting insulin aspart in type 2 diabetes inadequately controlled by once-daily insulin detemir and oral antidiabetes drugs: the STEP-Wise™ randomized study. Endocr Pract. 2011;6:1-26 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. Diabetic Med. 2002;19:393-399 x J.S. Christiansen, J.A. Vaz, Z. Metelko, M. Bogoev, I. Dedov. Twice daily biphasic insulin aspart improves postprandial glycaemic control more effectively than twice daily NPH insulin, with low risk of hypoglycaemia, in patients with type 2 diabetes. Diabetes Obes Metab. 2003;5:446-454 . Furthermore, these findings were reproduced in people from all the seven global regions studied, and were irrespective of the insulin regimen started, or indeed, for the most part, of whether the participants were insulin-treated at the time of starting the analogues or insulin-naïve. Although the reductions in HbA1c were large, the proportion of people then achieving a target level of <53 mmol/mol (<7.0%) was disappointing, reflecting the very poor blood glucose control at baseline, the short duration of follow-up and the limited titration of insulin doses over the 6 months of study.
That the HbA1c data are real is supported by the large and consistent reductions in FPG and PPPG control. Although people previously managed on lifestyle therapy alone or with OGLDs seemingly experienced greater improvements in glucose control than prior insulin users (Table 2), their baseline levels tended to be higher. This result is not unexpected, similar findings with regard to pre-study treatment regimen having been reported in the IMPROVE observational study of 52,419 people from 11 countries with T2D starting or switching to biphasic insulin aspart as part of routine clinical care  x P. Valensi, M. Benroubi, V. Borzi, J. Gumprecht, R. Kawamori, J. Shaban, et al. The IMPROVE study—a multinational, observational study in type 2 diabetes: baseline characteristics from eight national cohorts. Int J Clin Pract. 2008;62:1809-1819 . Also consistent with the glucose-lowering findings are the reductions in LDL cholesterol and triglycerides, but, surprisingly, SBP was also lower, which, together with the lack of body weight gain, suggests that factors other than insulin therapy itself are contributors to the improvements in metabolic status.
The most likely factor here is improvement in lifestyle and, in particular, in nutritional intake. Body weight gain in 6 months with an HbA1c improvement of around 22 mmol/mol (2.0%) or more would be expected to be around 4 kg  x H. Yki-Järvinen. Combination therapies with insulin in type 2 diabetes. Diabetes Care. 2001;24:758-767 , due to amelioration of urinary glycosuria and glucose concentration-driven glucose metabolism  x B. Ravikumar, P.E. Carey, J.E. Snaar, D.K. Deelchand, D.B. Cook, R.D. Neely, et al. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am J Physiol Endocrinol Metab. 2005;288:E789-E797 ; that this did not occur would suggest that participants and advising healthcare teams took advantage of the starting of insulin analogues to enhance self-care behaviours. This, in turn, is consistent with the improvement in blood pressure control and in the lipid profile, but the possibility remains that specific therapy changes (not recorded) could also have influenced the findings. Interestingly, the region with the numerically smallest fall in HbA1c (north Africa) was that with the numerically largest gain in weight, suggesting perhaps that, in this region, changes in self-management were less marked than elsewhere.
Overall, the large reduction in the HbA1c, FPG and PPPG levels following 24 weeks of use of these insulin analogues was associated with a low incidence of reported drug reactions (SADRs) and hypoglycaemia. While improvements in glycaemic control are usually associated with an increased risk of hypoglycaemia  x UK Prospective Diabetes Study (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 , the global cohort from this study reported a decrease in the rate of all hypoglycaemic episodes from 3.1 events/person-year at baseline to 1.6 events/person-year in the 4 weeks before the end of the study. The reduction in reported relative event rate was even more marked for major hypoglycaemic episodes. Although the percentage reduction in event rate appears high, in absolute terms it is low, consistent with other reports of hypoglycaemia in people with T2D , , and  x P. Valensi, M. Benroubi, V. Borzi, J. Gumprecht, R. Kawamori, J. Shaban, et al. The IMPROVE study—a multinational, observational study in type 2 diabetes: baseline characteristics from eight national cohorts. Int J Clin Pract. 2008;62:1809-1819 x A. Philis-Tsimikas, G. Charpentier, P. Clauson, G.M. Ravn, V.L. Roberts, B. Thorsteinsson. 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;28:1569-1581 [Erratum in: Clin Ther 2006;28:1967] x A.J. Martorella. Iatrogenic hypoglycemia in patients with type 2 diabetes: comparison of insulin analog premixes and human insulin premixes. Postgrad Med. 2011;123:7-16 . Explanations for these findings might again be better self-management behaviours, including more consistent eating patterns as a result of patient education given at the time of starting insulin analogues, although the possibility that investigator recording of hypoglycaemia events differed in some way at 24 weeks from that at baseline cannot be excluded.
Unsurprisingly, differences in hypoglycaemia rate for the study insulin regimens were, however, influenced by pre-study therapy type. Thus, prior insulin users reported a marked decrease in incidence of events in all therapy subgroups, with the greatest numerical reductions being in those transferring to insulin detemir. Insulin-naïve patients generally experienced a slight increase in the rate of overall hypoglycaemia, with the exception of the insulin aspart group. This is not consistent with reports from RCTs. Regional baseline rates of hypoglycaemia varied considerably, but all reported reductions in overall hypoglycaemia (Table 4). The greatest reductions in rate were evident from north Africa and Russia, explained by the baseline rates being highest.
Even though the large body of data generated by this study offers the opportunity to explore other important disease and therapy-related questions, there were limitations inherent in the study design. In particular, concomitant medication and dietary intake were not controlled, and the latter remains largely unmeasurable. The study was non-randomised and lacked a standardised treatment protocol and a control arm, with most safety and efficacy parameters based on participant recall, diverse diaries or self-reported information. The circumstances under which participants came under the care of the investigators are not known, and these could have been a trigger for starting modern insulin therapy while at the same time improving other aspects of diabetes care. Additionally, the findings could have been influenced by a study effect as, although entry was retrospective, further data collection was prospective following informed consent. Against that view, insulin dose titration after baseline was small.
Another limitation of the study is the heterogeneity of global healthcare systems involved, although this was part of the design, with the intention of trying to identify how cultural, resource and perhaps genetic influences might have different effects on the safety and efficacy profile of the different analogues. This proved not to be the case because, for the most part, the patterns of improvement in glucose control (including postprandial), blood lipid control and hypoglycaemia, and without weight gain, were consistent between regions.
In summary, in people whose HbA1c suggested diabetes management neglect, starting an insulin analogue, whether in a current insulin user or not, appears to provide a valuable opportunity for broad improvements in self-management and metabolic control, independently of the type of insulin begun. With both lipids and blood pressure improving, cardiovascular risk will clearly be usefully reduced. Furthermore, starting these insulins was not associated in these circumstances with any tolerability or safety problem, notably of hypoglycaemia or body weight. Further analysis of this large database will seek to define the factors predicting changes in metabolic profile, and to build guidelines for diabetes management in the individual.
References in context
|P. Valensi, M. Benroubi, V. Borzi, J. Gumprecht, R. Kawamori, J. Shaban, et al.||The IMPROVE study—a multinational, observational study in type 2 diabetes: baseline characteristics from eight national cohorts||Int J Clin Pract. 2008;62:1809-1819||2008|
References in context
|H. Yki-Järvinen||Combination therapies with insulin in type 2 diabetes||Diabetes Care. 2001;24:758-767||2001|
References in context
|B. Ravikumar, P.E. Carey, J.E. Snaar, D.K. Deelchand, D.B. Cook, R.D. Neely, et al.||Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes||Am J Physiol Endocrinol Metab. 2005;288:E789-E797||2005|
References in context
|UK Prospective Diabetes Study (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||1998|
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