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The effectiveness and safety of beginning insulin aspart together with basal insulin in people with type 2 diabetes in non-Western nations: Results from the A1chieve observational study

Philip D. Home, Zafar A. Latif, Guillermo González-Gálvez, Vinay Prusty and Zanariah Hussein

Diabetes Research and Clinical Practice, 3, 101, pages 326 - 332

Received 3 January 2013, Revised 15 May 2013, Accepted 6 June 2013, Published online Oct-2013


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5. Discussion

Globally, excluding the Western world, adding insulin aspart to a basal insulin or switching from a premix or a human insulin-based regimen to insulin aspart plus a basal insulin was associated with significant improvements across all aspects of glycaemic control, however measured, and to similar final levels in this analysis. The same is true of those with no previous insulin therapy starting insulin aspart plus a basal insulin. Indeed, the results achieved seem similar despite apparent differences in blood glucose control, so that the group starting higher (the insulin-naïve group) had the greatest falls, and those with marginally better but still poor control at baseline (the human insulin multiple injection regimen), the smallest. While the mean final levels achieved are not to conventional targets (e.g. HbA1c < 53 mmol/mol (<7.0%), this is after only 24 weeks, and compared with baseline levels is a clinically significant improvement of some magnitude. It seems reasonable to speculate that the conformity of the 24-week results simply reflects the broadly similar insulin regimens then being used, participant characteristics not being very different apart from the 4-year shorter duration of diabetes in the prior insulin-naïve group (Table 1).

As with the overall A1chieve study [10] and [11] x P. Home, N. El 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 x S. Shah, A. Zilov, R. Malek, P. Soewondo, O. Bech, L. Litwak. Improvements in quality of life associated with insulin analogue therapies in people with type 2 diabetes: results from the A1chieve observational study. Diabetes Res Clin Pract. 2011;94:364-370 , these results were attained without associated weight gain or increase in hypoglycaemia. Good tolerability of the regimen(s) is confirmed by the health-related quality of life data, where the final levels are consistent with other reports of people with type 2 diabetes in moderate blood glucose control [13] x P. Clarke, A. Gray, R. Holman. Estimating utility values for health states of type 2 diabetic patients using the EQ-5D (UKPDS 62). Med Decis Making. 2002;22:340-349 , with very useful improvements from baseline that presumably reflect participants’ poor metabolic control at that time and possibly an associated neglect of health care. The circumstances in which people entering A1chieve had come to the attention of the physicians who began the insulin therapy are not known, and while some of the poor control may represent clinical inertia in ambulatory care [14], [15], [16], [17], and [18] x J.B. Brown, G.A. Nichols, A. Perry. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27:1535-1540 x M.J. Calvert, R.J. McManus, N. Freemantle. Management of type 2 diabetes with multiple oral hypoglycaemic agents or insulin in primary care: retrospective cohort study. Br J Gen Pract. 2007;57:455-460 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 J. Gordon, R.D. Pockett, A.P. Tetlow, P. McEwan, P.D. Home. A comparison of intermediate and long-acting insulins in people with type 2 diabetes starting insulin: an observational database study. Int J Clin Pract. 2010;64:1609-1618 x K. Khunti, T. Damci, L. Meneghini, C.Y. Pan, J.F. Yale. on behalf of the SOLVE Study Group. Study of Once Daily Levemir (SOLVE™): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. Diabetes Obes Metab. 2012;14:654-661 , other parts may have been the stimulus for referral to a specialist, or an acute co-morbid disturbance resulting in hospitalisation.

Improvements in blood lipid profile are known to occur with improvements in blood glucose control secondary to insulin [19] x Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-86. , but changes of the order of magnitude seen here generally were from much poorer glucose control again. This, in addition to the improvement in SBP, together with the lack of weight gain and absence of increase in hypoglycaemia (except in the prior insulin-naïve population), suggests that insulin analogue therapy may in general have been part of a package of therapy offered by the physician and team. Part of that package could have included enhancement of other therapies, but baseline blood pressure was not high enough to prompt changes in anti-hypertensive therapy in a large part of our study population, suggesting that lifestyle advice and patient education had perhaps been delivered as well. Clearly, the message then would become the important one: that starting insulin analogue therapy can represent an opportunity for people in a state of neglected metabolic control to improve their overall vascular risk profile, though of course that might be true of other interventions too.

Diabetes duration of >10 years in the group consisting of prior insulin users is consistent with the need for a more complex insulin regimen, given the progressive nature of islet beta-cell dysfunction in type 2 diabetes [20] x R. Turner, C. Cull, R. Holman. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med. 1996;124:136-145 ; however, what is more unusual is the insulin-naïve sub-group treated with a prandial plus basal insulin regimen ahead of multiple OGLD therapy or a simpler insulin regimen. This might have occurred if the patient had an acute need at the time insulin was started (such as an in-patient), or if the extent of blood glucose deterioration was judged to be marked by the physician who saw the patient for the first time. Treatment guidelines do suggest that if a person with type 2 diabetes presents with HbA1c > 10.0% (86 mmol/mol), then insulin should be recommended early on, but our patient group was >7 years from diagnosis [3] x S.E. Inzucchi, R.M. Bergenstal, J.B. Buse, M. Diamant, E. Ferrannini, M. Nauck, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379 . Considering patients’ relatively low BMI and SBP levels it is possible that latent autoimmune diabetes of adulthood (LADA) was the case here, but given the number of participants that were recruited in a short period of time this seems unlikely to account for many. It is more likely that our population included a large numbers of Asians, for whom some greater degree of islet beta-cell function, and thus insulin deficiency, is believed to be significant in the pathogenesis of hyperglycaemia.

There are few RCTs in people with type 2 diabetes that compare the use of insulin aspart with human insulin, both combined with a basal insulin [21] and [22] x R.G. Bretzel, S. Arnolds, J. Medding, T. Linn. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care. 2004;27:1023-1027 x A. Gallagher, P.D. Home. The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes. Diabetes Res Clin Pract. 2005;67:196-203 . Treatment with insulin aspart ± NPH insulin in a 3-month RCT of 231 people with type 2 diabetes resulted in a mean (SD) HbA1c reduction of 0.91 (1.00) % compared with a 0.73 (0.87) % reduction in participants treated with human insulin ± NPH insulin (p = 0.025) [21] x R.G. Bretzel, S. Arnolds, J. Medding, T. Linn. A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care. 2004;27:1023-1027 . PPPG levels were also improved to a greater extent with insulin aspart compared with human insulin. Mean pre-meal-time doses were similar for the two insulins (10–13 U for insulin aspart and 10–14.5 IU for human insulin) and there was no statistical difference between the groups in hypoglycaemia. Improved PPPG control with insulin aspart vs. human insulin both with NPH insulin was also seen in a 12-week crossover study of 21 people with type 2 diabetes [22] x A. Gallagher, P.D. Home. The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes. Diabetes Res Clin Pract. 2005;67:196-203 , although there was no difference in HbA1c between the two insulins. The 4-T Study – a 3-year RCT in 708 insulin-naïve people with type 2 diabetes – did investigate the addition of insulin aspart to insulin detemir: mean HbA1c after 3 years was 6.9% (mean reduction of 1.2% from baseline), with a median rate of hypoglycaemia of 1.7 events/patient/year [9] x R.R. Holman, A.J. Farmer, M.J. Davies, J.C. Levy, J.L. Darbyshire, J.F. Keenan, et al. 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl J Med. 2009;361:1736-1747 . To our knowledge, this sub-group analysis is the only available data examining beginning insulin aspart with a basal insulin in routine clinical practice.

The large amount of data generated by the A1chieve study has enabled the investigation of therapy and prior regimen in our sub-groups, but there are limitations to consider when interpreting these findings. Because the study was not randomised, concomitant medications, patient education and dietary behaviours may all have changed in concert with use of the new insulin; indeed (see above), it seems likely that this occurred. There may also have been a study effect, even though the data were collected in routine clinical practice without pre-defined visits or protocol driven care. Confounding could have occurred through regional differences skewing the results, and limiting overall generalizability of the findings; however, given the extent of the changes and indeed the very limited changes for body weight and hypoglycaemia, it does not seem likely that changes in one or two global continents could account for the changes in the whole population reported here. Unfortunately, even with the number of participants in A1chieve, once selection is performed for insulin then broken down into four subgroups, as here, further segmentation by global region or country results in numbers too small to be analytically reliable, and so was not attempted.

In conclusion, this study provides further support for the use of basal plus prandial insulin regimens in people with type 2 diabetes with inadequate glycaemic control, at least in the context of provision of other aspects of diabetes care.

 
x

Table 1 Participant characteristics according to pre-study insulin therapy.

Insulin-naïve Insulin-experienced
Basal insulin Premix insulin NPH plus meal-time human insulin
n 1594 519 947 586
Male/female(%) 59.7/40.3 52.2/47.8 52.3/47.7 44.5/55.5
Age (years) 53.1 (12.7) 54.1 (12.2) 52.7 (14.5) 53.7 (12.7)
Body weight(kg) 74.1 (16.8) 78.9 (17.8) 78.6 (17.3) 81.3 (18.2)
BMI (kg/m2) 26.9 (5.4) 28.8 (6.7) 28.9 (6.1) 29.6 (6.0)
Duration of diabetes (years) 7.1 (6.1) 10.9 (6.3) 11.7 (7.1) 11.7 (6.9)
HbA1c (%/mmol/mol) 10.1 (2.1)/87 (23) 9.7 (1.7)/83 (19) 9.4 (1.7)/79 (19) 9.4 (1.6)/79 (17)

References in context

  • Participant characteristics are provided in Table 1.
    Go to context

  • It seems reasonable to speculate that the conformity of the 24-week results simply reflects the broadly similar insulin regimens then being used, participant characteristics not being very different apart from the 4-year shorter duration of diabetes in the prior insulin-naïve group (Table 1).
    Go to context

Values are mean (SD) unless otherwise noted.

BMI, body mass index.

References

Label Authors Title Source Year
[3]

References in context

  • Type 2 diabetes is a progressive disease and insulin therapy is needed in most people to ensure continuing adequacy of blood glucose control [1].
    Go to context

  • Treatment guidelines do suggest that if a person with type 2 diabetes presents with HbA1c>10.0% (86 mmol/mol), then insulin should be recommended early on, but our patient group was >7 years from diagnosis [3].
    Go to context

S.E. Inzucchi, R.M. Bergenstal, J.B. Buse, M. Diamant, E. Ferrannini, M. Nauck, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care. 2012;35:1364-1379 2012
[9]

References in context

  • The 4-T Study – a 3-year RCT in 708 insulin-naïve people with type 2 diabetes – did investigate the addition of insulin aspart to insulin detemir: mean HbA1c after 3 years was 6.9% (mean reduction of 1.2% from baseline), with a median rate of hypoglycaemia of 1.7 events/patient/year [9].
    Go to context

R.R. Holman, A.J. Farmer, M.J. Davies, J.C. Levy, J.L. Darbyshire, J.F. Keenan, et al. 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes N Engl J Med. 2009;361:1736-1747 2009
[13]

References in context

  • Good tolerability of the regimen(s) is confirmed by the health-related quality of life data, where the final levels are consistent with other reports of people with type 2 diabetes in moderate blood glucose control [13], with very useful improvements from baseline that presumably reflect participants’ poor metabolic control at that time and possibly an associated neglect of health care.
    Go to context

P. Clarke, A. Gray, R. Holman Estimating utility values for health states of type 2 diabetic patients using the EQ-5D (UKPDS 62) Med Decis Making. 2002;22:340-349 2002
[19]

References in context

  • Improvements in blood lipid profile are known to occur with improvements in blood glucose control secondary to insulin [19], but changes of the order of magnitude seen here generally were from much poorer glucose control again.
    Go to context

Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977-86.
[20]

References in context

  • Diabetes duration of >10 years in the group consisting of prior insulin users is consistent with the need for a more complex insulin regimen, given the progressive nature of islet beta-cell dysfunction in type 2 diabetes [20]; however, what is more unusual is the insulin-naïve sub-group treated with a prandial plus basal insulin regimen ahead of multiple OGLD therapy or a simpler insulin regimen.
    Go to context

R. Turner, C. Cull, R. Holman United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus Ann Intern Med. 1996;124:136-145 1996
[21]

References in context

  • Treatment with insulin aspart ± NPH insulin in a 3-month RCT of 231 people with type 2 diabetes resulted in a mean (SD) HbA1c reduction of 0.91 (1.00) % compared with a 0.73 (0.87) % reduction in participants treated with human insulin ± NPH insulin (p=0.025) [21].
    Go to context

R.G. Bretzel, S. Arnolds, J. Medding, T. Linn A direct efficacy and safety comparison of insulin aspart, human soluble insulin, and human premix insulin (70/30) in patients with type 2 diabetes Diabetes Care. 2004;27:1023-1027 2004
[22]

References in context

  • As a result, in regressing to the same level, improvements were greatest in the insulin-naïve group (mean HbA1c [SD] change from baseline −2.8 [2.0] % (31 [22] mmol/mol); p<0.001) and smallest in the human multiple injection group (−1.8 [1.6] % (20 [17] mmol/mol); p<0.001).
    Go to context

  • Improved PPPG control with insulin aspart vs. human insulin both with NPH insulin was also seen in a 12-week crossover study of 21 people with type 2 diabetes [22], although there was no difference in HbA1c between the two insulins.
    Go to context

A. Gallagher, P.D. Home The effect of improved post-prandial blood glucose control on post-prandial metabolism and markers of vascular risk in people with Type 2 diabetes Diabetes Res Clin Pract. 2005;67:196-203 2005

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