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An observational non-interventional study of people with diabetes beginning or changed to insulin analogue therapy in non-Western countries: The A₁chieve study

Philip Home ^a , Nabil El Naggar ^b, Mohammed Khamseh ^c, Guillermo Gonzalez-Galvez ^d, Chunduo Shen ^e, Praful Chakkarwar ^e, Wenying Yang ^f.

Received 20 September 2011, Revised 10 October 2011, Accepted 13 October 2011, Published online 01 December 2011

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Abstract

Aim

The aim of A₁chieve was to remedy the deficit of data on the efficacy and safety of insulin analogues in routine clinical care in less well-resourced/newly developed countries.

Methods

A non-interventional, 6-month, observational study of 66,726 people with type 2 diabetes, both insulin users and non-insulin users, started on insulin detemir, insulin aspart or biphasic insulin aspart in 28 countries across four continents.

Results

Baseline HbA_1c (±SD) was poor: 9.5 ± 1.8%. At 6 months, improvement was −2.1 ± 1.7% in the entire cohort, and −2.2 ± 1.7% and −1.8 ± 1.7% for prior non-insulin users and insulin users. All three analogue therapies gave similar results, again independently of prior insulin use, but also from seven pre-specified country groupings. Overall, hypoglycaemia did not increase in those new to insulin, and fell in those switching insulins. There was no change in body weight (−0.1 ± 3.7 kg), while lipid profile and systolic blood pressure (−6.3 ± 17.1 mmHg) were improved.

Conclusions

Beginning insulin analogue therapy in people with type 2 diabetes and poor blood glucose control is associated with marked improvements in diverse aspects of vascular risk factor profile without evidence of clinically significant safety or tolerability problems.

Keywords: Observational study, Type 2 diabetes, Insulin analogues, Efficacy, Hypoglycaemia.

1. sec0005 Introduction

The progressive nature of type 2 diabetes (T2D) over time results in the majority of people with diabetes being unable to maintain HbA_1c targets on a management regimen of lifestyle changes with oral glucose-lowering drugs (OGLDs) [1] and [2]. Furthermore, suboptimal glycaemic control commonly persists even in insulin users [3]. What is sometimes described as “clinical inertia” or “patient resistance” further results in people remaining on inappropriate therapy regimens for too long [4], [5], and [6]. It is known that when therapies are actively assessed, titrated and increased in number, glycaemic targets are more likely to be achieved [7]. Accordingly, the American Diabetes Association (ADA) and International Diabetes Federation (IDF) guidelines emphasise the importance of continually modifying therapy regimens when HbA_1c goals are no longer maintained. In practice, however, most people with T2D still experience significant periods when their HbA_1c levels are well above 53–64 mmol/mol (7.0–8.0%), increasing their risk of developing diabetes-related health complications [8], [9], and [10].

Modern insulin analogues were designed to aid achievement of better glycaemic control while addressing concerns over tolerability, notably in regard of hypoglycaemia and body weight gain [11] and [12], and their clinical benefits have been assessed in randomised controlled trials (RCTs) and observational studies [6], [13], [14], [15], [16], [17], [18], and [19]. These studies have shown that a change of therapy from OGLDs or conventional insulin preparations to insulin analogues can be associated with clinically significant improvements in efficacy measures, while being well tolerated.

Well-designed RCTs are a rigorous way of assessing treatments in a restricted population sample. However, they focus on a selected patient group under intensive clinical supervision, and may not represent the reality of the people in everyday life, or when seen in normal clinical practice. Furthermore, these studies are often performed in restricted geographical areas, such that information from less well-resourced countries is relatively sparse. While there are limitations with observational studies with regard to potential bias, study effects and lack of a control group, they can have less stringent inclusion and exclusion criteria, and, being much less costly, can address larger numbers of people in more diverse environments [20], [21], and [22].

The aim of the A₁chieve study was, therefore, to broaden the knowledge of the clinical safety and effectiveness of insulin analogues in a large and diverse population from a globally broad variety of clinical care. As the largest observational study ever conducted in insulin therapy, A₁chieve has explored both beginning insulin in non-insulin users and switching to these analogues in more than 65,000 people from 28 different countries across four continents. Part of the intention behind the study was to explore how the insulins performed in countries in which resource, practice and genetic differences might be expected (or not) to influence outcomes.

2. sec0010 Methods

3. sec0035 Results

4. sec0110 Discussion

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 HbA_1c), 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 HbA_1c of 22 mmol/mol (2.0%) or more are remarkable, and larger than would be expected from data from most RCTs [13], [14], [15], [16], [17], [24], and [25]. 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 HbA_1c 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 HbA_1c 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 [6]. 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 HbA_1c improvement of around 22 mmol/mol (2.0%) or more would be expected to be around 4 kg [26], due to amelioration of urinary glycosuria and glucose concentration-driven glucose metabolism [27]; 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 HbA_1c (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 HbA_1c, 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 [28], 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 [6], [14], and [29]. 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 HbA_1c 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.

sec0115 Conflict of interest

Philip Home or institutions with which he is associated receive funding from Novo Nordisk and other insulin manufacturers for his research, advisory and educational activities. Mohammed Khamseh is a speaker for Novo Nordisk. Guillermo Gonzalez-Galvez is a board member and speaker for Novo Nordisk. Praful Chakkarwar and Chunduo Shen are employed by Novo Nordisk. This study was sponsored by Novo Nordisk A/S Denmark. The sponsor took part in the development of the protocol, the process of data collection and analysis, funding of medical writing services, and in reviewing the manuscript, but not in participant selection, choice of therapies (study or otherwise), provision of therapies including insulin, or continuing clinical management of the participants.

Acknowledgements

The authors would like to thank all participants who provided data, and all investigators involved in the A₁chieve study. The authors would also like to thank Helen Coulson of Watermeadow Medical for writing assistance, funded by Novo Nordisk.

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Footnotes

^a Institute of Cellular Medicine – Diabetes, Newcastle University, Newcastle upon Tyne, UK

^b Internal Medicine, Hai Aljamea Hospital, Jeddah, Saudi Arabia

^c Endocrine Research Center (Firouzgar), Institute of Endocrinology & Metabolism, Tehran University of Medical Sciences, Tehran, Iran

^d Instituto Jalisciense de Investigacion en Diabetes y Obesidad, Guadalajara, Mexico

^e Novo Nordisk International Operations A/S, Zürich, Switzerland

^f China-Japan Friendship Hospital, Beijing, China

Corresponding author at: Institute of Cellular Medicine – Diabetes, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. Tel.: +44 191 222 7154; fax: +44 191 222 0723.

This study was funded by Novo Nordisk.

Clinical trial registration: Clinicaltrials.gov, NCT00869908.

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