Original Article
Titration of basal insulin or immediate addition of rapid acting insulin in patients not at target using basal insulin supported oral antidiabetic treatment – A prospective observational study in 2202 patients

https://doi.org/10.1016/j.dsx.2016.08.006Get rights and content

Abstract

Aim

Optimal treatment intensification strategies in patients with type-2 diabetes mellitus (T2DM) receiving basal insulin supported oral antidiabetic therapy (BOT) remain controversial. The objective of the present study was to compare outcomes of BOT-intensification by either the uptitration of long-acting insulin glargine or by the immediate addition of a rapid acting insulin analogue (RAIA).

Methods

This was a prospective, observational, 24-week study in T2DM patients with BOT using insulin glargine and baseline glycated hemoglobin (HbA1c) between 7.0 and 8.5%. Patients were stratified by their physicians to one of the following treatment intensification strategies: Basal insulin titration to target with discretionary subsequent addition of RAIA at weeks 12 or 24 (GLAR), or immediate addition of RAIA at baseline (GLARplus).

Results

A total of 3266 patients were prescreened of whom 2202 fulfilled the selection criteria. Of these, 1684 patients were documented in the GLAR group and 518 in the GLARplus group. In the GLAR group, in 91 (5.5%) and 21 patients (1.3%) RAIA was added at weeks 12 and 24, respectively. The groups displayed similar baseline characteristics; except, mean diabetes duration was slightly shorter in the GLAR group (8.7 vs. 9.4 years). During the study, insulin glargine dose was increased from 18.7 to 26.4 U (plus 7.7 U) in GLAR and from 24.9 to 27.3 U (plus 2.4 U) in GLARplus patients. Mean RAIA dose was 9.6 ± 4.7 U at the final visit. After 24 weeks, HbA1c was reduced by 0.8 and 0.9% in the GLAR and GLARplus groups, respectively (both p < 0.001). An HbA1c of ≤7.0% was achieved in 49.2% of GLAR and 48.5% of GLARplus patients. In both groups, we observed improvements in cardiovascular risk factors such as lipids and blood pressure. The rates of symptomatic (1.6 vs. 1.7%) and severe (0.18 vs. 0.19%) hypoglycemic episodes were low and comparable in both groups.

Conclusion

These findings provide evidence that treatment intensification in patients with type 2 diabetes not at glycemic target on BOT with insulin glargine is equally safe and effective using either long-acting insulin titration alone or the addition of a rapid-acting insulin analogue.

Introduction

Effective glycemic control in patients with type 2 diabetes mellitus (T2DM) is necessary for preventing the onset and progression of microvascular complications [1], [2], [3], [4]. Therefore, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have recommended a glycated hemoglobin (HbA1c) target of around 7% with individualized treatment goals based on patient characteristics [5], [6]. The progressive nature of T2DM requires continuous treatment intensification to achieve and maintain the individualized HbA1c target. As an effective treatment intensification strategy, insulin glargine [7], [8], is frequently added when HbA1c goals are not met in patients exclusively using oral antidiabetic drugs [9], and several clinical trials have supported the efficacy of this basal insulin supported oral antidiabetic therapy (BOT) [10], [11], [12].

While basal insulin therapy can help to control fasting plasma glucose (FPG), elevations in postprandial blood glucose (PPG) also significantly contribute to the overall daily hyperglycemia of patients with T2DM. Therefore, treatment intensification strategies targeting PPG in addition to FPG may hold the potential of more effective control of glucose excursions. For the control of prandial glucose excursions, various rapid acting insulin analogs (RAIA) have been introduced (e.g., glulisine, lispro, and aspart) [8]. These insulin preparations were developed to overcome the slow and prolonged absorption associated with regular human insulin in order to mimic more closely the physiological postprandial insulin levels [13], [14], [15], [16]. Moreover, RAIA have demonstrated beneficial safety and efficacy profiles [17], [18], [19], [20]. While the use of these agents has been advocated as a potential add-on therapy for intensifying BOT in T2DM patients [21], [22], [23], there is little “real life” evidence for efficacy and safety of a BOTplus regimen. The value of this approach in comparison to uptitrated BOT remains to be fully elucidated in clinical practice.

In the present study, we have compared two simple therapeutic intensification strategies involving either long-acting insulin glargine titration (GLAR) or immediate additional use of a RAIA at baseline (GLARplus).

Section snippets

Study design and patients

This is an observational, prospective, multicenter study conducted over a 24 week period comparing two treatment intensification arms. Patients were enrolled at office-based general practitioners or internists across Germany. This study was conducted in accordance with the Declaration of Helsinki. It was approved by the local Ethical committee, and all patients provided written informed consent prior to study participation.

Patient population

Patient eligibility was based on the following criteria: Age between 18

Results

Overall 3266 patients were screened, of whom 2202 were eligible based on the selection criteria, and were recruited into the trial (Fig. 1). Of these, 1684 subjects were assigned to the GLAR group and 518 to the GLARplus group. In the GLAR group, 91 (5.4%) and 21 (1.2%) patients had added RAIA therapy after 12 and 24 weeks, respectively. In the GLARplus group, insulin-glulisine represented the most frequently prescribed RAIA (77.6%), followed by insulin lispro (13.7%), and insulin aspart

Discussion

The most safe and effective way of treatment intensification in T2DM patients on established BOT remains to be determined. Most importantly, evidence from daily clinical practice, as opposed to randomized, controlled trials to answer this clinically relevant question is scarce. For this reason, studies have begun to compare and analyze various intensification strategies based on real life outcomes [21], [22], [24], [25], [26], [27], [28], [29], [30]. In the present investigation, we have tested

Conclusions

Outside of randomized clinical trials, insulin glargine titration and/or addition of RAIA (BOTplus) therapies are safe and effective in intensifying insulin therapy in patients on established BOT. A more pronounced effect on HbA1c reduction may be achieved by BOTplus especially in more advanced patients with longer diabetes duration. These findings support the idea to initially use the less intensive strategy of insulin glargine uptitration before adding a RAIA in most of the patients as they

Conflicts of interest

Thorsten Siegmund, Martin Pfohl, Thomas Forst, Stefan Pscherer, Peter Bramlage and Jochen Seufert have received research funding and/or consultancy honoraria from Sanofi. Johannes Foersch and Anja Borck are employees of the sponsor of the trial.

Funding

The study was funded by Sanofi-Aventis Deutschland GmbH, Berlin, Germany.

Author contributions

All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work. TS, MP, TF, SP, PB, JF, AB, JS revised it critically for important intellectual content. All authors approved the final version for publication.

Acknowledgements

None.

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