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Safety and Effectiveness of Bolus Insulin Aspart in People with Type 2 Diabetes: A1chieve Sub-Analysis

Introduction This sub-analysis evaluated clinical safety and effectiveness of bolus insulin aspart [with/without oral glucose-lowering drugs (OGLDs)] as the only insulin therapy. Methods A1chieve was an international, multicenter, prospective, open-label, non-interventional, observational, 24-week study in people with type 2 diabetes mellitus starting/switching to biphasic insulin aspart 30, insulin detemir or insulin aspart treatment (alone/in combination) in routine clinical practice. This sub-analysis evaluated clinical safety and effectiveness of bolus insulin aspart (±OGLDs) as the only insulin therapy. Data were analyzed for all patients, insulin-experienced and insulin-naive sub-groups, and sub-groups defined by the number of OGLDs prescribed at baseline (no OGLDs, one OGLD or ≥two OGLDs). Safety and effectiveness endpoints were assessed at baseline and following 24 weeks’ therapy. Results In total, 2,026 patients were included (insulin-experienced, n = 561; insulin-naive, n = 1,465) in this sub-analysis. Significant improvements from baseline after 24 weeks’ treatment with insulin aspart ± OGLDs were observed across all sub-groups for: glycated hemoglobin (range of means across sub-groups −1.6 to −2.4%; p < 0.001 for all comparisons), fasting plasma glucose (−2.5 to −3.8 mmol/l; p < 0.001 for all comparisons), post-breakfast post-prandial glucose (−3.4 to −5.8 mmol/l; p < 0.001 for all comparisons), and health-related quality of life (HRQoL; p < 0.001 for all comparisons). The proportion of patients reporting hypoglycemia events was significantly reduced from baseline after 24 weeks (insulin-naive cohort: 7.9–2.8%; p < 0.001; insulin-experienced cohort: 23.2–7.8%; p < 0.001). There were no reports of major hypoglycemia events at 24 weeks; risk of nocturnal hypoglycemia was <0.6 events/person-year. No serious adverse drug reactions were reported. Conclusion Insulin aspart ± OGLDs is associated with significant improvements in glycemic control and HRQoL, without increased risk of hypoglycemia, in people with type 2 diabetes and sub-optimal glucose control.


INTRODUCTION
Increased life expectancy and high global prevalence of type 2 diabetes mellitus [1,2] render treatment of this condition a lifelong personal and social burden [3][4][5]. Post-prandial hyperglycemia is a common phenomenon in people with type 1 and 2 diabetes, and incurs a significant risk of diabetes-related complications [6]. Therefore, achieving control of post-prandial glucose (PPG) level and fasting plasma glucose (FPG) level is important to maintain glycated hemoglobin (HbA 1c ) levels below target [6]. Despite the need to control PPG, the number of available drugs able to accomplish this is limited. Conventional oral glucose-lowering drugs (OGLDs) and lifestyle modifications, while fundamental to early management of the disease, are unable to maintain good glycemic control in the longer term, and there is a consequent additional requirement for exogenous insulin [7,8].
Compared with exogenous human insulin, the rapid-acting analog insulin aspart (NovoRapid Ò ; Novo Nordisk A/S, Bagsvaerd, Denmark) is associated with rapid absorption and early onset of action, which facilitates administration immediately before or shortly after a meal [9]. Subcutaneous administration of rapid-acting insulin analogs results in a physiologic profile that bears a closer resemblance to endogenous insulin than is achieved with subcutaneous administration of human insulin. By virtue of this action, insulin analogs, such as insulin aspart, offer advantages over human insulin (e.g., greater convenience [10]) and have the potential to reduce PPG excursions, thereby improving overall glycemic control [11,12]. Clinical research shows that insulin aspart is also associated with reduced hypoglycemia risk and greater treatment satisfaction versus human insulin when administered in a basal-bolus regimen among people with type 1 and 2 diabetes mellitus [13][14][15][16][17][18]. Guidelines generally recommend initiating insulin therapy when OGLDs fail to provide adequate glycemic control [19]; in this context, some healthcare professionals start patients on prandial insulin as the only insulin therapy [20,21]. While few studies have examined the safety and effectiveness of bolus-only insulin aspart, particularly as add-on to OGLDs, available evidence suggests beneficial effects on glycemic control when OGLD therapy is insufficient [22].
While well-designed randomized controlled trials provide a stringent way of assessing   [20]. In every country, participants gave informed consent and were free to withdraw from the study at any time.

MATERIALS AND METHODS
The study was conducted in accordance with the Declaration of Helsinki of 1964, as revised in 2008 [23], and Guidelines for Good Pharmacoepidemiology Practice [24].
Results presented here are from a subanalysis of patients treated with insulin aspart alone or in combination with OGLDs (excluding those who received basal-bolus insulin regimens).

Assessments
Assessments were at baseline (time when the treating physician prescribed insulin aspart), approximately 12 weeks after baseline (results not reported here), and study end (approximately 24 weeks after baseline). weight, and health-related quality of life (HRQoL). HRQoL was measured at baseline and after 24 weeks by self-report using the EQ-5D questionnaire [25], which evaluates five domains of patient health/lifestyle (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). The questionnaire also includes a rating for an individual's current HRQoL on a visual analog scale [VAS; ranging from 0 (worst imaginable health) to 100 (best imaginable health)]. Scores in the five domains were converted to a single utility value (UK VAS set), with '1.00' indicating 'full health' and '0.00' indicating 'deceased' [26,27].
Due to the non-interventional design of the analysis and lack of protocol enforcement to report all outcomes, data are described here as per available reports.

Statistical Analyses
Analyses were performed on data from all patients with a baseline visit who were treated with insulin aspart at least once during the study. For those patients who withdrew from the study, data collected until the date of withdrawal were used for analysis. Patients were split into two cohorts according to whether they had received insulin before the study (insulin-experienced and insulin-naive) or not. Sub-group analyses were then conducted in each cohort according to the number of OGLDs received at baseline (none, one, or Ctwo). Changes

Study Participants
In total, 3,898 patients from the A 1 chieve study received treatment with insulin aspart alone or in combination with OGLDs at baseline (insulin aspart alone, n = 1,560; insulin aspart ? one OGLD, n = 1,514; and insulin aspart ? Ctwo OGLDs, n = 824) [20]. Of these, 1,872 patients subsequently switched to insulin analog basalbolus regimens, basal insulin analog regimens, or biphasic insulin analog regimens before completing the study. Thus, 2026 people who received insulin aspart alone or in combination with OGLDs at baseline and after 24 weeks (or last follow-up visit) were included in this analysis (Table 1).
Among treating physicians, the need to improve glycemic control (93.0%) represented the predominant reason for changing/switching to insulin aspart therapy followed by the need to reduce the risk of hypoglycemia (44.9%) and reduce variability of plasma glucose levels (27.8%). Among insulin-experienced patients (n = 561), previous insulin therapies included premix human insulin (42.1% of patients), human soluble insulin (20.7%), insulin glargine (15.9%), neutral protamine Hagedorn (NPH, 7.0%), NPH plus human soluble insulin (3.6%), and others such as premixed insulin lispro (10.9%). Baseline characteristics were generally similar between patient sub-groups, although insulin-experienced patients appeared to have had longer mean diabetes duration and longer time since OGLD initiation than insulinnaive patients (Table 1). In both insulinexperienced and insulin-naive patients, metformin was the most frequently prescribed OGLD pre-study (71% and 80% of patients, respectively), and sulfonylurea was the second most frequently prescribed (44% and 64% of patients, respectively).
When patients switched to insulin aspart ± OGLDs at baseline the dose ranged from 0.45 to 0.47 U/kg in the different subgroups ( Fig. 1). In the insulin-naive cohort, mean (SD) insulin aspart dose was 0.40 (0.20) U/kg at baseline (Fig. 1). Following 24 weeks' therapy with insulin aspart, there were no obvious changes from baseline in mean insulin dose in either cohort (Fig. 1).

Number of OGLDs
Most insulin-experienced and insulin-naive patients were receiving the same number of OGLDs at baseline and following 24 weeks of treatment with insulin aspart ( Table 2). Most

Hypoglycemia Events
The proportion of insulin-experienced and insulin-naive patients reporting at least one hypoglycemia event was significantly decreased from baseline following 24 weeks of treatment with insulin aspart in patients receiving bid or tid insulin injections ( Table 3). The proportion of patients reporting at least one hypoglycemia event did not significantly change between baseline and 24 weeks in patients receiving qd or four times daily (qid) insulin injections OGLDs at baseline, and insulin-naive patients taking no OGLDs at baseline (Table 4).
At 24 weeks, no major hypoglycemia events were reported in the insulin-experienced or insulin-naive cohorts and the risk of nocturnal hypoglycemia was reduced to \0.6 events/ person-year, irrespective of baseline insulin   Table 5). There were no obvious differences in these parameters between sub-groups (Table 5).

Body Weight
Body weight remained stable throughout the study for insulin-experienced patients, irrespective of the number of OGLDs received (Table 5). In the insulin-naive cohort, there was a significant mean weight gain (0.6 kg) from baseline at 24 weeks in patients receiving no OGLDs at baseline and a significant weight loss (-0.2 kg) in the sub-group receiving Ctwo OGLDs at baseline (Table 5).     Table 5).  [29]. These data suggest that a prandial insulin regimen is able to effectively control glucose levels over an extended time in many patients.

While weight increases have been reported
with the longer-term use of prandial insulin [22], weight remained stable from baseline to 24 [30].
The limitations of the A 1 chieve study design have been discussed previously [20] and include the following: the lack of randomization, the absence of a control arm, and the absence of control for concomitant medication, dietary or lifestyle changes. In addition, the reporting of hypoglycemia events was based on patient recall of events over the preceding 4 weeks; although unlikely to affect the recording of major hypoglycemia episodes, this may have resulted in underestimation of mild events. Another limitation was that dose titration to optimize glycemic control was not a stipulation of this observational study and, therefore, glycemic control could have been better than recorded. A further improvement in glycemic control with up titration of insulin dose would appear realistic given the low rate of hypoglycemia events. Statistical power may also be limited in this sub-analysis as it includes a small proportion of the total A 1 chieve cohort of patients. Despite these limitations, the results from this analysis are highly informative, given that they are derived from a large number of patients, and also from a wide geographical range, including many less developed world economies, whose standards of clinical practice with respect to type 2 diabetes mellitus are less well documented.
The A 1 chieve study demonstrated that some healthcare professionals prefer to start patients on insulin therapy with prandial rather than basal insulin [20], and add basal insulin when required. Our sub-analysis shows that this strategy can be effective and well tolerated for the management of type 2 diabetes mellitus in patients poorly controlled on other treatment regimens. These findings warrant further investigation in clinical trials, given recent calls for an individualized approach to initiation of insulin regimens in people with type 2 diabetes mellitus and sub-optimal glycemic control [31].

ACKNOWLEDGMENTS
The A 1 chieve study and this manuscript were funded by Novo Nordisk A/S (Bagsvaerd, Denmark). Editorial assistance on this manuscript was provided by Martin Gilmour and Daniella Otway at ESP Bioscience (Crowthorne, UK), funded by Novo Nordisk A/S. Jian-Wen Chen is the guarantor for this article, and takes responsibility for the integrity of the work as a whole.
Compliance with ethics guidelines. All participants gave informed consent and were free to withdraw from the study at any time.