Lessons in initiating insulin in clinical practice

diabetes research and clinical practice 81s (2008) s16–s22

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Review

Lessons in initiating insulin in clinical practice Surendra K. Sharma a,*, Jing Ping Yeo b, Alan Garber c a

MG Medical College, Jaipur, India Novo Nordisk, International Operations Clinical Centre, Singapore c Baylor College of Medicine, Houston, TX, USA b

article info

abstract

Keywords:

Insulin therapy in type 2 diabetes (T2DM) can produce greater improvements in fasting

Insulin initiation

plasma glucose (FPG) and glycated haemoglobin (HbA1c) than oral antidiabetic drugs

Insulin analogue

(OADs). There is a growing trend to recommend initiation of insulin in T2DM patients

BIAsp 30

sooner in the course of the disease, and good results have been achieved in insulin-naı¨ve patients during randomised, controlled trials, often using aggressive dose titration algo-

Observational study

rithms. The Physicians’ Routine Evaluation of Safety & Efficacy NovoMix1 30 Therapy (PRESENT) study was a 6-month observational study of the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) as monotherapy or in combination with OADs in inadequately controlled patients with T2DM. This review article compares results from those patients who entered the study insulin-naı¨ve (either with or without previous OAD treatment), with results from randomised, controlled trials of BIAsp 30 in insulin-naı¨ve T2DM patients. It aims to provide guidance on the initiation of insulin in patients with T2DM, focusing on the efficacy of BIAsp 30 when used for this purpose, and highlighting both the low risk of hypoglycaemia associated with therapy, and the availability of delivery devices that can minimise injection site discomfort and help to overcome psychological insulin resistance. # 2008 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Failing targets and global recommendations . . . . . . . . . . . . . . . The PRESENT study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lesson 1: initiate insulin sooner . . . . . . . . . . . . . . . . . . . . . . . . . Lesson 2: the use of modern insulins—titration algorithms and Lesson 3: whose responsibility? . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Corresponding author at: Diabetes Thyroid & Endocrine Center, 11 Shivaji Nagar, Civil Lines, Jaipur 302006, India. Tel.: +91 98290 10233; fax: +91 141 2221598. E-mail address: [email protected] (S.K. Sharma). 0168-8227/$ – see front matter # 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.diabres.2008.06.009

diabetes research and clinical practice 81s (2008) s16–s22

1.

Introduction

Type 2 diabetes mellitus (T2DM) is a progressive disease associated with microvascular and macrovascular complications that stem from chronic uncontrolled hyperglycaemia [1,2]. The combination of insulin insensitivity and hyperglycaemia, as found in T2DM patients, results in a compensatory up-regulation in insulin secretion from beta-cells, which leads gradually to their exhaustion, with associated defects in glucose and lipid metabolism [3–5]. It has been proposed that T2DM proceeds via a mechanism in which cells are ‘scarred’ early in the disease’s history, creating a foundation on which microvascular and macrovascular complications can emerge in the future [6]. This ‘molecular memory’ phenomenon has been studied in animals, where it has been found that damage to vascular structures in the retinas of rats, resulting from a period of hyperglycaemia, is not reversed after good control is re-established [7]. The metabolic memory thesis provides some basis for an explanation of the positive effect of early insulinisation. Reports also suggest that early initiation of insulin can improve endogenous insulin secretion and metabolic control [8], and minimise the development of complications over time [9,10]. Indeed, a short, intensive course of insulin has led to a remission-like state in some patients. For example, 44% of patients with T2DM treated with a 2–3-week course of intensive insulin therapy maintained euglycaemia with diet therapy alone 1 year post-intervention [11]. There appears to be no glycaemic threshold for the reduction of the risk of either microvascular or macrovascular complications: the lower the HbA1c, the lower the risk [12]. Until recently, the predominant focus of therapy has been on lowering HbA1c levels, with a strong emphasis on fasting plasma glucose (FPG) [13]. However, the relative contribution of fasting and postprandial blood glucose to HbA1c, and the risks associated with each, have been much studied and debated. A recent study in 290 patients with T2DM assessed the relative contribution of fasting and postprandial glucose to overall diurnal hyperglycaemia. It found that in poorly controlled patients (>10.2% HbA1c), postprandial glucose accounted for only 30% of the hyperglycaemia, but this proportion increased rapidly with decreasing HbA1c. Thus, in patients with HbA1c <7.2%, postprandial glucose accounted for 70% of the hyperglycaemia, with FPG contributing only 30% [14]. Epidemiological studies have shown a strong association between postprandial glycaemia (PPG) and cardiovascular risk and outcomes [15,16]. Even the loss of PPG regulation precedes deterioration of FPG regulation as diabetes progresses [17], and the International Federation of Diabetes (IDF) 2007 PPG guidelines state that postmeal hyperglycaemia is harmful and should be addressed [18]. Thus it is important to take care of both FPG and PPG levels at any HbA1c level, and this can best be achieved with a premix insulin, which provides both mealrelated and basal insulin. The premix insulin biphasic insulin aspart (BIAsp) 30 is made up of 30% rapid-acting soluble insulin aspart and 70% protaminated insulin aspart, which has a prolonged duration of action [19]. The efficacy and safety of BIAsp 30, either as monotherapy or in combination therapy with oral antidiabetic drugs (OADs), has been well established by various clinical trials, but to confirm its efficacy and safety

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in real-life clinical practice, a large-scale, multi-national, observational study was required. The aim of this article is to use data from the Physicians’ Routine Evaluation of Safety and Efficacy of NovoMix1 30 TherapyTM (PRESENT) study to provide guidance on initiation of insulin in insulin-naı¨ve patients with T2DM in routine clinical practice.

2. Failing targets and global recommendations The benefits of achieving good glycaemic control in T2DM are well established. In view of this, medical advisory bodies have set targets for glycaemic control of HbA1c <7% (American Diabetes Association; ADA/European Association for the Study of Diabetes; EASD) or HbA1c 6.5% (American Association of Clinical Endocrinologists; AACE; American College of Endocrinology; ACE). While it is difficult to assess the level of glycaemic control in a ‘real-life’ clinical setting (compared with levels seen upon entry into a clinical trial), a number of reports have concluded that, in general, these stringent targets are not being met. In the USA, for example, the National Health and Nutrition Examination Survey (NHANES) study showed that 42.3% of adults with diabetes have HbA1c >7% and 14% have HbA1c >14% [20]. Furthermore, according to figures from the UK and Germany, 76% of T2DM patients receiving insulin have HbA1c >7.0, 32% 9.0 and 18% 10.0 [21]. Numerous reasons have been cited for this failure, among them clinical inertia in the intensification of anti-diabetic therapy, exacerbated by infrequent blood glucose and HbA1c monitoring [22]. Among both patients and care providers there is also a documented resistance to insulin therapy, which arises as a result of factors including fear of hypoglycaemia, anticipation of weight gain, inconvenience of pre-meal dosing, and an unwillingness to self-inject. Starting insulin may also be perceived by some patients as being a result of their failure to control their diabetes [23–25]. Apart from acting to dissuade patients from initiating insulin, this ‘psychological insulin resistance’ (PIR) can lead to poor adherence in those who have successfully begun treatment, resulting in an increased risk of complications [25]. Thus, good counselling is needed before patients are initiated on insulin therapy; while either basal bolus therapy with multiple daily injections or continuous subcutaneous insulin infusion with an insulin pump provide the most physiological approach to insulin replacement therapy, regimen simplicity and convenience must be balanced against metabolic control. In 2007, AACE updated its treatment guidelines to stress the importance of timely pharmacological intervention, and recommended that patients naı¨ve to therapy with an HbA1c >10% should begin with either premixed insulin or basal– bolus therapy, rather than initiating multiple OADs. Basal– bolus therapy, or premixed insulin, is also recommended for patients receiving treatment but with an HbA1c >8.5% [26].

3.

The PRESENT study

PRESENT was a 6-month, prospective, observational study involving 21,977 patients (analysis population) from 13

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diabetes research and clinical practice 81s (2008) s16–s22

countries (India, Iraq, Jordan, Kuwait, Lebanon, Qatar, Romania, Russia, Saudi Arabia, South Africa, South Korea, Turkey and UAE). The aim of the PRESENT study was to assess the safety and efficacy of BIAsp 30 in routine clinical practice in a multi-national and multi-ethnic population with T2DM and poor glycaemic control. Patients previously treated with OAD only (n = 8583), insulin only (n = 5942), OAD + insulin (n = 4673) or diet (i.e. drug-naı¨ve) (n = 1707), were transferred to BIAsp 30 with or without OADs [27]. Results from the study provide useful guidance for primary care practitioners regarding initiating insulin in clinical practice, and that guidance has been presented here, in the form of three lessons.

4.

Lesson 1: initiate insulin sooner

Various non-insulin anti-diabetic drugs (thiazolidinones [TZDs]; incretin-based drugs; alpha-glucosidase inhibitors; non-sulphonylurea [SU] insulin secretagogues; pramlintide) have entered the market in the last decade. In some cases, these drugs have advantages that include oral administration, low rates of hypoglycaemia, and no association with significant weight gain, which effectively lowers barriers to compliance. They are included in the guidelines for treatment developed by medical bodies, and could in theory be employed by physicians as alternatives to the earlier use of insulin [26]. With this in mind it is important to note, as described in the 2007 update to the AACE/ACE guidelines, that these OADs have a limited capacity to reduce HbA1c, and, as they rely on endogenous insulin to function, are less effective for patients with HbA1c 9.5%. A meta-analysis of 42 trials (>8000 patients) of TZDs found a significant negative correlation between baseline HbA1c and change in HbA1c (P = 0.004) [28], a trend that suggests these drugs become less effective as endogenous insulin secretion declines [4,5]. Although glycaemic control is improved following the addition of SUs to metformin, deterioration of HbA1c resumes as soon as 6 months after SU initiation [29]. Approximately 53% of patients randomised to an SU treatment arm required insulin therapy over the 6-year study period [30]. A recent review of trials of glitazones as third-line oral agents concluded that, while they are suitable in this role when added to an SU plus metformin, and have a comparable effect to insulin for HbA1c <9.5%, insulin is more effective in patients with HbA1c 9.5% [31]. In comparison to these OADs, insulin can produce greater improvements in FPG, PPG and HbA1c. Theoretically it can bring any patient to glycaemic goal, although in practice efficacy is limited by frequency of hypoglycaemic episodes and patient compliance. Typically, the options available when initiating insulin are: basal insulin injected at bedtime, with the dose titrated according to FPG measurements; or a once- or twice-daily regimen of premixed insulin that targets both PPG and FPG in one injection. These approaches were compared in the INITIATETM (INITiation of insulin to reach A1c TargEt) trial [32], in which insulin-naı¨ve patients with T2DM and prior OAD treatment were randomised to twice-daily BIAsp 30 plus OADs, or insulin glargine at bedtime. After 28 weeks, mean HbA1c in the BIAsp 30 group (baseline 9.7%) was reduced by

Fig. 1 – Daily insulin dose at baseline and end-of-trial (EOT) in the PRESENT (insulin and oral antidiabetic drug-only patients) and INITIATE (biphasic insulin aspart 30 arm) studies.

2.8%, and in the glargine group (baseline 9.8%) by 2.4%. The proportion of patients achieving target HbA1c of <7% was 66 and 40% for BIAsp 30 and glargine, respectively. Daily insulin doses were 0.82  0.40 U/kg for BIAsp 30 (Fig. 1), and 0.55  0.27 U/kg for glargine at end of trial [32]. A further option is to initiate insulin as a basal–bolus regimen, which is intended to provide a more physiological plasma insulin profile. This approach is recommended by the AACE, alongside premixed insulin analogues, for patients with HbA1c >10% [26]. In the 26-week PREFER study, comparing a basal–bolus regimen of insulin detemir and insulin aspart with twice daily BIAsp 30, the authors concluded that patients already receiving basal insulin may achieve somewhat better control with basal–bolus therapy, whereas insulin-naı¨ve individuals may prefer BIAsp 30, as it proved equally effective in this group [33]. A full basal–bolus regimen is not necessary in all patients, and the convenience of a once- or twice-daily regimen is often desirable. Results from the PRESENT study suggest that earlier use of insulin in insulin-naı¨ve patients in everyday clinical practice results in similarly improved outcomes. For the purposes of this review, we investigated patients who participated in the PRESENT study and who were prescribed insulin for the first time at the beginning of the trial, either alone, or in combination with OADs (Table 1). In these patients, HbA1c decreased by 2.2% after 6 months, from a baseline of 9.8% (Fig. 2), and about one in four patients reached target HbA1c <7.0% after 6 months of treatment (Fig. 3). The daily insulin dose for these patients was 0.50 U/kg (Fig. 1). The improvement in glycaemic control was, therefore, greater under the controlled conditions of the INITIATE study than in the PRESENT study, which suggests that a more aggressive titration regimen of BIAsp 30 could result in better glycaemic control. The proportion of patients achieving the aggressive HbA1c target of 6.5% was similarly higher in the INITIATE study than the PRESENT study, but the difference was smaller with the <7.0% target. BIAsp 30 dosages were significantly lower in the PRESENT patients than the INITIATE patients, which is to be expected in

diabetes research and clinical practice 81s (2008) s16–s22

Table 1 – Baseline characteristics for insulin-naı¨ve patients entering the PRESENT study (all countries excluding Sri Lanka and China) N (safety population)

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in patients diagnosed with T2DM less than 5 years previously will benefit them in terms of improved quality of life and reduced complications [27].

8583

Diabetes duration (years) Mean (S.D.) Median Min–max

8.94 (6.06) 8.00 0.50–47.00

Baseline HbA1c (%) Mean (S.D.) Median Min–max

9.77 (1.85) 9.40 2.50–19.90

a randomised, controlled trial, with a strict dose intensification algorithm (Table 2). During the PRESENT study, we observed the positive effect of introducing insulin therapy within 5 years of the diagnosis of T2DM, with twice-daily BIAsp 30 in insulin-naı¨ve patients with HbA1c 7%. Thus it was assumed that initiating insulin

Fig. 2 – Changes in HbA1c between baseline and end-oftrial (EOT) during the PRESENT study, compared with changes in HbA1c in the biphasic insulin aspart 30 arm of the INITIATE study.

Fig. 3 – Proportion of patients in the PRESENT and INITIATE studies (biphasic insulin aspart 30 arm) achieving HbA1c =6.5% and <7.0% at end of trial.

5. Lesson 2: the use of modern insulins— titration algorithms and delivery devices Insulin analogues or modern insulins more closely simulate the endogenous release of insulin seen in healthy individuals than exogenous human insulin, and reduce long-term complications [34]. Premixed insulin analogues, consisting of both rapid- and intermediate-acting insulin analogue components, meet the needs of patients who require both basal and prandial insulin with a limited number of daily injections. Compared with premixed human insulin 30/70, in which there is considerable variability in the onset, duration of action, and peak insulin levels, with the rapid-acting insulin component of a premixed insulin analogue peak insulin levels are twice as high and reached in half the time [19]. Two premixed insulin analogue formulations are currently available: insulin lispro 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro; Lispro Mix 25) and biphasic insulin aspart 70/30 (BIAsp 70/30; 70% insulin aspart protamine suspension and 30% insulin aspart). In comparative trials, both the premixed insulins BIAsp 30 and Lispro Mix 25 have been found to provide more effective glycaemic control than basal insulin glargine once daily [32,35]. Twice-daily Lispro Mix 25 plus metformin was associated with lower mean HbA1c at end of trial than once-daily glargine plus metformin (7.4% vs. 7.8%; P = 0.002), and with a higher proportion of patients achieving HbA1c 7.0% (42% [30/71] vs. 18% [13/71]; P < 0.001) [35]. In the INITIATE study, the HbA1c reduction was also greater in the group of insulin-naı¨ve patients initiated on BIAsp 30, compared with glargine [32]. The PRESENT study had no titration algorithm, and major and nocturnal hypoglycaemia rates were lower than with previous treatment (from 0.54 to 0.03 events/(patient year), and from 3.02 to 0.53 events/(patient year), respectively). Thus, data from this observational study suggest that BIAsp 30 can be effective when initiating patients on insulin, and its use is not associated with high rates of hypoglycaemia (one of the barriers to insulin initiation). If the numbers of patients reaching recommended targets is to be improved, it follows that treatment satisfaction, on the part of both patient and physician, should be maximised, as this suggests a greater willingness to comply with the treatment regimen. Treatment satisfaction scores (using physicians’ perceptions of patient satisfaction) for BIAsp 30 in the PRESENT study were high, with more than 95% of both patients and physicians more satisfied with BIAsp 30 compared with previous treatment after 6 months. Treatment satisfaction has been shown to improve when patients are moved to pen delivery devices, both prefilled/ disposable and reusable. The development of these devices has improved the accuracy of insulin delivery, and enabled patients to administer doses more discreetly, with more control and with less pain than the traditional vial and syringe. During the PRESENT study 78.6% of physicians indicated that

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diabetes research and clinical practice 81s (2008) s16–s22

Table 2 – The INITIATE study titration algorithm (data from Ref. [32])

7.

FPG or pre-dinner SMPG

T2DM is a progressive disease in which timely intervention with the most effective and appropriate therapy to bring hyperglycaemia under control is imperative, if complications are to be limited. Insulin has been shown to be an effective intervention, and is most effective when initiated in patients recently diagnosed with T2DM, but it is also capable of bringing about larger decreases in HbA1c than alternative therapies, particularly when baseline HbA1c is >8.5%. Modern insulin formulations can help patients starting treatment to minimise the risk of hypoglycaemia, and the premixed analogue BIAsp 30 is effective when used for initiation of insulin in T2DM patients with poor glycaemic control. By the same token, modern pen-style delivery devices can help to minimise the disruption to daily routine associated with administering injections, and can help overcome potential barriers to starting insulin therapy. Physicians should work to encourage patients with T2DM to take responsibility for their own care, by regularly monitoring their blood glucose and using titration algorithms to help them reach their glycaemic targets. Patients with T2DM who manage their condition in this way will limit complications, and in turn give themselves the opportunity for a better quality of life.

mmol/L <4.4 4.4–6.1 6.2–7.8 7.9–10 >10

Dose adjustment (U)

mg/dL <80 80–110 111–140 141–180 >180

2 – +2 +4 +6

Pre-dinner insulin doses were titrated based on FPG values. The pre-breakfast BIAsp 30 dose was titrated according to values for pre-dinner self-measured plasma glucose (SMPG). FPG, fasting plasma glucose.

the pen used to administer BIAsp 30 met their expectations in terms of ease of handling. According to earlier studies, patients generally find pens to be more convenient than a vial and syringe, and rate them more highly in treatment satisfaction questionnaires for flexibility, quality of life and overall preference [26,36,37], which suggests pens could improve treatment compliance and have a positive effect on breaking down PIR. However, while pens are commonplace in Europe (70–90% of insulin delivery) their use in the USA remains low, primarily due to reasons of cost [36]. This is despite the potential to offset extra device costs against savings due to lower rates of complications that result from better treatment adherence, and attendant improved, sustained glycaemic control [38].

6.

Lesson 3: whose responsibility?

Physicians should be aware of the progressive nature of diabetes and the accumulating glycaemic burden. They should strive to overcome inertia in up-titrating doses of OADs, initiating early insulin, and intensifying therapy to meet the target glycaemic goal. Once insulin therapy is prescribed, patients may believe that their diabetes has become more severe, or that they have personally failed to control the disease with the prescribed treatment regimens [39]. Thus, patients may view insulin therapy as a last resort, or as a ‘threat’ or indeed ‘punishment’ for their personal failure. It is therefore the responsibility of the physician to make patients aware, at diagnosis, that diabetes is a progressive disease and it is likely that insulin therapy will be required at some point in the future. The subject of insulin therapy should be approached positively, and should be presented as an effective and flexible way to achieve glycaemic goals for any patient at any time during therapy [40]. Also, physicians need to emphasise patient education (diet, exercise, frequent self-monitoring of blood glucose, periodic monitoring of HbA1c, preventing and dealing with hypoglycaemia) in order to achieve successful insulin initiation and compliance. However, a perceived lack of opportunity and/or time for patient instruction, along with a lack of trained personnel, has been identified as one of the PIR considerations that act as barriers to the prescription of insulin [24,25]. Diabetes educators can also help patients to manage their disease, including the practicalities of insulin therapy.

Conclusions

Acknowledgements The PRESENT study was sponsored by Novo Nordisk International Operations. The authors would like to thank the patients and physicians for taking part in the study, and Harry Yeates for assistance in the preparation of this manuscript.

Conflict of interest Jing Ping Yeo is an employee of Novo Nordisk. Alan Garber has acted as a consultant for Novartis Pharmaceuticals Inc. and Novo Nordisk Inc., and has received research support from Diiachi Sankyo Inc. Surendra Sharma has no conflict of interest to declare.

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