The progressive nature of type 2 diabetes (T2D) necessitates that healthcare professionals use a management strategy that takes this disease progression into account. Diabetes management should therefore include regular patient reviews and periodic adjustments of treatment regimens to maintain good glycemic control with the goal of minimizing/delaying the onset of diabetes-related complications. The maintenance of glycemic control, as achieved in part through adherence to the treatment regimen, is the aim for both patient and healthcare professional alike. However, the nature of the pathological components of T2D means the disease is likely to progress even in those patients who adhered to treatment and maintained adequate glycemic control. The development of insulin resistance and beta-cell dysfunction dictates that, over time, the endogenous insulin response will diminish. The reduction of the endogenous insulin response progresses over time, manifested in a decline in glycemic control despite optimized oral antidiabetic therapy, until patients require insulin replacement therapy, which usually involves discontinuing all oral antidiabetic drugs (OADs) except for metformin. On reaching this point, the healthcare professional has a number of different approaches available with several different insulin options (as discussed in detail in elsewhere in this supplement: Spollett, 2012). This article will examine some of the practical considerations in intensifying insulin treatment, with a focus on modern treatments that may mitigate some of the concerns currently delaying insulin intensification.
The role of the nurse practitioner
As discussed in earlier articles in this supplement, the importance of a comprehensive team approach to T2D management is increasingly emphasized (Handelsman et al., 2011), and nurse practitioners (NPs) play a critical role as part of this team at all stages of disease progression (Conlon 2011). Outcomes have been shown to be comparable in large studies when patient care is managed by NPs rather than physicians in chronic care generally (Mundinger et al., 2000). NPs are increasingly the leaders of multidisciplinary teams for patients requiring chronic care, including T2D (Dancer & Courtney, 2010), and the substitution of diabetes NP-led care for physician-led care leads to cost savings as well (Arts, Landewe-Cleuren, Schaper, & Vrijhoef, 2011). The provision of diabetes care, such as routine monitoring, has also been shown to be superior in primary care practices that include NPs or physician assistants (Ohman-Strickland et al., 2008). Within shared medical appointments as part of the chronic care model, major roles of NPs are the promotion of self-management, decision support, and delivery system design (Watts et al., 2009). One recent large international study found that patient education significantly improves the percentage of patients reaching international clinical and metabolic targets, such as weight, blood pressure, A1c, and lipid profile (Gagliardino et al., 2011). Another recent study in poorly controlled patients with T2D in the United Kingdom found that just one single session with a diabetes specialist nurse and diabetes specialist dietician significantly improved A1c at 6 months, with improvements out to 1 year (Banerjee, Macdougall, & Lakhdar, 2011). Specifically in regards to insulin intensification, recent results of a large international survey showed that physicians viewed lack of time to educate patients as a significant barrier to insulin intensification, and the authors concluded that a multidisciplinary approach is key to successful management of T2D at this stage (Cuddihy, Philis-Tsimikas, & Nazeri, 2011).
Aiming for A1c goals: Are we missing the target?
Our understanding of the importance of achieving and maintaining strict glycemic control has been greatly advanced by a number of large-scale key clinical trials. The data from these trials provide the basis for the targets advocated in the current diabetes treatment guidelines from the American Diabetes Association (ADA) and the American Academy of Clinical Endocrinologists (AACE).
The United Kingdom Prospective Diabetes Study (UKPDS) established that reductions in macrovascular complications and significant reductions in microvascular complications are achieved with better control of blood glucose through intensified therapy, with substantial reductions in incidence or rate of progression demonstrable for every 1% reduction in A1c (Stratton et al., 2000). These reductions include a 14% decrease in all-cause mortality per 1% reduction in A1c, a 16% decrease in heart failure per 1% reduction in A1c, and a 37% decrease in microvascular endpoints per 1% reduction in A1c (Stratton et al., 2000). In patients with poor glycemic control, even short periods of elevated blood glucose may increase the risk of diabetes-related complications (Stratton et al., 2000). This risk is also retained over the long term, with an increased risk demonstrable up to 10 years after a period of initial elevated blood glucose levels despite subsequent improvement in control (Holman, Paul, Bethel, Matthews, & Neil, 2008). In this (UKPDS) study, a significant benefit to cardiovascular outcomes overall was associated with more intensive glycemic control, although impaired cardiovascular outcomes were seen in some patients for reasons that have not been elucidated. Other large studies have reported no additional beneficial effect on cardiovascular endpoints (Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation; ADVANCE, Veterans Affairs Diabetes Trial; VADT) or in fact harm (Action to Control Cardiovascular Risk in Diabetes; ACCORD) associated with intensive control (summarized in an ADA consensus document: Skyler et al., 2009); differences may be because of these more recent trials being of shorter duration, carried out in patients with longer disease duration, using an even more aggressive target A1c levels, and including higher thiazolidinedione use.
The wealth of trial data around glycemic control is reflected in clinical goals oriented toward decreasing A1c levels. The general consensus from regional and national associations is that A1c levels should be kept <7% (ADA/European Association for the Study of Diabetes [EASD]; CDA [Nathan et al., 2009; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2008]) or ≤6.5% (AACE/ACE; [Rodbard et al., 2009]) with scope for individualization of these goals in the case of tolerability issues. An ADA consensus panel suggested targets of <7% may be appropriate, if attainable without significant hypoglycemia, in patients with a short duration of diabetes, long life expectancy, and no significant cardiovascular disease. Conversely, the panel suggested that targets >7% may be appropriate in patients with long duration of disease, limited life expectancy, and significant cardiovascular or other comorbidities (Skyler et al., 2009). Despite the prominence of these goals, a large percentage of patients fail to achieve clinical targets, and data from a diabetes registry study suggests that the average A1c prior to treatment intensification is 9% (Brown & Nichols, 2003). Meanwhile, delay of insulin initiation is a well-documented phenomenon in everyday clinical practice (Calvert, McManus, & Freemantle, 2007; Nichols, Koo, & Shah, 2007; Rubino, McQuay, Gough, Kvasz, & Tennis, 2007). The Diabetes Attitudes, Wishes, and Needs (DAWN) study, which examined the attitudes of patients and healthcare professionals to insulin therapy, showed a tendency to delay insulin therapy until absolutely necessary amongst general practitioners and nurses (Peyrot et al., 2005). Furthermore, it appears that this situation is mirrored when insulin therapy is being intensified as well as when it is being initiated. A recent Canadian study demonstrated that following 3 years of insulin therapy, nearly 70% of patients did not reach a glycemic target of 7% and 20% of patients had an A1c >9%. Thus, the average A1c upon intensification of insulin therapy suggests we are delaying dose increases too often, possibly because of clinical inertia (Harris, Kapor, Lank, Willan, & Houston, 2010). Further data from both the United States and EU show only a third of patients reach A1c targets 6.5%–7.5% (Massi-Benedetti, 2006).
Tips for insulin intensification
- Keep in mind that failure to intensify therapy leads to widespread poor glycemic control.
- Know all the options available for intensifying insulin regimens.
- Individualize treatment plans based on patient psychological as well as clinical profile.
- Continued support and education is crucial for adherence to more complex regimens.
Barriers to success of insulin therapy
The failure to achieve glycemic targets can therefore be seen as a major issue in the management of patients with T2D. There are a number of barriers that contribute to the failure to achieve blood glucose control, with the prominent ones being the lack of titration of therapy (requiring intensification); system barriers (such as access to care); and patient barriers (such as lifestyle, education, and psychology; Barnett, 2004). Alongside this, the type of health care provided, that is, specialist or primary care provider, is a key aspect of diabetes management; because of increases in prevalence, T2D is increasingly being managed in the primary care setting (Brez et al., 2009). The movement of diabetes management from specialists to primary care can impact patterns of insulin use. A recent study of patient and physician perceptions showed that the major barriers to an effective transition from secondary care to primary care were, in the opinion of the patient, a possible lack of confidence or trust in the primary care physician's ability to manage diabetes, poor motivation, or nonadherence (Brez et al., 2009). It is therefore vital to ensure healthcare providers (HCPs) who treat patients with diabetes are adequately educated on management of the disease, and that the expectations of the patients are effectively managed. The location of the patient/caregiver is also important as national/regional differences may profoundly influence patient care. A recent study exploring treatment approaches in United States, United Kingdom, and Germany for primary care-based T2D management found US HCPs were the most active in questioning, testing, prescribing, and advice giving (von dem Knesebeck et al., 2010).
Awareness of the barriers that prevent patients from achieving glycemic control is therefore an essential component of management of the condition. Self-management is a very effective strategy for many patients but not for all (Redman, 2007). It is therefore essential that HCPs are able to evaluate and subsequently identify patients who will be able to achieve success with more complicated treatment regimens without increasing risk. For example, patient literacy can have a significant impact on the effectiveness of disease management programs (Rothman et al., 2004). A recent survey of US patients showed patients’ preferences for delivery of diabetes self-management support were influenced by ethnicity, language proficiency, and health literacy (Sarkar et al., 2008).
One destination, many routes
Guidelines, such as those advocated by the EASD, ADA, and AACE, show a broad consensus regarding the A1c targets for patients with T2D (<7% or ≤6.5%). The guidelines also provide a general consensus with regard to the recommended approaches to initial therapy with diet/exercise ± metformin considered as standard for patients diagnosed with the early stages of T2D. As T2D progresses, the treatment choice broadens with the evidence base supporting a number of treatment options. In addition to universal considerations such as duration of disease, current level of glycemic control, efficacy, and safety, the clinical choices made by the HCPs are also dictated by a number of individual factors including patient needs/physician familiarity and localized prescribing practices. In particular, when insulin is a viable and utilized treatment option, HCPs must weigh the need to increase insulin dosing frequency and dose, as well as make changes to the type of insulin, with the clinically important need to minimize the risk of hypoglycemia. The consensus EASD and ADA algorithm on the management of hyperglycemia discusses the initiation and intensification of insulin therapy and provides a set of markers on when insulin intensification should take place (Nathan et al., 2009). Following initiation with basal insulin, patients should be regularly monitored. If A1c remains ≥7%, then a single prandial insulin, with the timing dictated by blood glucose measurements, should be included, and further prandial injections should be considered if A1c remains ≥7% after another 3 months.
Doses of insulin must be individualized and should be titrated following initiation to optimize and maintain control. Nevertheless patients may still fail to achieve glycemic targets, and recommendations from Hirsch and colleagues state that if patients are not at goal after 3–6 months of therapy then consideration should be given to a change in regimen. A number of insulin regimen changes are included in Table 1 (Hirsch, Bergenstal, Parkin, Wright, & Buse, 2005). It is important that insulin intensification (the qualitative change in regimen) is effectively differentiated from insulin optimization (dose titration). Although different routes to optimization should be explored before HCPs can consider insulin intensification, it should not be delayed too long. To effectively facilitate both the optimization and intensification of insulin therapy, it is essential for patients to undergo frequent re-evaluation of their regimen. A 3-year study following insulin intensification in primary care T2D patients suggested a need for more frequent reviews and dose titration to ensure that insulin dose was optimized, and that intensification was undertaken as soon as needed (Dale, Martin, & Gadsby, 2010).
A major study of interest that examined different approaches to insulin intensification was the work by Holman and colleagues (2007), the 4-T study. The study was an independent academic 3-year, multicenter, open-label, randomized, controlled clinical trial conducted in the United Kingdom and Ireland, which included 708 patients who were suboptimally controlled (A1c 7%–10%) on metformin and sulfonylureas (maximum tolerated doses for at least 4 months). The study compared three different strategies for insulin initiation while allowing subsequent intensification when necessary. Patients were initiated on either biphasic insulin twice daily, basal insulin only daily, or prandial insulin three times daily (Figure 1). Addition of prandial insulin to basal or premixed insulin, or of basal insulin to prandial insulin, was allowed if indicated by continuing suboptimal control (Figure 1). Patients were followed for 3 years, including postintensification of regimen (Holman et al., 2007, 2009). At the end of 3 years, A1c levels were comparable between all three treatment groups (7.1%; 6.9%; 6.8% for biphasic, prandial, and basal starts, respectively), suggesting all three pathways were valid treatment approaches. Respective rates of weight gain (5.7 kg; 3.6 kg; 6.4 kg) and hypoglycemia (3.0; 1.7; 5.7 episodes per patient-year) showed the lowest cumulative burdens over 3 years in the basal start insulin group, with the highest cumulative burdens in the prandial start group (Holman et al., 2009). Interestingly, data from patients included in the 4-T study showed that it was not the increasing number of daily injections that was a concern for the patients in the group who agreed to undergo insulin intensification, but the increased likelihood of having to inject insulin in public (Jenkins, Hallowell, Farmer, Holman, & Lawton, 2011). Nurse prescribers play a key role in allaying these specific patient fears.
The use of basal insulin as an add-on to OADs is a popular and well-documented approach to insulin initiation (Nathan et al., 2009). However, as patients achieve greater glycemic control with the use of basal insulin, the issue of mealtime glycemic excursions is likely to become more prominent as a limiting factor (Monnier, Colette, & Owens, 2008). As A1c is improved, the relative contribution of mealtime glycemic excursions to the residual overall hyperglycemia increases (Figure 2; Monnier, Colette, & Owens, 2008). Alongside this, as the disease progresses, it is the endogenous prandial insulin response that is progressively most diminished (Coates, Ollerton, Luzio, Ismail, & Owens, 1994). The implication of these factors is that addition of prandial insulin may become necessary to decrease A1c to guideline-advocated target levels.
For patients who are having difficulty achieving effective glycemic control, owing to the contribution of these postprandial spikes, there are a number of different approaches to adding rapid-acting insulin. The introduction of a full basal–bolus regimen can be perceived as overcomplicated and may be a step too far for patients who are used to their once-daily basal regimen. The key challenge for the nurse prescriber is therefore in “keeping it simple” to support adherence to whichever insulin regimen is used, but not at the cost of poor glycemic control. The sensible option may therefore be regarded as a stepwise approach to the introduction of bolus insulin. Adding a single daily dose before the meal that produces the largest postprandial spike is an intuitive way to start (Monnier & Colette, 2008). This approach should minimize the impact of the intensification process on the patient.
The recent Orals Plus Apidra and Lantus (OPAL) study explored the addition of a single-dose prandial addition (glulisine added prebreakfast or prelunch) to insulin glargine. OPAL found significantly improved A1c compared with baseline irrespective of the timing of the glulisine dose. This result suggests that this may be a practical intermediary step between a basal-only insulin regimen and a full basal–bolus regimen (Lankisch, Ferlinz, Leahy, & Scherbaum, 2008). Another recent study, STEP-Wise, similarly reported that different strategies for stepwise addition of prandial insulin aspart in patients treated with insulin detemir to one or more meals were equally effective at intensifying therapy in patients with type 2 diabetes (Meneghini, Mersebach, Kumar, Svendsen, & Hermansen, 2011).
In patients already receiving prandial insulin, one possible approach to reducing the magnitude of mealtime glucose excursions is in the use of pramlintide acetate, which can be used synergistically with insulin, although increased monitoring and possible insulin dose reduction must be considered. A systematic review and meta-analysis exploring the utility of pramlintide in T2D showed small weight loss, significant reductions in A1c, and no increased risk of hypoglycemia in randomized controlled trials of patients with/without insulin (Singh-Franco et al., 2011). Patients receiving pramlintide experienced significantly increased levels of nausea compared with controls (Singh-Franco et al., 2011).
An additional approach to achieving glycemic control is through the use of biphasic insulin. Data from randomized, controlled trials suggest the sequential addition of biphasic insulin, to keep pace with the changing pathophysiology of T2D, is a sound strategy for initiation and intensification (Garber et al., 2006). There is little specific guidance for the management of hyperglycemia with biphasic insulin. There is, however, a consensus statement based on the results of a global expert panel. This document provides a consensus algorithm for the sequential addition of one of the biphasic insulins, biphasic insulin aspart, and is summarized in Table 2 (Unnikrishnan et al., 2009). An additional randomized controlled trial comparing basal–bolus insulin with premixed insulin found both treatment approaches to be equally effective at reducing A1c; therefore the choice between approaches will be at the HCP's/patient's choice and be influenced by factors such as injection frequency and eating habits (Ligthelm, Gylvin, Deluzio, & Raskin, 2011). However, there has also been a suggestion, by the PREdictable and For Every Patient Reliable (PREFER) study, that there may be different advantages to each. This study found a full basal–bolus regimen was significantly superior to twice-daily biphasic aspart in glycemic control, and the authors concluded that “insulin treated patients may benefit more from a transfer to a basal bolus regimen and insulin-naïve patients may benefit more from the convenience of biphasic insulin (Liebl et al., 2009).”
A final route to effective glycemic control is via the use of insulin pumps, which some consider the gold standard in terms of continued glycemic control for those willing and able to accept the extra labor intensive process of pump management. A recent study assessing pump use in patients with T2D showed significant reductions in A1c (-1.2 ± 1.2%, p < .001) without severe hypoglycemia on switching to pump therapy (Edelman et al., 2010). Perhaps because of the greater capacity to fluctuate dosing as needed, patients also exhibited a significantly greater preference for insulin pump therapy compared with baseline therapy (Edelman et al., 2010).
Does A1c tell the whole story?
It is understood that A1c is the recognized measurement of glycemic control and is predominantly used as the barometer of therapeutic effectiveness in diabetes. It is, however, important to be aware that, by its very nature, A1c is a measurement of average blood glucose encompassing both hyperglycemic and hypoglycemic states. There is increasing recognition that A1c may be a “blunt instrument.” With their insightful analysis of the type 1 diabetes study, the Diabetes Complications and Control Trial (DCCT), Hirsch and Brownlee (2005) observed that the discrepancies between conventionally treated and intensively treated patients could not be explained by A1c alone (Figure 3; Hirsh & Brownlee, 2005). It was therefore postulated that glucose fluctuations were a possible cause of the compounded divergence between the conventionally and intensively treated groups. This theory is, however, controversial and the findings are a source of on-going debate (Kilpatrick, Rigby, & Atkin, 2006). There are, however, mechanisms described by Monnier and colleagues that add weight to this argument, notably the long-term impact of oxidative stress following even minor glucose excursions (Monnier & Colette, 2008). What is clear is that reduced blood glucose variability means greater predictability for patients, which may help them adjust their insulin dosing and may also support reduced hypoglycemia (Niskanen, Virkamaki, Hansen, & Saukkonen, 2009). Despite A1c being the gold standard in assessing the efficacy of diabetes management, it does not reflect glycemic stability (Derr, Garrett, Stacy, & Saudek, 2003), and, as such, it may be that more detailed tools such as continuous glucose monitoring system (CGMS)/mean amplitude of glycemic excursions (MAGE) are needed to ascertain the patterns of glycemic excursions and to identify a clearer pattern of underlying glycemic control (Monnier & Colette, 2008).
Toward a patient-centric approach
The established guidelines for the management of hyperglycemia advocate stringent targets for A1c levels and the continued titration of insulin dose is aimed at achieving these targets. Each patient is an individual and it is important to remember that some patients may not benefit from aggressive titration, but these patients are likely to be in a minority. The recent article by Pozzilli and colleagues, postulating an ABCD of glycemic management, formulated an adapted target scope to utilize existing therapies, but with a patient-focused adjustment of A1c target (Pozzilli et al., 2010). With these targets and recent data in mind, it is still vital for the nurse prescriber to utilize a patient-centric approach to care. Intensification specifically should be tempered by both a patient's willingness and the risk associated with hypoglycemia. A patient with a fixed daily routine, more limited support systems, a preference for few injections, and reluctance to self-monitor blood glucose may be more appropriate for premixed analogs, while a basal–bolus regimen would be preferable for a willing, capable patient with a variable daily routine and meal pattern.
Choosing between insulins
To effectively follow the patient-centric approach, it is important that the insulin regimen used is tailored to the specific needs of the patient. When used early in the course of the disease, insulin may act supplementary to the endogenous insulin produced by the pancreas. As the disease progresses, the exogenous insulin replaces the endogenous insulin. For patients who require basal insulin therapy there are, at present, three different basal insulins commonly used in clinical practice (detemir, glargine, neutral protamine Hagedorn [NPH]). Each basal insulin has its own clinical attributes that will influence use in managing different patients. The basal analogs detemir and glargine, with similar pharmacokinetic/pharmacodynamic profiles, are recommended for once-daily use in T2D (Heise & Pieber, 2007; King, 2010). With respect to the efficacy in reducing blood glucose, all three basal insulins are generally comparable in terms of glycemic control (assuming titration to equivalent targets), but basal analogs are associated with a lower risk of hypoglycemia compared with NPH in both type 1 and type 2 diabetes therapy (Monami, Marchionni, & Mannucci, 2008, 2009). Data from clinical studies have shown that glargine and detemir are comparable for glycemic control and hypoglycemia risk; however, use of detemir is associated with less weight gain (Raskin, Gylvin, Weng, & Chaykin, 2009; Rosenstock et al., 2008) and reduced variability (Heise & Pieber, 2007).
There is also a range of rapid-acting insulins available (aspart, lispro, glulisine, human soluble insulin). As with the basal analogs, the rapid-acting analogs have modified profiles compared with human soluble insulin because of modification of their amino acid structure. This modification confers a number of advantages over human soluble insulin, the most significant of which may be the improved control over postprandial blood glucose. The analogs lispro, aspart, and glulisine all demonstrate an approximate onset of action of between 5 and 15 min, compared with 30–60 min for human soluble insulin, a peak of activity at 1 h (2–4 h for human soluble insulin), and duration of action of 4–5 h compared with 6–10 h for human soluble insulin (Chapman, Noble, & Goa, 2002). The improvement in the pharmacokinetic/pharmacodynamic profile may provide a number of patient-centric benefits, including improved postprandial glucose control, increased convenience, reduced risk of hypoglycemia, and increased support for calorie counting and dose titration.
An additional approach to glycemic control mentioned previously within this article is via the use of biphasic insulins (such as biphasic insulin aspart 70/30, biphasic human insulin). The pharmacokinetic/pharmacodynamic differences between analog and human insulin-based preparations are substantial; most notably, an earlier onset of action, faster absorption, faster time to maximum concentration, and higher total peak concentration with the analog products (Jacobsen, Sφgaard, & Riis, 2000). These differences translate into a significantly reduced risk of hypoglycemia compared with human biphasic insulin, as shown by a recent meta-analysis of clinical data (Davidson et al., 2009), although all insulin therapies are associated with a risk of severe hypoglycemia.
A potential approach to glycemic control, which has recently been approved but only for exenatide and insulin glargine, may be the use of basal insulins alongside glucagon-like peptide-1 (GLP-1) receptor agonists. Clinical studies in patients receiving basal insulin (glargine) have shown the addition of GLP-1 receptor agonists are associated with weight decrease, insulin dosage decrease, and improved glycemic control when compared with the addition of placebo (Buse et al., 2011). Another study found that in patients taking basal insulin and OADs, the addition of premeal fixed-dose pramlintide improved glycemic control as effectively as titrated rapid-acting insulin analogs (Riddle et al., 2009).
Barriers to intensification
Although less research has been carried out on patient barriers specific to intensification of insulin, many of the barriers to initiation will still apply. Fear of self-injecting and worsening diabetes will decrease with insulin experience, while other issues, such as fear of weight gain, hypoglycemia, and regimen complexity, will grow. These worries, as well as the greater perceived patient burden represented by intensification (Vijan, Hayward, Ronis, & Hofer, 2005), lead to an increased need for psychological support and education to empower patients and improve adherence and outcomes. Strategies for psychological support of patients with type 2 diabetes throughout the course of disease are discussed in an accompanying article in this supplement (Bartol, 2012).
Following the effective titration of insulin, a change of insulin regimen (intensification) may be necessary to maintain glycemic control in patients failing to achieve targets. It is important that continued patient monitoring is provided and that HCPs’ motivation to intensify is present, because it is commonplace for patients to remain on their prior regimen despite a failure to achieve glycemic targets. In patients who are undergoing intensification, it is the role of the nurse prescriber to ensure through support, education, and monitoring, that the change in regimen, be it stepwise addition of prandial insulin to basal or progression from basal insulin to premix insulin, is achieved as seamlessly and successfully as possible with minimal negative impact on the patient.
The assistance of Watermeadow Medical Inc, New York, NY, USA, funded by Novo Nordisk Inc, Princeton, NJ, USA, in preparing this article is gratefully acknowledged.
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