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Insulin initiation in type 2 diabetes: What are the treatment regimen options and how can we best help patients feel empowered?

Spollett, Geralyn R. MSN, ANP-CS, CDE (Associate Director)1

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Journal of the American Academy of Nurse Practitioners: April 2012 - Volume 24 - Issue - p 249-259
doi: 10.1111/j.1745-7599.2012.00721.x


Is insulin inevitable?

Progression of type 2 diabetes

The pathophysiology of type 2 diabetes (T2D) involves a genetic predisposition to the progressive loss of beta-cell mass and function in the setting of insulin resistance (DeFronzo, 2004; Tripathy & Chavez, 2010; UKPDS 33, 1998). Although the environmental triggers of physical inactivity, overweight and chronic excess calorie consumption are well known, individual susceptibility to T2D is variable (Kahn, Hull, & Utzschneider, 2006). Potentially, T2D is preventable with appropriate intervention if it is identified very early in its natural history (Brubaker & Drucker, 2004; Mudaliar & Henry, 2009; Pournaras et al., 2010). However, the reality for most patients is that the diagnosis is made after years of pathophysiologic changes have occurred and glycemic control will inevitably worsen despite interventions (UKPDS 16, 1995), and the patients’ (and their providers’) best efforts at disease self-management (Harris, Klein, Welborn, & Knuiman, 1992; Turner, Cull, Frighi, & Holman, 1999). For example, the 6-year follow-up of the U.K. Prospective Diabetes Study (UKPDS) demonstrated the progressive loss of beta-cell function inherent in T2D in nonobese and obese patients alike on conventional dietary therapy or sulfonylurea therapy (Figure 1; UKPDS 16, 1995). The study also demonstrated the persistent increase of hyperglycemia characterizing diabetes, with fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels incrementally increasing throughout the 6 years regardless of dietary or oral antidiabetic drug (OAD) therapy (Figure 2; UKPDS 16, 1995).

Figure 1
Figure 1:
Progressive beta-cell dysfunction over 6 years in subsets of patients with type 2 diabetes (A) remaining on allocated diet therapy (n= 376) or sulfonylurea (n= 511); or (B) allocated to diet therapy (n= 110) or metformin (n= 159). Reproduced with permission, and © 1995 ADA, from UKPDS 16, Diabetes, 44, 1249–1258.
Figure 2
Figure 2:
Progressive hyperglycemia as measured by (A) fasting plasma glucose (FPG; note: 1 mmol/l = 18 mg/dL); and (B) HbA1c. Reproduced with permission, and © 1995 ADA, from UKPDS 16, Diabetes, 44, 1249–1258.

Progression of interventions to insulin

Recommended target HbA1c levels are usually <6.5% (American Academy of Clinical Endocrinologists [AACE], European Association for the Study of Diabetes [EASD]) or <7.0% (American Diabetes Association [ADA]) and attaining these target HbA1c levels, while minimizing effects such as weight gain and hypoglycemia, is the primary goal. The traditional approach to reaching this goal is to increase the level of intervention from diet and exercise through OADs to injectable therapies, namely insulin and the glucagon-like peptide-1 receptor agonists (GLP-1RAs), although AACE places GLP-1RAs among initial recommended treatments. This approach is well established in the evidence-based algorithms of diabetes societies’ treatment guidelines (ADA, 2011; IDF, 2005; Nathan et al., 2009; Rodbard et al., 2007), which are periodically updated to take account of new drug developments and trial data. It is important to remember throughout the course of T2D disease management that the ultimate goal is to provide the patient with an individually tailored, flexible regimen that maintains health and quality of life. The aim is to guard against the potential complications of T2D without imposing undue self-management burdens or exposing the patient to the risk of adverse side effects such as hypoglycemia and/or weight gain. Healthcare providers often delay insulin initiation, prescribing multiple oral medications and continuing to use them past their effectiveness, in an effort to avoid exposing patients to the possible side effects of insulin. As a result, insulin initiation often occurs too late. Patients may have already experienced years of inadequate glycemic control and the chronic complications of diabetes may have already begun to develop.

In some cases, such as in the very elderly, the potentially negative impact of insulin initiation upon the patient's independence and daily routine might be considered to outweigh the potential health benefits. For most patients, however, the scope exists for “user-friendly” and supportive insulin introduction with the expectation of minimal lifestyle disruption outweighed by a beneficial impact on prognosis (LaSalle, 2010; Snoek, 2002).

Tips for insulin initiation in type 2 diabetes

  • Address need for future use of insulin at diagnosis or early in the disease process.
  • Emphasize not as a failure, but a treatment upgrade.
  • Do not see as a last resort and thus delay too long.
  • Be ready to address barriers to initiation.
  • Individualize therapy: choose the right insulin for the patient.
  • Adjust other oral or injectable therapies when appropriate.

Insulin is an upgrade, not a failure

Removing the word “failure”

One unfortunate consequence of the late positioning of insulin within the current treatment paradigm is that it is often viewed as a treatment of “last resort.” This is compounded by references throughout diabetes literature that uses the term “failure” (DAWN website; Dunning, 2004; Jeavons, Hungin, & Cornford, 2006; Meece, 2006; Peyrot et al., 2005; Polonsky, 2005b) that can all too easily be mistakenly conveyed as patient rather than treatment failure. It is important to remember that many patients have issues with guilt, about having contributed to the diagnosis of diabetes through their inability to normalize their glycemia and weight (Funnell, Kruger, & Spencer, 2004; Korytkowski, 2002; Korytkowski, Niskanen, & Asakura, 2005) and that every effort must be made to help patients to understand the progressive nature of diabetes. The need for advancing therapy reflects a disease state and not a “personal failure.”

Patient misconceptions surrounding insulin

The successful understanding and application of any treatment, including insulin, requires the patient to be an enthusiastic and motivated partner in the treatment decision. This is of vital importance, as many patients often present with the preconception that insulin will not effectively provide glycemic control (Davis & Renda, 2006; DAWN website; Peyrot et al., 2005). For example, respondents (n= 1610) expressed low confidence in the efficacy of insulin in the DAWN study, as demonstrated by the mean rating of 1.96 (±1.01) on the ability of insulin to improve the management of diabetes (fully disagree= 1, fully agree= 4; Peyrot et al., 2005). Similarly, many patients attribute the complications of diabetes to insulin use, and not suboptimal glycemic control (Brod, Kongsφ, Lessard, & Christensen, 2009). Fear of potential side effects, particularly weight gain and hypoglycemia, also deters patients from admitting the need for insulin initiation (Brod et al., 2009; Polonsky et al., 2005b). However, after an initial decline, HbA1c eventually tends to rise again as diabetes worsens regardless of the type of therapy (UKPDS 33, 1998). This rise in HbA1c occurs against a backdrop of progressive beta-cell decline in the setting of continued, but unchanging, insulin resistance, as shown in Figure 3 (Levy, Atkinson, Bell, McCance, & Hadden, 1998).

Figure 3
Figure 3:
HbA1c values over 10 years with conventional or insulin therapy; reproduced with permission, and © 1998 UKPDS 33, Lancet, 352, 837–853.

Patient misconceptions surrounding disease progression

Consequently, it is crucial that patients understand that progression of the disease is a natural feature of their diabetes and not a personal failure. Figure 3 may be used by members of the healthcare team as a teaching aid to reassure patients that, while the decline in glycemic control is a normal feature of T2D, the use of insulin has a positive effect. Patients should be encouraged to feel that, despite the inevitability of disease progression, they are successfully addressing the need for aggressive treatment and that insulin is an essential component in this process.

Make it about patient control

Insulin improves glycemic response even after OADs fail (Holman et al., 2007; Turner et al., 1999) and, therefore, patients should be informed that insulin will provide an opportunity for them to take greater control over their T2D (Kunt & Snoek, 2009). Individualized patient education should be an integral part of the disease management process, during which the outcomes and clinical implications of insulin should be communicated in an easily understandable way (IDF, 2005). Insulin is more effective when patients are adequately managed and there is timely initiation of treatment (Raccah et al., 2006). Care should be focused on providing patients with support to cope with their disease. In many cases, there is an immediate need to change patients’ negative beliefs and perceptions about insulin therapy (Brod et al., 2009; Kunt & Snoek, 2009; Peyrot, Rubin, & Khunti, 2010; Polonsky et al., 2005a, 2005b). This can be applied at diagnosis, with the patient being encouraged to take the view that excess bodyweight may have triggered a disease predisposition, and therefore, they are not “at fault.” Going forward, they can take control of their disease through a series of measures that will ensure their optimal health and well-being.

Patient-driven algorithms

Patient-driven algorithms that empower patients to self-manage their diabetes have been shown to improve glycemic control and disease outcome (Blonde, Merilainen, Karwe, & Raskin, 2009; Davies et al., 2005; LaSalle, 2010; Meneghini, Koenen, Weng, & Selam, 2007; Rosenstock et al., 2008WHO, 2004). Notably, both the treat-to-target with once-daily Insulin Therapy: Reduce A1C by Titrating Effectively (TITRATE®) study (Blonde et al., 2009) and The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation 303 (PREDICTIVE™ 303) study (Meneghini et al., 2007) found that empowering patients to self-manage their insulin dose, through the use of simple, patient-directed, titration algorithms, led to measurable improvements in their condition. (The algorithm in the TITRATE® study, e.g., prescribed decreasing the insulin detemir dose by three units in those with a 3-day average FPG falling below target, and increasing the dose by three units in those with a 3-day average FPG above target.) In the 26-week PREDICTIVE™ 303 trial (Meneghini et al., 2007), 2794 patients with T2D randomized to the 303 algorithm (self-management with treat-to-target or self-adjusting dosing) with the basal insulin analog insulin detemir attained improvements in glycemic control comparable to the 2826 patients randomized to the standard-of-care algorithm (physician-led). Patients following the self-management algorithm experienced a 0.6% decrease in HbA1c from baseline (p<.0001 vs. baseline) from 8.5% to 7.9%, compared to the 0.5% (p<.0001 vs. baseline) decrease from 8.5% to 8.0% in patients following the physician-led algorithm. In the initial glargine studies (Rosenstock et al., 2008), a treat-to-target model was also used. The algorithm used (Table 1) is more aggressive and covers a broader range of glucose values, compared to the TITRATE® algorithm. In another trial of patients with T2D, a self-management treatment algorithm for initiation and titration of the basal insulin analog insulin glargine resulted in significantly greater decreases in HbA1c (1.22% vs. 1.08%, p<.001) and FPG (62 mg/dL vs. 57 mg/dL, p<.001) levels compared to an investigator-led treatment algorithm, respectively (Davies et al., 2005). Although the study indicates a number of testing times to consider for dose adjustment, fasting glucose levels provide an accurate indication of basal insulin efficacy forming the basis for this algorithm commonly used in the clinical setting. In clinical practice, patients taking glargine once daily (regardless of time of administration) monitor the fasting glucose level and use that result to make adjustments in the glargine dosage. While effective, the treat-to-target algorithm may be too complex for certain patients. A simple algorithm widely used is to increase the glargine by two units every 2 days until a fasting glucose level below 130 mg/dL is achieved and maintained.

Table 1
Table 1:
Insulin glargine titration algorithm. © 2008 Springer, reproduced with permission from Rosenstock et al., 2008. Diabetologia, 51, 408–416

What time is the right time?

Given the expectation that insulin will beneficially impact prognosis, there is a great deal to be gained, and little to lose, by not delaying insulin initiation (ADA, 2011; Dailey, 2005; IDF, 2005; Marre, 2002; Nathan et al., 2009; Riddle, 2004; Rodbard et al., 2007)—an event that is unfortunately common in clinical practice (Nichols, Koo, & Shah, 2007; Rubino, McQuay, Gough, Kvasz, & Tennis, 2007; Valensi et al., 2008). In fact, insulin initiation is often delayed between 1.8 and 5 years (Rubino et al., 2007; Nichols et al., 2007).

Effects of delaying insulin

Delaying insulin and consequently experiencing worsening glycemic control, in some cases, may lead to frustration with treatment, lower motivation, and less active self-care and may exacerbate comorbid depression (Lustman & Clouse, 2005; Peyrot et al., 2010). The UKPDS 49 demonstrated that a delay of 3–9 years in initiating insulin, and the consequent progressive deterioration in glycemic control, resulted in a 50–75% decline in number of patients able to reach an HbA1c target level of <7% (Turner et al., 1999). Further evidence supporting the timely initiation of insulin was also seen in the UKPDS, which showed that when insulin is initiated earlier, a lower dose was required, resulting in less weight gain and a lower risk of hypoglycemia (Turner et al., 1999). Additionally, recommendations from both the EASD and the ADA support the early use of insulin as the second step in the treatment strategy after lifestyle changes and OADs (Nathan et al., 2009). Thus, when patients are taking high doses of OADs, any indication of deteriorating glycemia should trigger serious consideration of insulin (Riddle, 2004).

Indications insulin should be considered

In the treat-to-target in T2D (4-T) study, indications for the initiation of insulin included suboptimal glycemic control (HbA1c level of 7.0–10.0%) while receiving high doses of OADs for at least 4 months (Holman et al., 2007). Other signs that should be noted are frequent blood glucose readings above target (HbA1c >8%) and symptoms of poor control, such as nocturia, vaginitis, fatigue, and sudden weight loss. At this stage, there is little point in increasing already high OAD doses to the maximum recommendations; however, newer agents, such as dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) and GLP-1RAs, may be added, provided that some beta-cell capacity remains (Buse et al., 2011; Fonseca et al., 2007, 2010; Yoon, Cavaghan, Brunelle, & Roach, 2009). Although incretin-based therapies were presumed to be used only while endogenous beta-cell capacity remains, data from the Liraglutide Effect and Action in Diabetes (LEAD) program with liraglutide show good efficacy in patients throughout the continuum of T2D treatment, including those on multiple OADs and those being considered for insulin therapy (Russell-Jones et al., 2009; Zinman et al., 2009). Above all, the time for the initiation of insulin is right when an informed and motivated patient feels his own treatment goals are no longer being met, at which point a dialog between patient and provider can lead to ready acceptance of the need to initiate insulin.

Making insulin effective and easy

Overcoming barriers

Patients commonly harbor several psychological barriers (DAWN study; Korytkowski, 2002; Peyrot et al., 2005) to insulin therapy that can be overcome with the right approach and sufficient support from the nurse practitioner (NP; Funnell et al., 2004; Home et al., 2003; Jeavons et al., 2006; Korytkowski, 2002; Korytkowski et al., 2005; Kunt & Snoek, 2009; Leslie, & Satin-Rapaport, 1995; Snoek, 2002). The most common barrier is the fear of injection pain, which is readily overcome by a demonstration dry injection with one of the modern insulin pen delivery devices that are increasingly used (Korytkowski, 2002; Korytkowski et al., 2005).

Concerns about potential embarrassment caused by the need to inject insulin in a public place can be relieved by the demonstration of an insulin pen that can be used discretely (Korytkowski, 2002; Korytkowski et al., 2005). Another major patient concern is hypoglycemia. Here, the NP can explain the circumstances in which hypoglycemic events can arise, the accompanying identifiable symptoms, as well as treatment options. NPs can advise the patient that long-acting modern insulin analogs have a much more physiologic action profile than earlier products, with serious hypoglycemia actually being a very rare event in T2D (Brange & Vølund, 1999; Bolli & Owens, 2000; Havelund et al., 2004). Upon initiating insulin, patients should also be provided with contact numbers for support networks (e.g., the Diabetes Support Network, and the ADA). Many patients find that insulin has a noticeable, positive impact on their well-being and it is common for patients to report that they wished they had understood sooner how insulin could be such a positive intervention (DAWN website).

Choosing the right insulin

Individualizing therapy by choosing an initial insulin that best meets the patient's specific needs will help to build patient confidence (Mooradian, Bernbaum, & Albert, 2006). The different types of insulins available offer the opportunity for tailoring different treatment regimens. The most common starting point for insulin therapy is once-daily basal insulin. Basal insulin alone does not directly address the deficit of prandial insulin release that characterizes T2D, but it might facilitate the endogenous prandial insulin response via beta-cell rest and reduction of glucotoxicity (Meneghini, Liebl, & Abrahamson, 2010). However, there are a number of additional strategies available. Patients may be required to start insulin therapy using a basal insulin and prandial insulin based on initial levels of hyperglycemia (Hirsch & Brownlee, 2005), and premixed insulins can provide specific benefits as well. Each regimen presents benefits and risks, balancing improved glycemic control with potential risk of hypoglycemia and/or weight gain. Data from the UKPDS demonstrated that the addition of insulin can result in modest weight gain over time (UKPDS 33, 1998) and, as different weight gaining potentials can be attributed to the different types of insulin available (Holman et al., 2007), this must be considered when treatment is initiated.

Basal insulins.

Basal insulins can be introduced with once-daily dosing using a “start low and go slow” policy (Bolli & Owens, 2000; Havelund et al., 2004; Riddle, 2004). Three different basal insulins are most commonly utilized: glargine, detemir, and neutral protamine Hagedorn (NPH), each with distinct properties that may be beneficial for different patients. Glargine and detemir have similar pharmacokinetic/pharmacodynamic profiles and are indicated for once-daily therapy. These modern basal insulin analogs carry a lower risk of nocturnal and prebreakfast hypoglycemia in T2D compared to the traditional basal human insulin NPH (Hermansen et al., 2006; Home & Kurtzhals, 2006; Riddle, Rosenstock, & Gerich, 2003). For example, compared to NPH, insulin glargine is associated with a 16% reduced incidence of symptomatic hypoglycemia (relative risk [RR] 0.84, 95% confidence interval [CI] 0.75–0.95 [Horvath et al., 2007] and between 2.5 and 3.8 fewer events/patient-year [Duckworth & Davis, 2007]), overall hypoglycemia reductions of 11% (RR 0.89, 95% CI 0.83–0.96 [Tran et al., 2007]), and nocturnal hypoglycemia reduced 34% and 43% (RR 0.66, 95% CI 0.55–0.80, p<.0001 [Horvath et al., 2007] and RR 0.57, 95% CI 0.44–0.74 [Tran et al., 2007]). Similarly, compared to NPH, insulin detemir is associated with reduced incidence of symptomatic hypoglycemia (4.9 vs. 9.7 events/patient-year), overall hypoglycemia reductions of 28% (RR 0.82, 95% CI 0.74–0.90, p<.0001), and nocturnal hypoglycemia reductions of 37% (RR 0.63, 95% CI 0.52–0.76, p<.00001 [Horvath et al., 2007]). It needs to be taken into consideration, however, that NPH is a more economical choice and for some patients this is a real issue. Patients with the dawn phenomenon (abnormal early morning hyperglycemia possibly as a result of overnight hormone release) may find that NPH given at bedtime can improve the fasting glucose level.

Insulin detemir also has been associated with reduced weight gain versus other basal insulins, both in basal–OAD and basal–bolus regimens, in clinical and observational studies (Dornhorst et al., 2008; Haak, Tiengo, Draeger, Suntum, & Waldhäusl, 2005; Hermansen et al., 2006; Mitri & Hamdy, 2009; Philis-Tsimikas et al., 2006; Raslová et al., 2004; Tinahones, Martin, Carndona, & Macias-Gonzalez, 2008). Figure 4 depicts reduced weight gain with insulin detemir versus NPH in equivalent dosing regimens (e.g., once-daily vs. once-daily, twice-daily vs. twice-daily). This weight advantage with insulin detemir may be beneficial for patients struggling with weight management. The concept of basal insulin plus OADs has gained great popularity in recent years because it is well tolerated, and can be intensified at a later stage by the addition of prandial insulins once patient confidence is established (Marre, 2002).

Figure 4
Figure 4:
Reduced weight gain with insulin detemir versus neutral protamine Hagedorn (NPH). Data from Haak et al. (2005), Hermansen et al. (2006), Philis-Tsmikas et al. (2006), and Raslová et al. (2004). *Insulin detemir once daily + oral antidiabetic drug (OAD) versus NPH once daily + OAD; †insulin detemir once daily or twice daily + insulin aspart versus NPH once daily or twice daily + human soluble insulin; ‡insulin detemir once daily or twice daily + insulin aspart versus NPH once daily or twice daily + insulin aspart.

Prandial insulins.

In addition to basal insulin analogs, several rapid-acting insulin options are available, including lispro, aspart, glulisine, and regular human insulin. The pathophysiology of T2D is characterized by notable attenuation of the prandial insulin response, with consequent postprandial hyperglycemia (Ceriello, 2003; DECODE, 1999; DeFronzo, 2004; IDF, 2007; Krssak et al., 2004; Monnier, Lapinski, & Colette, 2003). Thus, a short-acting (regular human) mealtime insulin could be considered the most physiologic approach to insulin initiation. However, such products are the most restrictive for the patient, as they often require three times daily dosing at mealtimes and the matching of dose to calorie consumption (Brange, 1997; Brange, Owens, Kang, & Vølund, 1990; DeWitt & Hirsch, 2003). Amino acid modifications in the rapid-acting analogs provide advantages over human regular insulin. The analogs have a faster onset of action compared with human regular insulin (5–15 vs. 30–60 min, respectively) as well as a shorter duration of action (Chapman et al., 2002) that can lead to several benefits. The rapid-acting insulin analogs can be dosed at mealtimes, providing greater flexibility, while short-acting regular insulin should be dosed 30 min before a meal. If the injection timing is not accurate with regular insulin, the risk of hypoglycemia is heightened (Barnett & Owens, 1997; Brange, 1997; Brange et al., 1990; Holman et al., 2007; Overmann & Heinemann, 1999). Patients’ willingness to take and self-manage mealtime insulin is an important consideration for prandial insulin regimens.

Premixed insulins.

Patients may find a premixed product, which combines a fixed dose of basal and regular or analog rapid-acting insulin to be more convenient (Fonseca et al., 2010). Premixed insulins also carry the risk of hypoglycemia if the injection timing is not matched to the meal. This is particularly true for the basal/regular combination. In most cases, the premix analogs are preferred as the rapid-acting insulin better match the prandial glucose rise and fall. Premix insulin injections can be taken initially with the largest meal, then at a second meal for twice-daily premix therapy, or even with a third meal in the case of premix analogs, if greater control is needed (Garber et al., 2006). If suboptimal control persists on two or three premix insulin injections, patients may be switched to basal–bolus therapy (once-daily basal insulin + prandial insulin, twice or three times daily, as required).

Comparing differing initiation options.

In the 4-T study, the addition of basal, prandial, or premixed insulin as first insulin therapy to OADs resulted in clinically relevant and sustainable reductions in HbA1c levels, with biphasic, prandial, and basal regimens lowering HbA1c from 8.6% to 7.3%, from 8.6% to 7.2%, and from 8.4% to 7.6%, respectively, after 1 year (Holman et al., 2007). After 3 years of follow-up, however, HbA1c decreased to 7.1%, 6.8%, and 6.9% for the three regimens, respectively, with no significant difference between these results (Holman et al., 2009). Additionally, in the 1-year study and the 3-year follow-up study, the cumulative burden of hypoglycemia and weight gain was lowest when insulin was started with a basal-only regimen, suggesting it may be particularly beneficial for certain patients. Similar results have been reported from the DURAbility of Basal versus Lispro mix 75/25 insulin Efficacy (DURABLE) study, in which premixed insulin resulted in more weight gain and higher rates of overall hypoglycemia than basal insulin (Buse, J. B. et al., 2009).

Managing other therapies

Metformin and OADs.

When insulin is started, decisions often have to be made about the patient's other oral therapies. Diet and exercise should continue to help reduce insulin-related weight gain and improve insulin resistance. Metformin is generally continued, as it may act additively with insulin and mitigate the weight gain associated with insulin use. Other drugs, such as sulfonylureas and thiazolidinediones, are generally discontinued as a result of concerns about hypoglycemia and fluid retention, respectively (Nathan et al., 2009). However, in some clinical settings, the sulfonylurea may be continued during titration and discontinued when the patient approaches their glycemic target.

Incretin therapies.

In recent years, incretin-based therapies, GLP-1RAs, and DPP-4 inhibitors (which inhibit degradation of GLP-1) have been developed, as a result of the effects of GLP-1 to glucose dependently improve insulin secretion and decrease glucagon secretion, as well as slowed gastric emptying and enhanced satiety, and have entered clinical use. These therapies offer the advantage of carrying a very low risk of hypoglycemia (Gautier, Choukem, & Girard, 2008; Neumiller, 2009; Richter, Bandeira-Echtler, Bergerhoff, & Lerch, 2008; Russell-Jones, 2009). As an additional benefit of GLP-1RAs, mean weight loss ranging from 0.2 to 3.24 kg and 1.2 to 7.1 kg has been reported with both liraglutide (1.8 mg once daily) and exenatide (10 μg twice daily), respectively, compared to active comparators (Apovian et al., 2010; Buse, J. et al., 2009; DeFronzo et al., 2005; Gao et al., 2009; Garber et al., 2009; Kadowaki et al., 2009; Kendall et al., 2005; Marre et al., 2009; Nauck et al., 2009; Russell-Jones et al., 2009; Shyangdan, Royle, Clar, Sharma, & Waugh, 2010; Zinman et al., 2007, 2009). Studies of DPP-4 inhibitors (e.g., saxagliptin, sitagliptin) have found overall weight neutrality (Richter et al., 2008). These studies also found reductions in mean HbA1c levels ranging from 1.0% to 1.5% with once-daily liraglutide and from −0.77% to −1.21% with twice-daily exenatide. DPP-4 is are associated with slightly smaller HbA1c reductions of 0.6%–0.7% (Richter et al., 2008) and one head-to-head study (Pratley et al., 2010) found greater reductions following treatment with liraglutide compared to sitagliptin. Studies also demonstrate improved glycemic control when DPP-4 inhibitors or GLP-1RAs are either added to a basal insulin (Fonseca et al., 2007; Yoon et al., 2009) or given prior to insulin (Buse et al., 2011), although current guidelines do not give evidence-based advice on the combination of incretins with insulin (use with insulin is off-label except for sitagliptin and exenatide and insulin detemir with liraglutide). In October 2011, the FDA approved the use of exenatide as add-on therapy with glargine in patients with T2D. Moreover, as these drugs stimulate insulin secretion in a glucose-dependent manner, they tend to improve insulin secretion after meals during periods of hyperglycemia, thereby lessening the risk of hypoglycemia with insulin therapy (Fonseca et al., 2007; Neumiller, 2009). GLP-1RAs also glucose dependently suppress alpha-cell glucagon secretion, which means they potentially may be effective alongside insulin even when beta-cell function is severely limited. While the addition of a DPP-4 or GLP-1RA might enable insulin dose reduction in overweight insulin-resistant patients (Lane, Weinrib, & Rappaport, 2011; Tzefos & Olin, 2010), it may be preferable to establish patients on an incretin therapy before insulin initiation (Charbonnel & Cariou, 2011). This approach may avoid the problem of down-titrating the insulin dose, which would simplify insulin initiation. As more patients are treated with incretins, many clinicians predict it may become common practice to add insulin to these agents with the expectation of lower insulin dose requirements.

Adverse drug reactions associated with DPP-4 inhibitors include headache, nasal congestion, upper respiratory tract as well as urinary tract infections, and pancreatitis. In severe cases, hypersensitivity reactions can include angioedema, anaphylaxis, and exfoliative skin diseases such as Stevens–Johnson syndrome. DPP-4 inhibitors have an advantage over sulfonylureas and thiazolidinediones, in that they are weight neutral. This class of medications can be used in patients with diminished renal function, making them a valuable addition to drug therapy used for T2D.

GLP-1RAs also carry the risk for pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis according to post marketing data. In mice and rats, liraglutide causes thyroid C-cell tumors but there are no data confirming this in humans. Because of its mechanism of action in the gut, GLP-1RAs are contraindicated in patients with severe gastrointestinal disorders including gastroparesis.


Insulin is a natural continuation of the T2D treatment sequence and should not be feared or viewed as a consequence of behavioral failure on the patient's part. The progression to treatment with insulin should not be delayed, and patients should be encouraged and supported to take this step. Current insulins and injection devices are much better accepted than providers often realize, and advances continue to reduce the risk of hypoglycemia and offer greater flexibility in dosing. The use of pen devices, coupled with sensitive counseling and support from the NP, can make insulin initiation an easy process for the patient. The efficacy of insulin can be enhanced by the continued use of metformin and/or incretin therapies, while some other drugs become redundant or increase the potential for side effects and should be discontinued.


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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Insulin therapy; type 2 diabetes; patient education

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