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Therapeutic choices, and the nurse practitioner's role, in type 2 diabetes when metformin alone is no longer enough

Tierney, Kathryn MSN, APRN-BC, FNP (Nurse Practitioner)1

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Journal of the American Academy of Nurse Practitioners: April 2012 - Volume 24 - Issue - p 234-248
doi: 10.1111/j.1745-7599.2012.00720.x


Type 2 diabetes (T2D) is a chronic, progressive disease requiring both patients and healthcare providers to make ongoing informed choices about lifestyle and drug therapies. Choosing appropriate therapies is crucial to maintaining blood glucose as close to normal levels (glycated hemoglobin [A1c] levels of 4.5–6%) as possible (referred to as “glycemic control”) and to avoid the long-term complications associated with chronically high glucose levels. These long-term complications include microvascular disorders (e.g., kidney and eye complications) and macrovascular disorders (the cardiovascular system) that can lead to an increased risk of heart attacks and stroke (ADA, 2011). When choosing appropriate therapies, it must be remembered that T2D is more than just high blood glucose and, as such, healthcare providers, including nurse practitioners (NPs), should pay careful attention to blood pressure, lipids, and other parameters as part of a comprehensive diabetes management program.

The mainstay of treatment early in the disease course is usually lifestyle modification with metformin, unless metformin is contraindicated. However, given the progressive nature of T2D, additional pharmacologic interventions will eventually be required by most patients. With the NP in particular in mind, this article outlines the usual treatment course early in the disease and how this relates to established treatment consensus statements, followed by a more detailed consideration of the options for combination therapy when first-line pharmacologic interventions become inadequate. The subsequent article in this series will examine the options available to patients when a patient's endogenous insulin secretion is sufficiently compromised (i.e., beta-cell failure) to warrant exogenous basal insulin therapy (Kruger, 2012; Spollett, 2012).

The early stages of T2D: First-line therapy

For patients at risk of developing T2D, lifestyle modifications, such as changes in diet and increased physical activity, are the first line of therapy recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) and by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) (Nathan et al., 2009; Rodbard et al., 2009). As discussed in the preceding article (Robertson, 2012), comprehensive patient education is key to successful treatment, not least at this early stage, and one of the important roles of NPs is to help engage and motivate patients to manage their condition, whether this is during the implementation of physician-directed care or during direct management of the condition.

For newly diagnosed patients in the early stages of the disease, metformin should be prescribed unless contraindicated (e.g., in cases of renal impairment) or not tolerated (Nathan et al., 2009). The aim of lifestyle and metformin therapy is to help patients to reach recommended blood glycemic “targets.” These targets are most commonly based on a measure of A1c levels and currently the ADA/EASD recommend an A1c target of <7%, and the AACE/ACE ≤6.5% (Table 1; Nathan et al., 2009; Rodbard et al., 2009). Of course, it is important to remember that, in some patients, achieving these targets may be neither possible nor practical, and more realistic goals may have to be agreed upon. Thus, the key message is that all T2D treatment choices should be evaluated on an individual basis, taking into account comorbidities, patients’ wishes, and ages, and should consider the impact of a new treatment on patients’ quality of life.

Table 1
Table 1:
Key recommendations for T2D management (data from Nathan et al., 2009; Rodbard et al., 2009).

In all cases, it is important to closely monitor disease progression through regular blood glucose monitoring. Both the ADA/EASD and AACE/ACE consensus statements recommend that patients using metformin are assessed every 3–6 months to establish if they are achieving or maintaining their glycemic goals. In my experience, routine A1c screening every 3 months is generally optimal. Only patients who have well-controlled blood glucose levels and stable lifestyles (in terms of exercise, diet, and work) would have A1c screening intervals increased to intervals of 4–6 months. For patients not achieving glycemic goals, titration of metformin, up to a maximal dose of 2000–2500 mg/day, may prove beneficial. In certain patients, the glycemic goal may need reevaluation, with a more realistic target set. In our experience, while an A1c value of ≤6.5% would be our primary objective, the realistic target depends entirely upon the individual patient and will be dictated by their age, comorbidities, and risk of hypoglycemia (Rodbard et al., 2009).

In the early stage of T2D, metformin is the most commonly used first-line pharmaceutical intervention as it is widely available, inexpensive, and there is substantial evidence to support its efficacy and safety at this stage in the treatment pathway (ADA, 2011; Nathan et al., 2007; Nathan et al., 2009). Metformin monotherapy typically lowers A1c levels by ˜1.5% and with its low risk of hypoglycemia has been used safely in patients with prediabetic hyperglycemia (Bailey & Turner, 1996; DeFronzo & Goodman, 1995; Knowler et al., 2002). The ADA/EASD guidelines consequently recommend metformin alongside lifestyle interventions at diagnosis and the AACE/ACE recognize metformin as the most appropriate choice for initial monotherapy and a cornerstone for ongoing treatments (see Table 2; Nathan et al., 2009; Rodbard et al., 2009). Moreover, metformin is not associated with weight gain, unlike some of the other oral antidiabetic drugs (OADs), and this is particularly important in patients who are overweight or obese (Bennett et al., 2011; Saenz et al., 2005). When metformin is contraindicated (or subsequently not tolerated), glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), and α-glucosidase inhibitors are alternatives considered by the AACE/ACE as appropriate first-line monotherapies when A1c values are in the range 6.5%–7.5% (Rodbard et al., 2009). It is important to note however, that the AACE/ACE algorithm predates the approval of liraglutide, and thus the recommendation for GLP-1 receptor agonists essentially refers only to twice-daily exenatide. Since the approval of liraglutide, the AACE/ACE has commented on the favorable hypoglycemic and weight-loss profile of liraglutide, although specific recommendations regarding its use have not been made (AACE, 2011). It is also important to be aware that, in the United States, the use of rosiglitazone is now severely restricted and α-glucosidase inhibitors are rarely prescribed.

Table 2
Table 2:
Preferred options for triple therapy regimens in T2D patients with A1c of 7.6%–9% (data from Nathan et al., 2009; Rodbard et al., 2009)

Tips for adding agents on to metformin

  • For almost all patients, at some point in the course of their treatment, lifestyle modification and metformin alone will no longer be enough to maintain adequate glycemic control.
  • Consider both clinical and individual patient factors when choosing between available therapies.
  • Consider potential contraindications, including renal and hepatic insufficiency.
  • Aim to match the efficacy and safety profiles of particular drugs to the needs to the patient.
  • Continue support and education to manage expectations of any new therapies introduced.
  • Monitor regularly and do not delay intensifying treatment when glycemic targets are not reached using existing regimens.

Progressing to combination therapy: The importance of treatment guidelines

Because of the progressive nature of T2D, many patients will move on to combination therapy (i.e., add one or more drugs into their monotherapy regimens) to maintain glycemic control. In 1995, metformin, sulfonylureas (SUs), and insulin were the only treatment options, and thus progressing through the limited treatment pathway was relatively straightforward. Now, there are 10 or more classes of antidiabetes agents available and thus guidelines (ADA, 2011) and consensus statements (ADA/EASD or AACE/ACE) (Nathan et al., 2009; Rodbard et al., 2009) have become ever more valuable tools in deciding the most appropriate treatment intensification strategy. That notwithstanding, the wealth of treatment options does also mean that it has not been possible to develop universally agreed upon standards. The key differences between the ADA/EASD and AACE/ACE algorithms, for example, are outlined in Table 1. The algorithm published by the AACE/ACE (Rodbard et al., 2009) makes combination therapy recommendations based upon patients’ A1c levels at the time patients present with suboptimal glycemic control and includes all currently available and FDA-approved treatments. The algorithm proposes that patients with A1c values of 6.5%–7.5% who have been unable to maintain glycemic control with lifestyle modification and metformin, or drug naïve patients who present with A1c values of 7.6%–9.0% should initiate noninsulin combination pharmacotherapy. At A1c values of >9.0%, only drug-naïve patients without symptoms of hyperglycemia would initiate noninsulin combination therapy. Drug-naïve patients presenting with symptoms of hyperglycemia and A1c values >9.0% should initially use insulin therapy without delay as the consequences of uncontrolled hyperglycemia can be severe (Hillson, 2008).

In contrast to the AACE/ACE algorithm, the ADA/EASD algorithm indicates that treatment intensification to combination therapy should occur when A1c levels are >7% and its recommendations focus more on well-established treatments. Thus, the ADA/EASD provides a two-tier algorithm with well-validated core therapies in tier 1 and less well-validated treatments in tier 2. Tier-1 treatments represent the most widely used and older agents, for which there are long-term efficacy and safety data. Furthermore, these agents are also considered to be the most cost-effective therapeutic strategies for achieving glycemic goals. With these considerations in mind, tier-1 agents are the preferred route for the majority of patients. Depending on a patient's individual circumstances, either or both of the AACE/ACE and ADA/EASD algorithms might be used to guide treatment intensification. It is important to note, however, that these algorithms are not intended to be static and will continue to evolve as more drugs come to market, clinical experience with newer agents increases, and long-term data become available. Consequently, treatment regimens may require modification in line with emerging evidence.

Dual therapy: Determining appropriate combinations

The concomitant use of two antidiabetic pharmacologic agents is known as dual therapy. This may arise from the addition of a second agent to first-line (usually metformin) treatment or by initiating two agents simultaneously in drug-naïve patients with high A1c values (7.6%–9.0%); in the latter case, one of the agents will usually be metformin (Rodbard et al., 2009). In general, the combination of two drugs should provide an additive effect on glycemic control (Bennett et al., 2011) and is arguably best realized by using agents with complementary modes of action. For example, metformin is a hepatic “insulin sensitizer” and helps to address one of the core problems of T2D, namely insulin resistance. Agents commonly used in combination with metformin, in contrast, tend to be those that stimulate or enhance insulin secretion (secretagogues), assuming beta-cell function is sufficient. Healthcare providers can, and should, account for other factors when choosing a second therapy; these include the need to minimize the potential for weight gain and/or hypoglycemia, relevant comorbidities that could preclude the use of certain second-line agents, and the regimen's compatibility with the patient's lifestyle and routine. This section considers those agents most commonly used in the United States in dual therapy, briefly detailing their mechanisms of action, modes of administration, and the advantages and disadvantages of their use. Additionally, the section describes differences in their uses as recommended by the ADA/EASD and AACE/ACE.

Traditional OADs

Insulin secretagogues

This group of antidiabetic treatments (Table 3) includes SUs and glinides, the latter often referred to as the meglinitides or prandial insulin secretagogues. SUs and glinides both act on pancreatic beta cells (although at slightly different locations) to stimulate the release of insulin and affect different phases of insulin secretion (Malaisse, 2003).

Table 3
Table 3:
Currently available FDA-approved insulin secretagogues.


SUs are effective OADs that can, compared to other antidiabetic agents such as TZDs, lower blood glucose by increasing insulin release from the beta cells in the pancreas (Kahn et al., 2006). They can be administered once, twice, or three times daily depending upon which SU is being used (Hillson, 2008). While all SUs can result in hypoglycemia, certain older, long-acting SUs such as glyburide and chlorpropamide have an increased risk of hypoglycemia compared with other agents in this class (Nathan et al., 2009). SUs stimulate the slow and sustained second phase of insulin secretion and consequently act more slowly. Typically, SUs are more effective at reducing A1c values than the glinides, which primarily affect postprandial (postmeal) glucose (PPG). Glimepiride and glipizide are preferred by ADA/EASD because of their lower potential for inducing hypoglycemia (compared to glyburide and chlorpropamide).


SUs are able to lower A1c values by 1%–2% as monotherapy and in general are longer acting than glinides. The slower action of SUs mean that they are the preferred option in patients with elevated fasting plasma glucose (FPG) (Rodbard et al., 2009), but are associated with weight gain and so may not be suitable for overweight individuals.

Contraindications and side effects.

The main safety concern with SUs is hypoglycemia, as these agents stimulate insulin secretion irrespective of glucose concentration. Consequently, these agents are linked with defensive snacking and associated weight gain, in a similar manner to that observed with insulin treatments (Khan, 2004). SUs should not be used in individuals with glucose-6-phosphate dehydrogenase deficiency because of risk of hemolytic anemia (Amaryl [glimepiride] 2009).

Place in therapy.

The place for SUs in the ongoing treatment of T2D varies substantially between the algorithms published by the AACE/ACE and ADA/EASD. Neither association recommends the use of these agents for monotherapy; however, the ADA/EASD does include SUs in tier 1 of their algorithm, indicating the preferential use of these agents over all other noninsulin medications, particularly when A1c is <8.5% and there are no symptoms of hyperglycemia. Treatments occurring in tier 1 of the algorithm represent the most well validated, effective, and economical treatments available for achieving glycemic targets (Nathan et al., 2009). By contrast the AACE/ACE does not recommend SUs until after incretin therapies and TZDs (discussed later) have been considered. The disparity between these recommendations highlights the different approach taken by the two associations (Table 1). In summary, the ADA/EASD recommends SUs after metformin failure because of their wide availability, low cost, and extensive use. In contrast, the AACE/ACE does not consider the use of SUs until after incretin-based therapies or TZDs had first been considered. This is because of the increased risk of hypoglycemia, particularly in elderly patients and those with A1c values <7.5% often observed with SUs, particularly in drug-naïve individuals, compared with comparator antidiabetic treatments (Derosa et al., 2009; Gerich, Raskin, Jean-Louis, Purkayastha, & Baron, 2005; Rodbard et al., 2009).

SUs are effective agents for reducing blood glucose and in some cases can provide flexibility in mealtime dosing, for example, small meal, small dose (Hillson, 2008). However, the association of SUs with an increased risk of hypoglycemia, particularly when added to metformin (Handelsman et al., 2011), in addition to the negative effects on weight mean that these agents may be unsuitable for certain patient subtypes, such as the elderly or those who are overweight. These agents are also cautioned against for patients with renal problems, a common comorbidity in patients with T2D. The benefit to risk balance should therefore be considered at an individual patient level before treatment is initiated.


Glinides are rapidly effective orally administered, antidiabetic agents, typically administered just before meals (Nathan et al., 2009). They exert their effect in a similar way to the SUs (Nathan et al., 2009; Rodbard et al., 2007) but in contrast produce earlier insulin secretion. They therefore have a fast and short duration of action, resulting in reductions in PPG (Hillson, 2008; Rodbard et al., 2009), with little effect on FPG (Blicklé, 2006). They are consequently associated with a low risk of late postprandial hypoglycemia (Rodbard et al., 2009). These agents are useful in patients who require short-acting preparations and for those who require flexible mealtime doses (Hillson, 2008). Furthermore, glinides are mainly removed by the liver and so can be useful in patients with renal insufficiency (Blicklé, 2006; Prandin® prescribing information [repaglinide], 2011; Starlix® prescribing information [nateglinide], 2011).


Glinides are reported to reduce A1c by between 0.5% and 1.5% (Nathan et al., 2009). Of the two available glinides, repaglinide has been shown to be more effective than nateglinide at reducing A1c and FPG when used combination with metformin (Raskin et al., 2003). Nateglinide is actually less effective at reducing A1c than metformin and so is only ever used in combination therapies (Blicklé, 2006).

Contraindications and side effects.

Because of the more potent effect on lowering blood glucose, repaglinide is associated with a greater incidence of minor hypoglycemia compared with nateglinide, and may cause weight gain (Rosenstock et al., 2004). In addition, in patients with severe renal impairment, repaglinide should be initiated at a dose of 0.5 mg and be carefully titrated thereafter (Prandin® prescribing information [repaglinide], 2011). In patients with hepatic impairment, repaglinide and nateglinide should be used with caution (Prandin® prescribing information [repaglinide], 2011; Starlix® prescribing information [nateglinide], 2011).

Place in therapy.

The ADA/EASD algorithm did not include glinides in either tier of its algorithm, rather choosing to categorize these agents under “other therapies.” The rationale for this was that glinides were considered to have lower glycemic efficacy compared with first- and second-tier agents and were relatively expensive. The AACE/ACE, by contrast, recommend glinide use before SU use in patients with A1c values between 6.5% and 7.5%, primarily because they are less likely to induce hypoglycemia in patients with lower A1c values. In patients with A1c values >7.6% glinides are recommended after SUs have been considered (Rodbard et al., 2009). From a practical perspective glinides are most suitable for use in patients where there is a need to control PPG excursions, and particularly in patients whose A1c values are <7.5%. The need to administer these agents multiple times daily (at meal times) may be problematic for patients who find treatment adherence difficult and SUs, used 1–2 times a day, may help improve compliance in these particular patients. Furthermore, cost may preclude the use of glinides in certain healthcare environments, as similar SU agents are inexpensive and more readily available.



TZDs work through peroxisome proliferator-activated receptor gamma (PPAR-γ) to increase the sensitivity of skeletal muscle and adipose tissue to insulin with a weaker effect on the liver. Monotherapy with TZDs can decrease A1c values by between 0.5% and 1.5%. However, recent safety concerns and adverse events have reduced their use, particularly rosiglitazone, which is now restricted in the United States. Furthermore, TZDs are relatively expensive compared to metformin and SUs.

Contraindications and side effects.

Pioglitazone and rosiglitazone are the only FDA-approved TZDs still available; troglitazone troglitazone was withdrawn over 10 years ago due to liver toxicity. Although risk of hypoglycemia is low with TZDs, the main adverse effects are peripheral edema and associated weight gain, as well as an increased risk of bone fractures. Pioglitazone has been linked with an increased risk of bladder cancer, hepatic effects, and macular edema. Both have received black box warnings with respect to congestive heart failure and are contraindicated in patients with New York Heart Association (NYHA) class 3 or 4 heart failure. Rosiglitazone, but not pioglitazone, has also been associated with an increased risk of myocardial infarction (Bennett et al., 2011). The FDA has consequently restricted the use of rosiglitazone-containing medications as part of a Risk Evaluation and Mitigation Strategy (REMS), designed to manage serious risks of marketed drugs. In order to prescribe and receive rosiglitazone-containing medicines, patients and healthcare providers are now required to enroll in the Avandia-Rosiglitazone Medicines Access Program (Avandia® prescribing information [rosiglitazone], 2011a).

Place in therapy.

In the ADA/EASD algorithm pioglitazone was the only TZD included, and then only as a tier 2 therapy. Both TZDs were included in the AACE/ACE algorithm as they were primarily associated with a lower risk of hypoglycemia compared with SUs (Bennett et al., 2011) in addition to providing patients with greater flexibility with respect to timing of administration (Rodbard et al., 2009). However, following the release of the ADA/EASD algorithm, many studies have been published regarding the safety of TZDs, and the FDA have issued updated safety communications regarding their use (FDA, 2011).

Currently, patients using pioglitazone are recommended to continue unless otherwise advised by their healthcare provider. However, as indicated above, rosiglitazone is only available through a restricted distribution program and only prescribers who acknowledge the potential increased risk of myocardial infarction associated with its use should prescribe this drug (Avandia®[rosiglitazone] Risk Evaluation and Mitigation Strategy, 2011b). These safety concerns were identified and debated following the publication of both the AACE/ACE and ADA/EASD algorithms and are therefore still included. Situations such as this should reinforce the fact that any published recommendations or official guidelines are not fixed but evolve over time to reflect not only emerging clinical and postmarketing safety and adverse event data, but also the existence of “newer” treatments coming to market. It is also therefore vitally important that healthcare providers are aware of updates to the current guidelines and appreciate the need to continually reevaluate a patient's treatment in light of new evidence and changes in labeling.

Newer antidiabetic agents: Incretin-based therapies

The incretins are gut-derived hormones (principally glucose-dependent insulinotropic polypeptide [GIP] and GLP-1). They promote the secretion of insulin from pancreatic beta cells in the presence of elevated blood glucose, and a decrease in the release of glucagon. In the fasting state, these hormones are secreted at low basal levels, but increase rapidly and transiently following food ingestion. In patients with T2D, the incretin effect (Drucker et al., 2010) is greatly reduced and the insulinotropic effect of GIP is largely absent. GLP-1, however, retains physiologic activity in patients with T2D and hence antidiabetic therapies have focused on GLP-1 and ways in which the insulinotropic effect of this hormone can be utilized. As a consequence two classes of drugs—the DPP-4 inhibitors and GLP-1 receptor agonists—have been developed, collectively termed “incretin-based” therapies (Table 4).

Table 4
Table 4:
Currently available and FDA-approved incretin-based therapies.

DPP-4 inhibitors

DPP-4 inhibitors target the incretin system, but rather than acting directly at GLP-1 receptors to promote insulin secretion, this drug class inhibits the DPP-4 enzyme responsible for terminating the action of GLP-1 and GIP. By inhibiting the DPP-4 enzyme, the time that gut-released GLP-1 and GIP hormones remain in circulation is prolonged and enables secretion of insulin to continue for longer.


In clinical trials, DPP-4 inhibitors have had modest efficacy in the range 0.5%–0.8% (Nathan et al., 2009; Rodbard et al., 2009). However, unlike SUs, they are not associated with a high risk of hypoglycemia, as their activity is glucose dependent (i.e., only during hyperglycemia). In combination with metformin, reductions in A1c levels with DPP-4 inhibitors are greater than using either agent alone, and are not associated with an increase in the number of hypoglycemic events (Bennett et al., 2011). DPP-4 inhibitors can reduce FPG and PPG and are therefore recommended in patients where these parameters are elevated (Rodbard et al., 2009). Furthermore, DPP-4 inhibitors do not promote weight gain and are considered to be weight neutral (Nathan et al., 2009).

Contraindications and side effects.

DPP-4 inhibitors are not associated with any major long-term toxicities, although some rare allergic reactions have been described for sitagliptin, and saxagliptin (as well as with the metformin combinations) (Janumet® prescribing information [sitagliptin/metformin], 2011; Januvia® prescribing information [sitagliptin], 2011; Kombiglyze® prescribing information [saxagliptin/metformin], 2011; Onglyza® prescribing information [saxagliptin], 2011; Rodbard et al., 2009). Main adverse effects are upper respiratory infections and headache. As DPP-4 inhibitors (with the exception of linagliptin) are cleared through the kidneys, dosages need to be reduced in patients with moderate (sitagliptin) or severe (sitagliptin and saxagliptin) renal impairment (Rodbard et al., 2009). Linagliptin, however, appears safe for use in patients with any degree of renal impairment (Graefe-Mody et al., 2011). Sitagliptin has been associated with some postmarketing reports of acute pancreatitis (not detected during initial trials), acute renal failure, and severe allergic reactions and if these adverse events are suspected, treatment should be discontinued (Januvia® prescribing information [sitagliptin], 2011). With saxagliptin upper respiratory and urinary tract infections are more common but acute pancreatitis has not been reported (Onglyza® prescribing information [saxagliptin], 2011). Fixed combination formulations of metformin plus sitagliptin and saxagliptin tend to be associated with rare occurrences (0.03 cases/1000 patient years) of lactic acidosis because of metformin accumulation. If suspected, patients should discontinue treatment and be hospitalized immediately (Janumet® prescribing information [sitagliptin/metformin], 2011; Kombiglyze® prescribing information [saxagliptin/metformin], 2011). The combination of sitagliptin and simvastatin (Juvisync™ prescribing information [sitagliptin/simvastatin], 2011) has recently been approved by the FDA. Extensive clinical experience with this combined formulation is not yet available; however, in clinical studies of sitagliptin involving patients whose background therapy included simvastatin, the incidences of adverse reactions for patients treated with sitagliptin and simvastatin were similar to those for patients treated with control therapy (placebo or active comparator) and simvastatin (Juvisync™ prescribing information [sitagliptin/simvastatin], 2011).

At the time of writing, linagliptin has recently received FDA approval and extensive safety data are not currently available; however, the most common side effects reported for this drug so far have been upper respiratory tract infections, muscle pain, and headaches (Tradjenta® prescribing information [linagliptin], 2011).

Place in therapy.

There are currently three DPP-4 inhibitor-related treatments available for use in the United States, and as the vast majority of patients also use metformin, sitagliptin and saxagliptin are available in fixed combinations with metformin (see Table 4). All DPP-4 inhibitors, including the metformin combinations, are supplied as a single tablet and taken orally, generally once or twice a day with or without food.

The ADA/EASD algorithm did not include DPP-4 inhibitors in either of the two tiers of preferred agents, choosing to relegate these therapies in to the category of “other therapies.” This decision was reported as being because of lower glycemic efficacy, limited clinical data, and relative expense of these treatments compared with other first- and second-tier agents (Table 1). In contrast, the AACE/ACE algorithm gave DPP-4 inhibitors a higher priority for use in add-on therapy to metformin and lifestyle, second only to the GLP-1 receptor agonists (see later). A good safety profile (in particular, the low risk of hypoglycemia) and modest glycemic efficacy, coupled with the absence of weight gain, are the main reasons that the AACE/ACE recommended DPP-4 inhibitors compared with other nonincretin-based treatments. DPP-4 inhibitors were not considered the first-choice incretin-based therapy because GLP-1 receptor agonists provide greater glycemic efficacy, are additionally associated with weight loss, and have additional potential benefits such as beta-cell protection and positive effects on blood pressure (Nathan et al., 2009; Rodbard et al., 2009).

From a practical perspective, DPP-4 inhibitors may be suitable choices for patients at risk of experiencing hypoglycemia, but who prefer an oral tablet over an injectable therapy as required for GLP-1 receptor agonists. Like metformin, DPP-4 inhibitors are oral agents and so do not represent a major change for patients with respect to treatment intensification. Furthermore, in patients where weight gain may be undesirable, these agents may provide suitable alternatives to agents such as SUs as they are weight neutral. Dose adjustment is required for sitagliptin and saxagliptin in patients with moderate, severe, or end-stage renal failure; however, the emergence of linagliptin (not excreted via the kidneys) makes it an attractive option for patients with renal disease, as no dose adjustment is necessary. These drugs are relatively new and costs are still relatively high and this may be a factor that needs careful consideration before treatment commences.

GLP-1 receptor agonists

Native GLP-1 is a gut-derived hormone secreted in response to meals and is responsible for promoting the glucose-dependent stimulation of insulin secretion. However, as the short half-life of native GLP-1 makes it of little clinical use, longer-acting therapies that are resistant to DPP-4 enzymatic breakdown have been developed. Exenatide is a twice-daily short-acting GLP-1 receptor agonist that is a synthetic form of exendin-4, which was originally isolated from the saliva of the Gila monster lizard (Heloderma suspectum). Exenatide has an amino acid sequence that is 53% similar to native GLP-1 (Göke et al., 1993) and exhibits resistance to degradation by endogenous DPP-4 enzymes, consequently, prolonging the duration of activity compared with native GLP-1 (Moller, 2001). Liraglutide is a once-daily human GLP-1 analog, sharing 97% amino acid sequence with native GLP-1. It can be dosed independently of meals but preferably at the same time each day. With liraglutide, minor modification of the native GLP-1 molecule, including the addition of a fatty acid moiety, promotes albumin binding and allows prolonged absorption in vivo, while also offering resistance against the action of DPP-4 (Wick & Newlin, 2009). Exenatide (Byetta® prescribing information, 2011) and liraglutide (Victoza® prescribing information, 2011) are currently approved by the FDA for the treatment of T2D. A longer-acting version of exenatide that allows for once-weekly administration has recently received approval in the United States.


The GLP-1 receptor agonists are most useful as add-on therapy for patients with inadequately controlled T2D on diet and exercise and oral monotherapy and who do not have a history of pancreatitis (discussed in the following section). From clinical trial data, GLP-1 receptor agonists are typically expected to deliver a reduction in A1c of between 0.4% and 1.5% (Nauck, 2011). In head-to-head trials, GLP-1 receptor agonists have been shown to have greater glycemic and weight reduction efficacy than DPP-4 inhibitors (Bergenstal et al., 2010a, 2010b; Pratley et al., 2010). A large randomized phase 3 study over 52 weeks with liraglutide versus sitagliptin confirmed this observation. In this study, reductions in A1c were significantly greater for liraglutide 1.8 mg compared with sitagliptin (−1.51% vs. −0.88%, respectively; p<0.0001; Figure 1), as were reductions in weight (−3.68 kg vs. −1.16 kg, respectively; p<0.0001; Pratley et al., 2011). This study also demonstrated that, compared with sitagliptin, patients treated with liraglutide (1.8 mg) had significantly (p<0.05) improved treatment satisfaction as determined by scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ). This was despite the need to inject liraglutide compared with the orally administered sitagliptin. This suggests that treatment outcomes such as improved glycemic control and weight loss are important drivers of treatment satisfaction and may help overcome treatment barriers, such as the need to inject. Interestingly, in an extension of this study (to 78 weeks) where patients stopped using the DPP-4 inhibitor (sitagliptin) and switched to liraglutide, further glycemic improvements were observed. In addition, DTSQ scores were again significantly improved with liraglutide (1.2 mg; Montanya et al., 2011; Pratley et al., 2011).

Figure 1
Figure 1:
Changes in A1c over 52 weeks of treatment with liraglutide (1.2 and 1.8 mg) and sitagliptin. (Data from Pratley et al., 2011.)

Similar beneficial glycemic effects have been observed for exenatide when compared with sitagliptin. In a 4-week, randomized, crossover study in patients with T2D, subjects were treated with either exenatide (5 mg BID, Week 1; 10 mg BID, Week 2) or sitagliptin (100 mg once daily) for 2 weeks and then switched to the alternate treatment for the remaining 2 weeks. This study demonstrated that while both exenatide and sitagliptin could reduce 2-h PPG (2 h-PPG) levels from baseline (133 mg/dL and 208 mg/dL vs. 245 mg/dL, respectively), reductions were significantly greater for exenatide compared with sitagliptin treatment (p<0.0001). Furthermore, in patients who switched from sitagliptin to exenatide, 2-h PPG levels continued to reduce (−76 ± 10 mg/dL), whereas those subjects switching from exenatide to sitagliptin showed increases in 2-h PPG levels (+73 ± 11 mg/dL). Consistent with these postprandial glycemic benefits, exenatide also promoted increased insulin secretion and suppression of postprandial glucagon release compared with sitagliptin (DeFronzo et al., 2008).

Studies investigating the efficacy of long-acting exenatide (exenatide once weekly) against sitagliptin have also demonstrated significant A1c reductions with exenatide once weekly (−1.5% vs. −0.9%, respectively, p<0.0001). Once again these glycemic improvements were accompanied by significant additional benefits, such as weight loss (−2.3 kg vs. −0.8 kg, respectively, p=0.0002) and as observed for liraglutide, exenatide once-weekly treatment was associated with improvements in treatment satisfaction (DTSQ) (Bergenstal et al., 2010b).

Overall, these data demonstrate there are key differences in the therapeutic actions of GLP-1 receptor agonists and DPP-4 inhibitors (sitagliptin) and consequently may have implications for their use in clinical practice (DeFronzo et al., 2008).

Head-to-head comparisons between the GLP-1 receptor agonists have also been performed in the Liraglutide Effect and Action in Diabetes (LEAD)-6 (Buse et al., 2009, 2010) and the DURATION-6 trials (Amylin, Eli Lilly & Co., 2011; Buse et al., 2011b). The LEAD-6 trial compared exenatide and liraglutide over an initial 26-week period (Buse et al., 2009), followed by a 14-week extension phase (Buse et al., 2010). The 26-week phase of the LEAD-6 trial demonstrated that while both agents were generally well tolerated, liraglutide was associated with significantly greater improvements in glycemic control compared with exenatide (Figure 2). In the 14-week extension phase, patients who switched to liraglutide were observed to have significant further improvements in A1c, weight, and systolic blood pressure, indicating the potential cardiometabolic benefits of liraglutide (Figure 2; Buse et al., 2010).

Figure 2
Figure 2:
Reductions in A1c values with exenatide and liraglutide treatment. © 2010, and reproduced with permission from American Diabetes Association, from Buse et al. (2010).

The DURATION-6 trial (Amylin, Eli Lilly & Co., 2011; Buse et al., 2011b) compared the long-acting exenatide once weekly with liraglutide over 26 weeks and demonstrated that reductions in A1c were greater with liraglutide compared with exenatide once weekly (−1.48% vs. −1.28%, respectively), significantly more patients reached A1c <7% (60.2% vs. 52.3%; p=0.008), and patients receiving liraglutide lost more weight than those taking once-weekly exenatide once weekly (−3.58 kg vs. −2.68 kg, respectively).

Contraindications and side effects.

While the incidence of hypoglycemia is low with GLP-1 receptor agonists, there are a few instances where they should be used with caution or they are contraindicated. For example, when used in combination with SUs, consideration should be given to reducing the dosage of the SU (Byetta® prescribing information [exenatide], 2011; Victoza® prescribing information [liraglutide], 2011). With regard to exenatide, excreted via the kidneys, patients with severe (Victoza® prescribing information [liraglutide], 2011) or end-stage renal disease should avoid this medication (Byetta® prescribing information [exenatide], 2011). Although clinical experience in patients with renal impairment is limited, liraglutide may be a more suitable option in these patients as it is completely degraded enzymatically in the body and does not pass through kidneys. However, there have been some postmarketing reports of renal failure and caution should be exercised when initiating or escalating doses of liraglutide in patients with renal impairment (Victoza® prescribing information [liraglutide], 2011). A recently published meta-analysis of data from the six LEAD studies showed that mild renal impairment had no effect on the efficacy and safety of liraglutide (Davidson, Brett, Falahati, & Scott, 2011).

Mild and transient nausea and vomiting are the most common side effects with both GLP-1 receptor agonists although these events are less persistent in patients using liraglutide compared with exenatide (Buse et al., 2009), Initial doses of each drug are consequently kept small to limit the extent of these problems: recommendations for liraglutide are a starting dose of 0.6 mg/day, escalated in weekly increments to 1.2 mg/day and (if necessary) 1.8 mg/day, while exenatide therapy should be initiated at 5 μg exenatide twice daily for at least 1 month prior to increasing (if necessary) to 10 μg. It is critical to manage a patient's expectations with regards to the use of GLP-1 receptor agonists, so that nausea does not come as a surprise, and the patient knows that it will very likely dissipate quickly (Handelsman et al., 2011; Victoza® prescribing information [liraglutide], 2011).

Patients with T2D are at three times the risk of developing pancreatitis compared with unaffected individuals; however, the use of GLP-1 receptor agonists has been associated with instances of pancreatitis in a small number of patients. With respect to exenatide, pancreatitis was identified through postmarket reporting, rather than during initial clinical trials, however, such observations ensured that pancreatitis monitoring was subsequently performed in future clinical trials of GLP-1 receptor agonist therapies, such as liraglutide. As a consequence, seven cases of pancreatitis were identified in the LEAD trials (Buse et al., 2009; Marre et al., 2009; Nauck et al., 2009; Victoza® prescribing information [liraglutide], 2011). Those using GLP-1 receptor agonists should therefore be monitored closely for risk factors (gallstones, excessive alcohol use, very high triglycerides), and signs/symptoms of acute pancreatitis and if suspected, treatment should be discontinued immediately (Byetta® prescribing information [exenatide], 2011; Elashoff, Matveyenko, Gier, Elashoff, & Butler, 2011; Victoza® prescribing information [liraglutide], 2011).

There have also been suggestions that GLP-1 receptor agonist treatment may cause the development of thyroid C-cell hyperplasia and neoplasia (Elashoff et al., 2011). Liraglutide has received a black box warning to this effect, because of observations made in rodents during preclinical development, and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma, or in patients with multiple endocrine neoplasia syndrome type 2 (Victoza® prescribing information [liraglutide], 2011). Patients starting liraglutide should be counseled regarding the risk for medullary thyroid carcinoma and the symptoms of thyroid tumors (masses in the neck, dysphagia, dyspnea, persistent hoarseness). If symptoms are noted patients should be referred to an endocrinologist for further evaluation (Victoza® prescribing information [liraglutide], 2011). However, monitoring of calcitonin, a marker of C-cell changes in several thousand patients with diabetes during liraglutide phase 3 trials, did not reveal a relationship between liraglutide therapy and plasma calcitonin (Hegedüs, Moses, Zdravkovic, Le Thi, & Daniels, 2011). Furthermore, human C-cells have barely detectable levels of GLP-1 receptors compared with the high levels on rodent C cells (Bjerre Knudsen et al., 2010). As with any new drug class, the long-term effects of GLP-1 receptor agonist treatment in humans will require further investigation (Hegedüs et al., 2011). Large trials such as Liraglutide Effect and Action in Diabetes Evaluation of Cardiovascular Outcome Results (LEADER®) over 5 years and other postmarketing activities required by the FDA are investigating long-term safety of these agents.

Although daily blood glucose monitoring is not required with GLP-1 receptor agonists (as they have a glucose-dependent mode of action), patients should be informed of the importance of adhering to previously established dietary restrictions, periodic glucose monitoring, and recognition of the signs of hypoglycemia. Further information regarding the use of these agents will be discussed in the article by Tom Bartol that appears later in this supplement (Bartol, 2012).

Place in therapy.

Exenatide and liraglutide are administered as a subcutaneous injection into the abdomen, thigh, or upper arm using a prefilled pen device, which should be demonstrated prior to use. Exenatide® (Byetta prescribing information, 2011) is a twice-daily injection, taken within 60 min prior to morning and evening meals, whereas liraglutide (Victoza® prescribing information, 2011) is given once daily, preferably at a consistent time, with or without food.

In Europe, exenatide once weekly is self-administered on the same day each week, using a vial and syringe system and reconstitution kit supplied with the medicine. Exenatide once weekly should be injected into the same sites as described for exenatide twice daily (European Medicines Agency, 2011). Healthcare providers should be aware, however, that in certain patient subgroups, such as the elderly who may have limited dexterity, exenatide once weekly may present significant challenges because of the complex reconstitution and administration procedure necessary with this agent.

GLP-1 receptor agonists were recommended in preference to glinides or SUs by the AACE/ACE as they are considered to be safer than these treatments and chosen over DPP-4 inhibitors because they are more effective in reducing A1c (Bennett et al., 2011; Pratley et al., 2010) and reducing PPG excursions, as well as weight (Rodbard et al., 2009). Overall, AACE/ACE consider GLP-1 receptor agonists as the most useful agents for metformin add-on therapy in patients (Handelsman et al., 2011), and recently exenatide has received FDA approval for use in conjunction with insulin glargine and diet and exercise in adults with T2D (Byetta® prescribing information [exenatide], 2011). However, the 2009 ADA/EASD algorithm only includes GLP-1 receptor agonists in tier 2, mainly as they considered these to be “less well-validated” therapies. Since these recommendations were developed, however, GLP-1 receptor agonists have been used extensively by large numbers of patients and updated versions of the ADA/EASD algorithm (currently underway) may reconsider this classification.

As with DPP-4 inhibitors, GLP-1 receptor agonists are particularly suitable in patients at risk of treatment-induced hypoglycemia, such as those with A1c value <7.5%. Furthermore, as these agents promote weight loss, their implementation into treatment plans for overweight and obese patients should be considered. Additional benefits such as reductions in blood pressure and improvements in cardiovascular disease risk markers may also make these agents desirable for use in patients with hypertension or a history of cardiovascular disease.

Beyond dual therapy

Because of the progressive nature of T2D, many patients will not be able to maintain long-term glycemic control with two (noninsulin) antidiabetic agents. Clearly, the next step depends on the current treatment plan and the individual circumstances of each patient. However, at this point, the ADA/EASD algorithm generally favors initiating insulin as an alternative dual therapy option, rather than progressing to noninsulin triple therapy combinations (Nathan et al., 2009). Such insulin-based regimens are covered in greater detail elsewhere in this supplement (Kruger, 2012; Spollett, 2012). The only triple-therapy option identified by ADA/EASD in their algorithm is metformin in combination with pioglitazone (a TZD) and an SU as one of the tier 2 (less well-validated) options. This contrasts with AACE/ACE, in which a number of triple-therapy combinations are recommended (Table 4; Rodbard et al., 2009). The combination of a TZD with a SU in triple therapy is noted, but it is not highly recommended as this combination is associated with weight gain and an increased risk of hypoglycemia (Rodbard et al., 2009). The use of DPP-4 inhibitors or GLP-1 receptor agonists, however, is generally well regarded because of the low risk of hypoglycemia and weight gain afforded by these agents, although these advantages may be ameliorated if in combination with an SU (Byetta® prescribing information [exenatide], 2011; Januvia® prescribing information [sitagliptin], 2011; Kombiglyze® prescribing information [saxagliptin/metformin], 2011; Onglyza® prescribing information [saxagliptin], 2011; Victoza® prescribing information [liraglutide], 2011). Regimens including GLP-1 receptor agonists might be favored over those including DPP-4 inhibitors, as the former can provide weight loss (depending on the other agents in the combination) rather than weight neutrality (Nathan et al., 2009). As no studies have investigated the concomitant use of GLP-1 receptor agonists and DPP-4 inhibitors, this is not currently recommended in any of the treatment algorithms (Nathan et al., 2009; Rodbard et al., 2009).

Recently, there has been interest in adding insulin therapy to GLP-1 receptor agonist-based dual therapy combinations, although such combinations are not approved by drug-regulatory authorities and are not included in ADA/EASD or AACE/ACE algorithms. (The addition of GLP-1 receptor agonists to established insulin therapy has also been considered [Buse et al., 2011a] and is discussed elsewhere in this supplement [Spollett, 2012].) The efficacy and safety of adding insulin detemir to patients not achieving glycemic control (A1c <7.0%) with metformin and liraglutide dual therapy has been investigated in a 52-week study (Rosenstock et al., 2011). Additional insulin detemir improved glycemic control while sustaining the weight loss and low rates of hypoglycemia achieved with metformin–liraglutide dual therapy. Such combinations may be a bridge to the more insulin-dominant regimens that become necessary with progressive beta-cell failure. These regimens are covered in greater detail elsewhere in this supplement (Kruger, 2012; Spollett, 2012).

The role of the NP

The role of the NP has evolved considerably in recent years. In all US states, NPs now have the authority to prescribe and intensify treatment for chronically ill patients autonomously within care settings. NPs are therefore important members of the multidisciplinary team supporting patients with T2D, having roles in both the development and implementation of treatment plans. This multidisciplinary approach to disease management forms part of the Chronic Care Model (CCM) of collaborative care (Wagner et al., 1996) and is a well-established organizational framework for chronic disease management. The CCM has six distinct concepts, healthcare organization, delivery system design, decision support, clinical information system, community resources and policies, and self-management support, that should be addressed in order to deliver optimal care for chronic illnesses (Bodenheimer, Wagner, & Grumbach, 2002). NPs, with their ability to address the multifactorial nature of chronic problems are particularly qualified to deliver chronic disease care within this framework (Fiandt, 2007). Many of the components of the CCM address alterations in practice management, for example, implementing clinical information systems to collate important individual and population patient data and the generation of practice teams designed to deliver effective, efficient clinical care through appropriate use of all team members, including the NP (Fiandt, 2007). However, a critical aspect of the CCM is to provide support and assistance for patients so that they can adequately self-manage their disease. In this situation NPs can play a vital role, being ideally placed to ensure patients are adequately educated about their diabetes and possess the skills and confidence to self-manage their condition. It is critical that patients understand their disease and appreciate that progression will occur even if treatment adherence is optimal. Patients should be made aware that diabetes progression is not a “failure” on their part and that because of limited beta-cell capacity there may ultimately be the need for exogenous insulin. NPs are well positioned to effectively deliver these messages and also to uncover any other concerns patients have with their treatments; for example, anxieties about weight gain or needle phobias. The close relationship between patient and NP is therefore extremely important, providing the opportunity to discuss new treatments or alterations to existing regimens in depth and ensure the specific needs and requirements of each patient are met.

Beyond treatment planning, the NP has a further obligation to continually monitor patients throughout their disease, carefully noting and recording any disease changes and acting upon these where necessary in order to optimize disease control. Certainly, additional treatments, if needed, should not be delayed, as the complications of uncontrolled hyperglycemia can be severe (Hillson, 2008). In terms of monitoring, A1c levels are typically assessed every 3–6 months, although more frequent monitoring (of blood glucose levels) may be necessary if therapies are adjusted quickly. On the other hand, less frequent assessments may be appropriate if A1c levels are stable (ADA, 2011). Furthermore, treatment modification may be necessary when alterations to official guidelines, published recommendations, and/or prescribing practices for existing treatments occur. The NP consequently also has a duty to their patients to keep abreast of these changes and reevaluate treatment in light of new evidence and label amendments.

Overall, the NP has a pivotal role to play in the care delivered to patients with T2D, both within the multidisciplinary team environment and in one-to-one consultations to ensure that the most optimal and appropriate care is provided for the patient.


The progressive nature of T2D means that many patients are unable to maintain glycemic control through lifestyle changes and metformin monotherapy alone. In the past, options for these patients were limited to a handful of drugs. However, there is now a plethora of treatments available to patients when they need to progress to dual or triple therapy. Labeling must be checked in all cases to ensure that treatment plans are consistent with approved combinations, warnings, precautions, and contraindications, and that adverse effects have received due consideration. NPs can play a vital role in this process.

Many of these newer agents offer important advantages over the traditional therapies. The DPP-4 inhibitors and the GLP-1 receptor agonists in particular provide glycemic control with a low risk of hypoglycemia and either weight neutrality (DPP-4 inhibitors) or weight loss (GLP-1 receptor agonists). Such considerations, along with the detailed appraisals of therapy options found in treatment guidelines, facilitate the selection of appropriate drug combinations in what might otherwise seem a bewildering array of possibilities: it is the breadth of choice that additionally offers healthcare providers the golden opportunity to tailor treatment regimens more carefully to patient needs. NPs, with frequent patient contact coupled with an understanding of the disease and its treatment options, are ideally placed to champion individualized therapy and, in so doing, bring about significant increases in the long-term health of patients with T2D.


The assistance of Watermeadow Medical, Witney, UK, funded by Novo Nordisk Inc, Princeton, NJ, USA, in preparing this article is gratefully acknowledged.


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      Type 2 diabetes; treatments; nurse practitioner; patient education

      © 2012 John Wiley & Sons, Inc