Postgraduate Medicine: Volume 122: No.1

James R. LaSalle, DO, FAAFP

Abstract: A large percentage of individuals with type 2 diabetes in the United States are not reaching their glycemic goals. In response to data from large outcomes trials and newer classes of therapeutic agents, various organizations and opinion-forming bodies recently updated their clinical practice recommendations for type 2 diabetes. The recommendations, as set by the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD), the American Association of Clinical Endocrinologists/American College of Endocrinology, and the Canadian Diabetes Association, are similar in their emphasis on lifestyle modification and the importance of treating fasting and postprandial glucose, both of which are significant contributors to achieving glycated hemoglobin (HbA_1c) targets. However, the recommendations differ in focus, depth, and specific treatment approaches. With the exception of the ADA/EASD consensus, dipeptidyl peptidase-4 (DPP-4) inhibitors have been included as alternative first- or second-line therapy due, in part, to their glucose-dependent mechanism of action that complements the actions of other oral antidiabetic drugs (OADs). The DPP-4 inhibitor, saxagliptin, demonstrates significant glycemia-lowering effects as monotherapy and in combination therapy, is weight neutral and well tolerated, and has a low risk of hypoglycemia. The added efficacy of saxagliptin in combination with other OADs in improving glycemic parameters has resulted in a significant proportion of patients achieving an HbA_1c <7% versus monotherapy or active comparator. Combination therapy with saxagliptin can thus offer a potential advantage in achieving glycemic goals for the majority of patients with type 2 diabetes without additional tolerability concerns.

Keywords: DPP-4 inhibitors; glucose control; HbA_1c; saxagliptin; type 2 diabetes

The majority of adults with type 2 diabetes are not at glycemic goal. According to the National Health and Nutrition Examination Survey, only half of adults in the United States with diabetes met the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) recommended glycated hemoglobin (HbA_1c) goal of < 7%, and almost one-third had an HbA_1c ≥8%.¹ While the percentage of patients with type 2 diabetes at goal has increased over the past 10 years, half of the patient population still experience inadequate glycemic control.^1,2 The proportion of patients who are not well controlled is further increased by the inclusion of newly diagnosed patients without an established treatment regimen to achieve glycemic control. These facts are not surprising given the pathophysiology and progressive nature of the disease, as well as the increasingly complex therapeutic regimens needed to address the various metabolic changes associated with type 2 diabetes. Among these changes are impaired insulin secretion, excess production of hepatic glucose, and increased renal glucose reabsorption.³

Historically, epidemiological evidence has demonstrated an association between poor glycemic control and increased risk of microvascular and macrovascular complications.^4,5 Subsequent studies have shown that aggressive glycemic control may provide the greatest promise in reducing the long-term consequences of type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that a 1% reduction in HbA_1c was associated with a reduced risk of death related to diabetes, myocardial infarction, and microvascular complications.⁴ More recently, large outcomes trials have demonstrated the vascular benefits of lowering HbA_1c early in therapy, although macrovascular risk reduction may not be realized for many years after treatment is initiated.^6,7

In response to the need for improved disease management, the various professional organizations and agencies that produce treatment guidelines have recently updated their clinical practice recommendations.⁸ A common thread among the different therapeutic guidelines is the recommendation to treat with combination therapy to reach glycemic goal; however, the guidelines vary in their specific treatment approaches.^8-10 Many of the therapeutic algorithms include a relatively new class of drug, dipeptidyl peptidase-4 (DPP-4) inhibitors, as a recommended treatment to reach target HbA_1c levels. This oral antidiabetic drug (OAD) class has demonstrated broad utility and a good tolerability profile as monotherapy and when used in combination with other OADs. The DPP-4 inhibitors currently approved by the US Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes are sitagliptin (Januvia^®; Merck, Whitehouse Station, NJ) and saxagliptin (Onglyza™; AstraZeneca/Bristol-Myers Squibb, Wilmington, DE/New York, NY).^11,12 These agents enhance levels of endogenous incretins that are released in a nutrient-dependent manner thereby maintaining glucose homeostasis.

Saxagliptin is a potent, selective DPP-4 inhibitor specifically designed for extended inhibition of the DPP-4 enzyme.¹³ The glucose-lowering effects of saxagliptin in treatment-naïve patients with type 2 diabetes were demonstrated in a preliminary 12-week “proof-of-concept” dose-ranging trial, at doses from 2.5 mg to 40 mg.¹⁴ Based on mechanism of action and efficacy and safety profiles, saxagliptin and other DPP-4 inhibitors appear well suited for combination therapy with other OADs in a wide range of patients.^15-20

This review briefly summarizes ADA and American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) clinical practice recommendations as well as those of the Canadian Diabetes Association (CDA), with a focus on the role of saxagliptin in clinical practice. Saxagliptin is approved in the United States as an adjunct to diet and exercise to improve glycemic control at a recommended dose of 2.5 mg or 5 mg once daily.¹¹ Data on the clinical efficacy and safety of saxagliptin 5 mg will be reviewed.

While type 2 diabetes treatment guidelines universally recommend lifestyle modification as a necessary adjunct to pharmacotherapy and specify metformin as the preferred choice for initial pharmacologic treatment, they differ in focus, depth, and recommended specific treatment approaches, as summarized in Table 1. ^9,10,21 One recommendation inclueds metformin titration for 1 to 2 months as tolerated;²¹ if the maximal tolerated dose fails to achieve or sustain the HbA_1c goal (as specified per the individual guideline), an additional OAD should be prescribed.^9,10,21 There is general agreement that HbA_1c values should be assessed approximately every 2 to 3 months; if HbA_1c is greater than the target goal, the intervention should be changed.^9,10,21 Preferred second-line medications vary among the guidelines, but combination therapy is a recognized option and is a recommended treatment algorithm based on HbA_1c levels (Table 1). The AACE/ACE guidelines advocate initiating combination therapy for patients with an HbA_1c of 7.6% to 9%.⁹ Baseline postprandial glucose (PPG) and fasting plasma glucose (FPG) should be assessed and targeted for treatment in addition to HbA_1c level; monotherapy and combination therapy for a patient with HbA_1c 6.5% to 7.5% should be treated with agents that target PPG, whereas including an agent in combination that targets FPG is recommended for patients with higher HbA_1c values (eg, 7.6% to >9%).⁹ Researchers have demonstrated that as overall contributors to HbA_1c, FPG and PPG must be lowered if optimal glycemic goals are to be achieved.^22,23 Notably, the respective contributions of FPG and PPG to HbA_1c progressively shift depending on the level of glycemic control; the contribution of PPG is more prominent in patients with moderate diabetes (HbA_1c >8.5%) whereas FPG has a greater role when patients progress from moderate to higher levels of hyperglycemia.²⁴ Both the ADA and CDA recommend combination therapy at higher HbA_1c levels compared with AACE/ACE. The ADA guidelines recommend early use of combination therapy for patients with HbA_1c >8.5% or use of OAD classes that have greater or more rapid glucose-lowering effect.²¹ The CDA advises initiating combination therapy in the presence of marked hyperglycemia (HbA_1c ≥9%).¹⁰

Variations among guidelines and consensus statements are likely due to different interpretations of available clinical evidence by diverse national and international associations and agencies.²⁴ As a result, there is minimal overlap in citations used to substantiate claims and recommendations in type 2 diabetes treatment guidelines. Clinicians are left to evaluate the applicability of guideline recommendations within their own practices and for individual patients.²⁵ Choosing among the therapeutic options can be a difficult task with the introduction of newer classes of agents, as guidelines for their use are likely to vary.

One such example includes recommendations for the use of DPP-4 inhibitors, which have been incorporated into the AACE/ACE algorithm as preferred for first- and second-line therapies, likely due in part to their effect on PPG.⁹ The CDA guidelines also include DPP-4 inhibitors based on their PPG-reducing effects.¹⁰ In contrast, ADA/EASD guidelines consider DPP-4 inhibitors to have less validated long-term data, and thus, currently do not include these agents in the tier 1 or 2 algorithms.²¹ There is general agreement among the guidelines that given their effect on PPG, DPP-4 inhibitors are well suited for combination with agents that primarily target FPG (Table 2).^9,10 The efficacy of saxagliptin in combination with other OADs to lower PPG and FPG, and to achieve HbA_1c goals has been studied and is discussed below.

Saxagliptin has been evaluated in combination trials for efficacy and safety in patients with type 2 diabetes as an add-on to metformin, glyburide, or a thiazolidinedione (TZD), or given in combination with metformin as initial therapy. These core phase 3 studies had the same primary and secondary efficacy endpoints. The primary efficacy endpoint was the change in HbA_1c from baseline to week 24. Secondary efficacy endpoints included: 1) change in FPG from baseline to week 24, 2) the proportion of patients achieving HbA_1c <7.0%, and 3) change from baseline to week 24 in area under the concentration-time curve from 0 to 180 minutes for PPG response to an oral glucose tolerance test.^18-20,26 Demographic and baseline characteristics were generally balanced across the randomized treatment groups in the individual studies, with a few small differences for the overall populations. Patients in the add-on combination studies had longer duration of diabetes and lower mean baseline HbA_1c than the treatment-naïve patients in the initial combination study.^18-20,26 Because saxagliptin, like other DPP-4 inhibitors, has few drug interactions and is well tolerated, the risk of additional adverse effects in combination with OADs is considered minimal.^15-17

In most treatment algorithms, metformin is recommended as first-line therapy; the addition of a DPP-4 inhibitor provides a complementary mechanism of action to that of metformin. This concept provided the rationale to assess the efficacy of saxagliptin and metformin combination therapy in 743 patients with a baseline HbA_1c 7% to 10% who were receiving stable doses of metformin (1500–2500 mg). Patients were randomized to also receive saxagliptin 2.5, 5, or 10 mg, or placebo once daily for 24 weeks.¹⁸

Sulfonylureas (SUs) are among the most frequently prescribed and least costly OAD, and are often utilized to manage glucose through uptitration until treatment failure, instead of initiating another agent.^27,28 In this regard, it was hypothesized that the addition of saxagliptin to submaximal SU treatment (defined as less than the maximum approved dose for each SU) would offer an improved strategy for achieving tighter glycemic control in contrast to uptitrating until glycemic failure. The efficacy of combination therapy with saxagliptin and glyburide was therefore assessed in 768 patients with a baseline HbA_1c of 7.5% to 10% and inadequate glycemic control on submaximal doses of glyburide.²⁶ During a 4-week lead-in period, all patients received glyburide 7.5 mg plus placebo, followed by 24 weeks during which they also received either saxagliptin 2.5 or 5 mg plus submaximal glyburide 7.5 mg once daily or placebo plus glyburide 10 mg plus uptitrated glyburide to a maximum dose of 15 mg/day.²⁶

Saxagliptin in combination with a TZD was also evaluated as it was expected to provide significant efficacy and have minimal hypoglycemia with less risk for weight gain in comparison with other commonly used treatment regimens (eg, a TZD plus insulin or insulin secretagogues, such as SUs).^21,29 The efficacy of saxagliptin as add-on to TZD was assessed in 565 patients with a baseline HbA_1c of 7% to 10.5% who had been receiving stable doses of TZD (rosiglitazone or pioglitazone). Patients received saxagliptin 2.5 or 5 mg, or placebo once daily as add-on to the TZD for 24 weeks.²⁰

A therapeutic approach based on complementary drugs taken in combination as initial therapy has the potential to enable more patients to reach glycemic targets earlier in the disease course and minimize the need for frequent dose titration. Thus, the efficacy of saxagliptin in combination with metformin as initial therapy was assessed in 1306 treatment-naïve patients with an HbA_1c of 8% to 12%. Patients received saxagliptin 5 or 10 mg plus metformin 500 mg, saxagliptin 10 mg plus placebo, or metformin 500 mg plus placebo for 24 weeks. In all 3 metformin groups, metformin was uptitrated in 500-mg increments to a maximum of 2000 mg/day.¹⁹

Saxagliptin 5 mg administered to patients whose glycemia remained inadequately controlled by metformin, glyburide, or a TZD, provided HbA_1c reductions of 0.8%, 0.6%, and 0.7%, respectively, as well as reductions in both FPG and PPG (Table 2).^18,20,26 Saxagliptin 5 mg given in combination with metformin as initial therapy yielded HbA_1c reductions of 2.5% (P < 0.0001 vs metformin monotherapy) and reductions in FPG and PPG at 120 minutes (3.3 mmol/L; 60 mg/dL and 7.7 mmol/L; 138 mg/dL, respectively; P < 0.0001 vs metformin monotherapy) during an oral glucose tolerance test.¹⁹ Similar to other DPP-4 inhibitors,³⁰ saxagliptin provided greater reductions in HbA_1c with higher baseline HbA_1c values^18,19 —up to –3.3% in treatment-naïve patients with baseline HbA_1c ≥10% with saxagliptin and metformin as initial therapy.¹⁹ The HbA_1c data support the AACE/ACE guideline recommendations to treat early with combination therapy based on HbA_1c 7.6% to 9%.⁹ Analyses of HbA_1c efficacy according to age, gender, race/ethnicity, and body mass index (BMI) demonstrated similar efficacy across all treatment groups for each trial.^18–20,26

The comprehensive efficacy of saxagliptin 5 mg in combination with metformin, glyburide, or TZD resulted in statistically significantly greater proportions of saxagliptin-treated patients achieving HbA_1c goals of <7% and ≤6.5% versus control at 24 weeks (Figure 1). More than twice as many patients treated with saxagliptin added to metformin or glyburide achieved HbA_1c goals of <7% and ≤6.5% relative to control.^18,26 Similarly, a statistically significantly greater proportion of treatment-naïve patients (mean baseline HbA_1c approximately 9.4%) treated with saxagliptin given in combination with metformin as initial therapy achieved HbA_1c goals of <7% or ≤6.5% versus metformin alone (all P ≥ 0.0001).¹⁹

Saxagliptin was generally weight neutral. Weight reductions with saxagliptin 5 mg as add-on to metformin (−0.9 kg) and given in combination with metformin as initial therapy (−1.8 kg) were similar to comparator (−0.9 kg and −1.6 kg, respectively).^18,19 Mean bodyweight increased with saxagliptin 5 mg added on to glyburide (+0.8 kg) versus uptitrated glyburide (+0.3 kg; P < 0.012).²⁶ A small increase from baseline body weight occurred in patients treated with saxagliptin 5 mg added on to a TZD (+1.4 kg) vs placebo (+0.9 kg).²⁰

Saxagliptin as an add-on to metformin, glyburide, or a TZD, or as initial therapy was generally well tolerated with a low propensity for hypoglycemia (Table 3).^19,20,26 The numbers of reported hypoglycemic events and confirmed (fingerstick blood glucose ≤ 50 mg/dL with associated symptoms) hypoglycemia were similar for saxagliptin as add-on to metformin or a TZD, or as initial therapy with metformin, compared with control treatment groups.^18-20 Reported and confirmed hypoglycemic events were not statistically significantly different for saxagliptin 5 mg (14.6% and 0.8%, respectively) versus uptitrated glyburide (10.1%; P = 0.1417 and 0.7%; P = 1.0000, respectively).²⁶ The most common adverse events (AEs) (≥5% of saxagliptin-treated patients and more commonly than those reported by placebo) reported from the 5 pooled, phase 3 saxagliptin clinical studies were upper respiratory tract infection, urinary tract infection, and headache.¹¹ Saxagliptin (5 mg) as add-on to TZD resulted in increased incidence of peripheral edema compared with TZD alone (8.1% and 4.3%, respectively), although no events resulted in study discontinuation.¹¹

Overall, saxagliptin is considered a generally well-tolerated OAD that offers increased efficacy when used in combination without additional safety concerns. Similarly, meta-analysis including the DPP-4 inhibitors sitagliptin and vildagliptin showed an increased risk for nasopharyngitis (risk ratio, 1.2), urinary tract infection (risk ratio, 1.5), and headache (risk ratio, 1.4) versus comparator treatments.³¹ A recent label change for sitagliptin indicates post-marketing reports of serious allergic and hypersensitivity reactions (eg, anaphylaxis, angioedema, and exfoliative skin conditions including Stevens–Johnson syndrome) in patients treated with this agent.³² To date no such associations have been made for saxagliptin.

While the DPP-4 inhibitor class is relatively new compared with other OADs, they have consistently demonstrated a well-tolerated profile with low absolute rates of AEs.³¹ Long-term extension studies up to 2 years have been conducted to evaluate safety and tolerability of saxagliptin,³³ sitagliptin,^34,35 and vildagliptin,^36-41 and have shown these agents to be generally well tolerated with low incidences of AEs and with no reported newly emergent, clinically relevant AEs versus short-term studies.

Saxagliptin is eliminated in part through renal pathways. Accordingly, renal impairment increases plasma exposure to saxagliptin compared with patients who have normal renal function.¹¹ Clinically relevant plasma increases were demonstrated in patients with moderate-to-severe renal impairment or end-stage renal disease (creatinine clearance <30 mL/min). For such patients, a one-step dosage adjustment from 5 mg to 2.5 mg saxagliptin is recommended.¹¹

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). Accordingly, the pharmacokinetics of saxagliptin are altered by CYP3A4/5 inducers and inhibitors.¹¹ The clinical relevance of these interactions, however, is dependent on the degree of CYP3A4/5 inhibition or induction. The concentration of saxagliptin is significantly increased when coadministered with ketoconazole, a strong CYP3A4/5 inhibitor.¹¹ Based on this drug-drug interaction, the recommended dose of saxagliptin should be limited to 2.5 mg daily in patients concomitantly receiving strong CYP3A4/5 inhibitors such as ketoconazole.¹¹

Additional concerns regarding the health care cost must also be addressed when considering treatment strategies for patients with type 2 diabetes. The International Diabetes Federation has estimated that by 2025, global expenditures for diabetes-related health care costs will exceed 302.5 billion US dollars.⁴² As health care costs continue to increase, managing type 2 diabetes and its associated complications will remain a challenge for both the health care provider and patients. Therefore, for the health care provider consideration of individual patient profiles, including metabolic and socioeconomic, must be addressed in efforts to effectively treat and manage type 2 diabetes.

A patient’s risk for serious health complications related to diabetes can be reduced by reaching and maintaining HbA_1c targets.⁴ New data presented from outcomes studies have indicated that treatment strategies must be driven by individual characteristics to achieve and maintain success. Long-term follow-up findings demonstrated that HbA_1c reductions to ≤ 7% confer macrovascular risk reductions during a mean of 10 and 17 years post-trial from the UKPDS and Diabetes Control and Complications Trial, respectively, even in the face of glycemic control deterioration.^6,7 Therefore, the strategy now recommended by various professional organizations is to reduce HbA_1c levels to <7% or ≤6.5% in most patients who have type 2 diabetes with minimal vascular risk factors.⁹ Less stringent targets should be considered for patients with long-standing type 2 diabetes, and those at high risk for hypoglycemic events and/or with multiple comorbidities.^8,43

Current guidelines established by the ADA/EASD, AACE/ACE, and CDA are moving toward recommending combination treatment early in the therapeutic regimen, perhaps because of their ability to reduce PPG. These guidelines note that the majority of patients with type 2 diabetes will require more than one OAD to control hyperglycemia over the course of their disease.^9,10,21 Selection of agents for combination therapy must take into consideration glucose-lowering effectiveness, and the complementarity of the agents’ mechanisms of action.²¹ Saxagliptin, given to patients whose glycemia had been inadequately controlled on metformin, an SU, or TZD monotherapy, and given in combination with metformin as initial therapy, demonstrated efficacy, regardless of baseline HbA_1c, age, gender, race/ethnicity, or BMI.^18,20,26 These findings appear to validate recommendations to use a combination of drugs that work via different mechanisms of action and to target both FPG and PPG. Treatment with saxagliptin 5 mg in combination with another OAD is a clinically relevant option for the treatment of diabetes in a broad range of patients.

Funding for this review was provided by Bristol-Myers Squibb and AstraZeneca. Technical and editorial assistance for this manuscript was provided by Trina Ricci, PhD, and Jeremy Henriques, PhD, Innovex Medical Communications.

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