Saxagliptin for the treatment of type 2 diabetes mellitus: Focus on recent studies

Abstract

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycemic control without causing weight gain or increasing hypoglycemic risk in patients with type 2 diabetes (T2DM). The efficacy and tolerability of saxagliptin, a once-daily DPP-4 inhibitor, administered as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, and as initial combination therapy with metformin, was demonstrated in pivotal 24-week clinical trials. Additional information about the clinical profile of saxagliptin was recently obtained from extension studies, head-to-head clinical trials, and post-hoc analyses. In extension studies, the efficacy and tolerability of add-on saxagliptin and initial saxagliptin-plus-metformin therapy were maintained for up to 102 weeks. Saxagliptin plus metformin was shown to be non-inferior to glipizide plus metformin in lowering glycated hemoglobin from base-line, with reduced body-weight and lower hypoglycemic risk. Post-hoc analyses indicate that the clinical benefits of saxagliptin extend across demographic subgroups and special populations. A meta-analysis found no evidence for increased cardiovascular risk in T2DM patients exposed to saxagliptin for > 1 year. On the basis of this clinical profile, saxagliptin is an attractive option for initial and add-on therapy for T2DM patients with inadequate glycemic control.

Key words::

• Dipeptidyl peptidase-4 inhibitor
• glycemia
• incretin
• oral antidiabetic drugs
• saxagliptin
• type 2 diabetes mellitus

Abbreviations
AACE	=	American Association of Clinical Endocrinologists
ACE	=	American College of Endocrinology
ADA	=	American Diabetes Association
AUC	=	area under curve
CI	=	confidence interval
CYP	=	cytochrome P450
DPP-4	=	dipeptidyl peptidase-4
EASD	=	European Association for the Study of Diabetes
FDA	=	US Food and Drug Administration
FPG	=	fasting plasma glucose
GLP-1	=	glucagon-like peptide-1
HbA1c	=	hemoglobin A1c (glycated hemoglobin)
HOMA-2β	=	homeostatic model assessment for β-cell function
MACE	=	major adverse cardiovascular events
OADs	=	oral antidiabetic drugs
PPG	=	postprandial glucose
T2DM	=	type 2 diabetes mellitus
XR	=	extended release

Key messages

• Saxagliptin is an orally active, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycemic control as monotherapy, as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione, or as initial combination therapy with metformin; saxagliptin is generally weight-neutral with a low risk of hypoglycemia.

• No additional safety or tolerability issues have been observed with saxagliptin treatment for up to 102 weeks.

• A meta-analysis of the saxagliptin clinical trial database found no evidence of increased cardiovascular risk in patients with T2DM exposed to saxagliptin for >1 year; instead, the data raised the hypothesis that saxagliptin may have potential cardioprotective effects, which is currently being assessed in a long-term outcomes study.

Introduction

Treatment of type 2 diabetes mellitus (T2DM) is designed to reduce the risk of microvascular and macrovascular complications by achieving glycemic control and addressing co-morbid risk factors. With respect to glycemic control, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend a glycated hemoglobin (HbA_1c) target < 7% (1), whereas the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) recommend a more aggressive HbA_1c target of ≤ 6.5% (2).Life-style interventions (e.g. nutrition, exercise, and weight loss) are the foundation of T2DM treatment, but a large majority of patients require oral antidiabetic drugs (OADs), either as single agents or in combination, to reduce blood glucose to target levels. Multiple classes of OADs as well as insulin are available, each with specific benefits and risks (Table I).

Table I. Overview of the benefits and risks associated with traditional oral antidiabetic drugs and insulin (2).

	Metformin	Sulfonylurea	Thiazolidinedione	Meglitinide	α-Glucosidase inhibitor	Insulin
Benefits
Lowering PPG	Mild	Moderate	Mild	Moderate	Moderate	Moderate to marked
Lowering FPG	Moderate	Moderate	Moderate	Mild	Neutral	Moderate to marked
Risks
Hypoglycemia	Neutral	Moderate	Neutral	Mild	Neutral	Moderate to severe
GI symptoms	Moderate	Neutral	Neutral	Neutral	Moderate	Neutral
Weight gain	Benefit	Mild	Moderate	Mild	Neutral	Mild to moderate
Fractures	Neutral	Neutral	Moderate	Neutral	Neutral	Neutral
Heart failure/edema	Contraindicated in CHF	Neutral	Mild to moderate; contraindicated in class 3 or 4 CHF	Neutral	Neutral	Neutral unless used with thiazolidinedione
Risk of use in renal insufficiency	Severe	Moderate	Mild	Neutral	Neutral	Moderate
Contraindicated in liver failure or predisposition to lactic acidosis	Severe	Moderate	Moderate	Moderate	Neutral	Neutral

Adapted from Rodbard HW et al., Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control. Endocrine Practice. 2009;15:540–59; reprinted with permission from the American Association of Clinical Endocrinologists.

CHF = congestive heart failure; FPG = fasting plasma glucose; GI = gastrointestinal; PPG = postprandial glucose.

The dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of OADs that are not associated with weight gain, increased hypoglycemic risk, or gastrointestinal side-effects, such as nausea and vomiting, and offer several advantages that may contribute to improved and sustained glycemic control (1). As an example, most DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin) are administered once daily; vildagliptin is administered once or twice daily. In addition, DPP-4 inhibitors have fewer side-effects compared with other OADs, which may also help to improve adherence and subsequently glycemic control (3). In addition, homeostatic model assessment for β-cell function (HOMA-2β) analyses as well as hyperglycemic clamp assessment suggest that DPP-4 inhibitors have a beneficial effect on β-cell function short-term (3);confirmation in long-term studies is needed to determine if this potential benefit contributes to sustained glycemic control.

DPP-4 inhibitors have a mechanism of action that is complementary to other OADs (2), and, therefore, they are an attractive option as add-on therapy to other OADs. Importantly, individual pooled safety assessments of three DPP-4 inhibitors’ clinical trial databases have shown no association with an increased risk of cardiovascular adverse events (4–6). In the current AACE/ACE guidelines, DPP-4 inhibitors are recommended with higher priority than sulfonylureas on the basis of their overall efficacy and safety profile (2). Specifically, DPP-4 inhibitors are recommended as monotherapy in patients with HbA_1c levels of 6.5%–7.5%, in dual combination therapy in patients with HbA_1c levels of 7.6%–9.0%, and in triple combination therapy in patients with HbA_1c levels > 9.0%. The ADA/EASD guidelines (1) do not currently list DPP-4 inhibitors as a preferred (i.e. tier 1 or 2) antidiabetic agent because of insufficient long-term data at the time the guidelines were written.

There are few data from direct comparisons of DPP-4 inhibitors, but prescribing information (7–10) and a recent review (11) offer some distinctions between the individual agents within this drug class. In 24-week studies, effects on glycemic control do not differ dramatically among the DPP-4 inhibitors (Table II). Although all DPP-4 inhibitors have a duration of action that allows once-daily dosing, plasma half-life values vary widely. Linagliptin has a long terminal half-life (>100 h), yet no drug accumulation occurs because of saturable binding to DPP-4 and rapid elimination of unbound drug (7,11). In contrast, saxagliptin has a relatively short terminal half-life (approximately 3 h) but an extended duration of action provided by its pharmacologically active metabolite (10,11). Moreover, differences in metabolism and excretion may impact the specific DPP-4 selected for use in special patient populations, particularly the elderly. In patients with hepatic impairment, no dosage adjustment is required for linagliptin, saxagliptin, or sitagliptin (mild or moderate impairment only; there is no experience with sitagliptin in patients with severe hepatic insufficiency) (7,8,10), while the use of vildagliptin is not recommended at all in this population (9). Based on the renal excretion characteristics of the DPP-4 inhibitors, recommendations for their use in patients with compromised renal function vary: for vildagliptin, use is not recommended at all (9); for patients with moderate or more severe renal impairment, dosage adjustment is recommended with sitagliptin (8), and the 2.5-mg dose is recommended with saxagliptin (10); no dosage consideration is necessary with linagliptin (7).

Table II. Overview of effects on glycemic control with DPP-4 inhibitors in 24-week placebo-controlled trials (7–10).

	Linagliptin	Sitagliptin	Vildagliptin	Saxagliptin
	5 mg	100 mg	100 mg ^f	2.5 mg	5 mg
Monotherapy
Base-line HbA1c, %	8.0	8.0	8.6, 8.4	7.9	8.0
Δ HbA1c, %	–0.4	–0.6	–0.8, –0.7	–0.4	–0.5
Difference versus Δ with placebo, %	–0.7^a	–0.8^b	–0.5^c, –0.7^c	–0.6^d	–0.6^d
Achieved HbA1c < 7%	25%	41%	–	35%	38%^c
Base-line FPG, mg/dL	164	170	–	178	171
Δ FPG, mg/dL	–9	–12	–	–15	–9
Difference versus Δ with placebo, mg/dL	–23^a	–17^b	–	–21^c	–15^c
Base-line PPG, mg/dL	258	257	–	279	278
Δ PPG, mg/dL	–34	–49	–	–45	–43
Difference versus Δ with placebo, mg/dL	–58^a	–47^b	–	–39^e	–37^c
Add-on to metformin
Base-line HbA1c, %	8.1	8.0	8.4	8.1	8.1
Δ HbA1c, %	–0.5	–0.7	–0.9	–0.6	–0.7
Difference versus Δ with placebo, %	–0.6^a	–0.7^b	–1.1^c	–0.7^d	–0.8^d
Achieved HbA1c < 7%	28%	47%	–	37%^c	44%^c
Base-line FPG, mg/dL	169	170	–	174	179
Δ FPG, mg/dL	–11	–17	–	–14	–22
Difference versus Δ with placebo, mg/dL	–0.21^a	–25^b	–	–16^c	–23^c
Base-line PPG, mg/dL	270	275	–	294	296
Δ PPG, mg/dL	–49	–62	–	–62	–58
Difference versus Δ with placebo, mg/dL	–67^a	–51^b	–	–44^c	–40^c

Statistical significance versus placebo: ^a95% confidence interval does not cross 0; ^bP < 0.001; ^cP < 0.05; ^dP < 0.0001; ^enot compared.

^fAdministered as 50 mg twice daily.

Δ = change from base-line; DPP-4 = dipeptidyl peptidase-4; FPG = fasting plasma glucose; HbA_1c = glycated hemoglobin; PPG = postprandial glucose.

Among the DPP-4 inhibitors approved for use in the treatment of T2DM, sitagliptin was the first agent approved in Europe and in the United States. Saxagliptin was the second approved DPP-4 inhibitor (approved by the European Medicines Agency on 1 October 2009, for use in combination with metformin, a thiazolidinedione, or a sulfonylurea; and by the US Food and Drug Administration (FDA) on 31 July 2009, as an adjunct to diet and exercise). This article provides an overview of saxagliptin, focusing first on its pharmacodynamic and pharmacokinetic properties, and then on clinical efficacy and safety data from phase III trials and more recent results from long-term extension trials, head-to-head trials, and post-hoc analyses.

Pharmacodynamics and pharmacokinetics

Saxagliptin is a potent, orally active, once-daily DPP-4 inhibitor that is indicated for improving glycemic control in adults with T2DM in combination with diet and exercise (10). Saxagliptin is also available in a fixed-dose combination with metformin extended release (XR) for once-daily dosing (12). By selectively inhibiting the DPP-4 enzyme, saxagliptin slows inactivation of the incretin hormones, specifically GLP-1, in patients with T2DM (10,13). As a result, concentrations of intact endogenous incretin hormones are increased, and their actions in stimulating glucose-dependent insulin secretion and in suppressing glucagon secretion and hepatic glucose production are greater in duration and magnitude.

The pharmacodynamic and pharmacokinetic profiles of saxagliptin have been previously reported (14–17). Saxagliptin is a highly potent, selective, reversible, competitive DPP-4 inhibitor with an enzyme dissociation constant (Ki) for DPP-4 of 1.3 nM at 37°C (14). Binding of saxagliptin to DPP-4 is reversible, but dissociation from the enzyme occurs slowly, consistent with a prolonged duration of action (14). When administered once daily, saxagliptin inhibited plasma DPP-4 activity in a dose-dependent manner, with 50% enzyme inhibition remaining 24 hours after administration of a 2.5-mg dose (17). Saxagliptin is metabolized to the active metabolite 5-hydroxy saxagliptin, which is half as potent as saxagliptin but retains the same specificity for DPP-4 as the parent drug (13).

Saxagliptin is well absorbed following oral administration; maximal plasma concentrations of saxagliptin and 5-hydroxy saxagliptin are reached within 2 and 4 hours, respectively. Systemic exposure to saxagliptin and 5-hydroxy saxagliptin is dose-proportional, with no substantial drug accumulation seen with once-daily dosing in spite of a prolonged pharmacodynamic effect on DPP-4 inhibition (17).Results of saxagliptin administered with a high-fat test meal demonstrate that saxagliptin can be taken with or without food.

Saxagliptin is primarily metabolized by cytochrome P450 (CYP) 3A4/5. Co-administration of saxagliptin with strong CYP 3A4/5 inhibitors results in higher exposure to saxagliptin but lower exposure to 5-hydroxy saxagliptin (16), and therefore the dose of saxagliptin should be reduced from 5 mg to 2.5 mg once daily when administered with a strong CYP 3A4/5 inhibitor (e.g. ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) (10). No clinically meaningful change in saxagliptin exposure has been demonstrated when co-administered with moderate CYP 3A4/5 inhibitors, such as diltiazem, and CYP substrates, such as simvastatin; therefore, no dose adjustment of saxagliptin is recommended when co-administered with such agents (16). No clinically meaningful drug–drug interactions were seen when saxagliptin was co-administered with the oral antidiabetic drugs metformin, glyburide, or pioglitazone, or with digoxin, famotidine, omeprazole, or a magnesium-aluminum hydroxide antacid (10).

Efficacy of saxagliptin in phase III trials

Saxagliptin has been evaluated as monotherapy and in combination with metformin, glyburide, or a thiazolidinedione (pioglitazone or rosiglitazone), as previously reported in a series of pivotal 24-week, phase III trials (18–22). In these studies, saxagliptin significantly reduced HbA_1c, fasting plasma glucose (FPG), and postprandial glucose (PPG); these effects were independent of age, gender, race/ethnicity, and body mass index (BMI) (18–22). Efficacy results for saxagliptin at the recommended dose of 5 mg once daily are summarized in Table III. Significantly greater adjusted mean changes from base-line HbA_1c, FPG, and 2-hour PPG were demonstrated with saxagliptin 5 mg monotherapy versus placebo (18). Moreover, saxagliptin allowed significantly more patients compared with placebo to achieve the ADA/EASD-recommended HbA_1c target of < 7% (1,18).

Table III. Glycemic parameters in pivotal, 24-week, phase III clinical trials of saxagliptin 5 mg once daily in T2DM patients (18–22).

	Monotherapy		Add-on to MET		Add-on to GLY		Add-on to TZD		Initial combination with MET
	SAXA n = 106	PBO n = 95	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Mean base-line HbA1c, %	8.0	7.9	8.1		8.5	8.4	8.4	8.2	9.4	9.4
Δ HbA1c, %	−0.5^a	0.2	−0.7^a	0.1	−0.6^a	0.1	−0.9^a	−0.3	−2.5^a	−2.0
Δ FPG, mg/dL	−9.0^b	6.0	−22.0^a	1.2	−10.0^e	1.0	−18.0	−3.6	−60.0^a	−47.0
Δ 2-hour PPG, mg/dL	−43.0^c	−6.0	−58.2^a	−18.0	−34.0^a	8.0	−72.0^g	−18.0	−138.0^a	−97.0
HbA1c < 7%, % of patients	38.0^d	24.0	43.5^a	16.6	22.8^a	9.1	41.8^h	25.6	60.3^a	41.1
HbA1c ≤ 6.5%, % of patients	—	—	—	—	10.4^f	4.5	20.7	9.4	45.3^a	29.0

Statistical significance versus placebo: ^aP = 0.0001; ^bP = 0.0074; ^cP = 0.0009; ^dP = 0.0443; ^eP = 0.0020; ^fP = 0.0117; ^gP < 0.005; ^hP = 0.0013.

Δ = adjusted mean change from base-line; FPG = fasting plasma glucose; GLY = glyburide; HbA_1c = glycated hemoglobin; MET = metformin; PBO = placebo; PPG = postprandial glucose; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide.

Add-on combination therapy with saxagliptin was evaluated in patients with T2DM inadequately controlled with monotherapy with metformin, glyburide, or a thiazolidinedione (19,20,22). As shown in Table III, add-on saxagliptin 5 mg was significantly more effective than add-on placebo in improving HbA_1c in each study and allowed a significantly greater proportion of patients to achieve an HbA_1c target of < 7%. Significant reductions in FPG and 2-hour PPG were also evident when saxagliptin was added to metformin, glyburide, or a thiazolidinedione. Saxagliptin administered as monotherapy or added to metformin or a thiazolidinedione improved β-cell function as measured by HOMA-2β, increased mean postprandial insulin and C-peptide area under the curve (AUC), and reduced postprandial glucagon AUC compared with the respective control group (placebo or add-on placebo) (18–20). Although saxagliptin plus glyburide did not affect the HOMA-2β assessment, it did increase postprandial insulin and C-peptide AUC, and lower postprandial glucagon AUC compared with up-titrated glyburide (22).

Saxagliptin plus metformin was also evaluated as initial combination therapy in treatment-naive patients. Consistent with the results of the other pivotal studies, saxagliptin plus metformin as initial therapy significantly improved HbA_1c, FPG, and PPG compared with either agent alone (Table III)(21). The greater reduction in HbA_1c with combination therapy was evident by week 4, and the enhanced reduction was maintained at all subsequent time points (21). Greater HbA_1c reductions are frequently seen in patients with higher base-line HbA_1c. In this study, the greatest HbA_1c reductions with combination therapy were seen in the subset of patients with base-line HbA_1c ≥ 10%. These patients achieved a 3.3% reduction in HbA_1c from base-line(21).Saxagliptin plus metformin as initial therapy significantly improved β-cell function in the HOMA-2β assessment versus metformin alone (P = 0.0004) and also produced numerically greater increases in postprandial insulin AUC and early insulin responses to a glucose load measured by the insulinogenic index compared with metformin (21).

Saxagliptin 5 mg was generally weight-neutral in pivotal 24-week clinical trials when used as monotherapy (18), as add-on therapy to metformin (20), or as initial combination therapy with metformin (21). When added to a thiazolidinedione or glyburide, small increases in mean body-weight were observed in all treatment groups (19,22).

Saxagliptin in combination with metformin XR demonstrated 24-hour efficacy as measured by plasma glucose values and continuous glucose monitoring system in the fasting and postprandial states in a 4-week, multicenter, randomized, double-blind, placebo-controlled phase IIIb trial (23). Saxagliptin 5 mg was compared with placebo as add-on treatment to metformin XR in patients with T2DM and inadequate glycemic control (screening HbA_1c 7%–10%). The change from base-line in 24-hour weighted-mean glucose was significantly greater for saxagliptin 5 mg plus metformin XR (−13.8 mg/dL) compared with placebo plus metformin XR (3.0 mg/dL; P = 0.0001). At week 4, the mean decrease in plasma glucose was sustained through a 24-hour period in saxagliptin-treated patients. Treatment with saxagliptin 5 mg plus metformin XR resulted in significant mean reductions from base-line in 4-hour weighted-mean PPG, 2-hour PPG, 3-day mean daily glucose, and FPG levels compared with placebo plus metformin XR (P ≤ 0.001) (23).

Safety and tolerability

Across the phase III program, saxagliptin was generally well tolerated (18–22). At the recommended dose of 5 mg once daily, the only adverse events that occurred at an incidence ≥5% and were more frequent in the saxagliptin group than in the corresponding control group were headache, upper respiratory tract infection, and urinary tract infection (Table IV). In the add-on to thiazolidinedione trial, peripheral edema occurred more frequently with saxagliptin plus thiazolidinedione than with placebo plus a thiazolidinedione (8.1% versus 4.3%) (19). In most cases, the peripheral edema was reported to have a pedal distribution, which is well recognized to occur when a thiazolidinedione is used in combination with another glucose-lowering agent (24).

Table IV. Incidence of hypoglycemia and adverse events (incidence ≥ 5%) occurring more frequently in patients treated with saxagliptin 5 mg than in those receiving control treatment in the pivotal 24-week trials (18–22).

Events, reported as n (%)	Monotherapy		Add-on to MET		Add-on to GLY		Add-on to TZD		Initial combination with MET
	SAXA n = 106	PBO n = 95	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Headache	10 (9.4)	7 (7.4)	11 (5.8)	13 (7.3)	19 (7.5)	15 (5.6)	10 (5.4)	7 (3.8)	24 (7.5)	17 (5.2)
Peripheral edema	–	–	–	–	–	–	15 (8.1)	8 (4.3)	–	–
URTI	9 (8.5)	11 (11.6)	9 (4.7)	9 (5.0)	16 (6.3)	18 (6.7)	17 (9.1)	13 (7.1)	–	–
Urinary tract infection	9 (8.5)	4 (4.2)	10 (5.2)	8 (4.5)	27 (10.7)	22 (8.2)	12 (6.5)	12 (6.5)	–	–
Reported hypoglycemia^a	5 (4.7)	6 (6.3)	10 (5.2)	9 (5.0)	37 (14.6)	27 (10.1)	5 (2.7)	7 (3.8)	11 (3.4)	13 (4.0)
Confirmed hypoglycemia^b	0 (0)	0 (0)	1 (0.5)	1 (0.6)	2 (0.8)	2 (0.7)	0 (0)	0 (0)	0 (0)	1 (0.3)

^aEvents consistent with symptoms of hypoglycemia with or without documented blood glucose levels.

^bFingerstick glucose < 50 mg/dL with associated symptoms.

GLY = glyburide; MET = metformin; PBO = placebo; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide; URTI = upper respiratory tract infection.

The incidence of reported hypoglycemia, defined as an event consistent with signs or symptoms of hypoglycemia with or without a documented blood glucose measurement, occurred at generally similar rates with saxagliptin 5 mg versus controls in the pivotal trials (Table IV) (18–22).The frequency of hypoglycemia was evaluated in pooled analyses of the monotherapy and add-on therapy trials. Reported hypoglycemic events occurred at a frequency of 5.6% with saxagliptin 5 mg compared with 4.1% with placebo in the pooled monotherapy trials, and at a frequency of 8.3% with add-on saxagliptin 5 mg therapy to metformin, a thiazolidinedione, or glyburide compared with 6.8% with add-on placebo (25). The frequency of reported hypoglycemia with saxagliptin plus metformin as initial therapy was 3.4% compared with 4.0% for metformin alone. Confirmed hypoglycemic events, in which symptoms were associated with a fingerstick glucose ≤ 50 mg/dL, were infrequent (<2.5%) across all phase III studies, and none of the hypoglycemic events required medical assistance (25). These findings illustrate the low risk and severity of hypoglycemia associated with saxagliptin.

Hypersensitivity-related events, such as urticaria and facial edema, were reported in 1.5% and 0.4% of patients who received saxagliptin 5 mg and placebo, respectively, in the pivotal 24-week trials (10). None of these events in patients receiving saxagliptin required hospitalization, nor were any reported by the investigators to be life-threatening. A dose-related decrease in mean absolute lymphocyte count within the normal range was observed in a pooled analysis of the pivotal trials among patients receiving saxagliptin 5 mg (10) but was not associated with clinically relevant adverse events. In summary, the pivotal trials demonstrated that saxagliptin has an attractive safety and tolerability profile.

Recent studies

Active comparator non-inferiority trials

Saxagliptin was compared with a sulfonylurea, glipizide, as add-on therapy to metformin in a 52-week randomized controlled non-inferiority trial (26). A total of 858 T2DM patients with HbA_1c of 6.5%–10.0% on stable doses of metformin ≥ 1,500 mg/d were randomized to receive saxagliptin 5 mg once daily or glipizide up-titrated to 20 mg/d (range 0 − 20 mg; median dose 20 mg) as needed to achieve an FPG ≤ 110 mg/dL (26). Saxagliptin plus metformin was effective in improving glycemic control over the 52-week study and was non-inferior to glipizide plus metformin. In the primary efficacy analysis at 52 weeks, the adjusted mean change from a base-line HbA_1c of 7.7% was –0.74% and –0.80% in the saxagliptin and glipizide groups, respectively; the between-group difference was 0.06% (95% confidence interval (CI) –0.05% to 0.16%) (26). The between-group difference and the upper limit of the 95% CI were below the predefined criterion for non-inferiority of < 0.3%. The magnitude of the HbA_1c reduction was greater at higher base-line HbA_1c in both study groups (26). A smaller rise in HbA_1c was seen from week 24 to week 52 in the saxagliptin plus metformin treatment group compared with glipizide plus metformin, indicating a longer period of sustained glycemic control with saxagliptin treatment (26).

Treatment with saxagliptin plus metformin was associated with a reduction in body-weight and significantly lower hypoglycemic risk than glipizide plus metformin (26).The adjusted mean changes from base-line body-weight were –1.1 kg with saxagliptin compared with +1.1 kg with glipizide; the between-group difference was –2.2 kg (95% CI –2.7 to –1.7; P < 0.0001). Nineteen hypoglycemic events were experienced by 13 (3.0%) patients in the saxagliptin group, compared with 750 events experienced by 156 (36.3%) patients in the glipizide group; the between-group difference was –33.2% (95% CI –38.1% to –28.5%; P < 0.0001). Overall, the incidence of adverse events, after excluding hypoglycemic events, was comparable between treatment groups (60.0% with saxagliptin versus 56.7% with glipizide). However, treatment-related adverse events were much less common with saxagliptin (9.8% versus 31.2%) because of the higher frequency of hypoglycemia in patients receiving glipizide (26). The majority of adverse events in both treatment groups were mild or moderate in intensity, and discontinuation rates due to adverse events were similar between groups (4.2% versus 4.4%) (26).

Saxagliptin was also compared with sitagliptin as add-on therapy to metformin in an 18-week, double-blind non-inferiority trial (27). In this study, 801 T2DM patients with HbA_1c of 6.5%–10% who were on stable metformin doses of 1,500–3,000 mg/d were randomized to receive saxagliptin 5 mg or sitagliptin 100 mg once daily for 18 weeks. Saxagliptin plus metformin was non-inferior to sitagliptin plus metformin in improving glycemic control (27). From a base-line HbA_1c of 7.7%, the adjusted mean change was –0.52% and –0.62% in the saxagliptin and sitagliptin groups, respectively; the between-group difference was 0.09% (95% CI –0.01% to 0.20%) (27). The between-group difference and the upper limit of the 95% CI were below the predefined criterion for non-inferiority of < 0.3%. The proportion of patients who achieved a therapeutic glycemic response defined as HbA_1c ≤ 6.5% was similar between groups (26.3% with saxagliptin plus metformin versus 29.1% with sitagliptin plus metformin) (27).The incidence and type of adverse events were comparable between treatment groups, with approximately 2% of patients in each group discontinuing because of adverse events (27). Hypoglycemic events occurred in approximately 3% of patients in each group, with most being mild in intensity (27).

Special populations

The safety and efficacy of saxagliptin in T2DM patients with moderate renal impairment (estimated creatinine clearance (CL_CR) 30 to < 50 mL/min) to severe renal impairment (CL_CR < 30 mL/min), including end-stage renal disease on hemodialysis, were evaluated in a 12-week randomized controlled trial (28). A total of 170 patients with HbA_1c of 7%–11% were randomized to receive saxagliptin 2.5 mg once daily or placebo. Saxagliptin significantly reduced HbA_1c compared with placebo; the adjusted mean change from base-line was –0.86% with saxagliptin compared with –0.44% with placebo (P = 0.007) (28). Subgroup analysis by base-line renal impairment category revealed numerically greater HbA_1cdecreases with saxagliptin than with placebo in patients with moderate renal impairment (–0.64% versus –0.05%) and severe renal impairment (–0.95% versus –0.50%), whereas the reduction in HbA_1c in patients with end-stage renal disease was similar between treatment groups (–0.84% versus –0.87%). Saxagliptin was well tolerated, with a safety profile comparable to placebo (28). These results suggest that saxagliptin is an effective and well tolerated treatment option for T2DM patients with inadequate glycemic control and renal impairment.

Post-hoc pooled analysis: elderly versus non-elderly patients

Treatment of T2DM in the elderly poses special challenges relating to an increased prevalence of co-morbid renal or cardiovascular disease, altered drug metabolism and excretion, and potentially greater risks from hypoglycemia and other adverse effects of pharmacotherapy. Among the antihyperglycemic agents used in treating T2DM, the thiazolidinediones carry warnings about edema and heart failure (29); the insulin secretagogues (sulfonylureas and meglitinides) are associated with a greater risk of hypoglycemia, especially in the elderly (30). Metformin is associated with gastrointestinal side-effects and is contraindicated in patients at risk for lactic acidosis, as might be seen in renal failure (31); GLP-1 agonists carry warnings about possible pancreatitis (32); and α-glucosidase inhibitors frequently cause gastrointestinal symptoms and may be linked to hepatotoxicity (33). By comparison, the DPP-4 inhibitors have a relatively favorable tolerability profile, carrying no boxed warnings. In addition, they may provide some protection against progressive β-cell loss (11). Therefore, these agents may be an especially suitable option in elderly patients; however, additional analyses of efficacy and safety in this population are warranted.

A pooled analysis of the saxagliptin monotherapy and add-on therapy trials showed that saxagliptin 5 mg once daily produced clinically meaningful reductions in glycemic parameters (HbA_1c, FPG, and PPG-AUC) in non-elderly (aged < 65 y) and elderly (aged ≥ 65 y) T2DM patients (34).The adjusted mean changes from base-line HbA_1c with saxagliptin and placebo were –0.68% and –0.01%, respectively, in patients aged < 65 years (between-group difference –0.67%; 95% CI –0.77% to –0.56%) and –0.73% and –0.17%, respectively, in patients aged ≥ 65 years (between-group difference –0.55%; 95% CI –0.97 to –0.14) (34).Similarly, saxagliptin 5 mg was more effective than placebo in enabling patients to achieve HbA_1c levels < 7% in both the younger and older cohorts at week 24 (34.4% and 44.9%, respectively) compared with placebo (19.0% and 16.9%, respectively). Saxagliptin was generally well tolerated in both age-groups; adverse event rates were comparable to placebo in the younger cohort (71.8% versus 67.2%) but numerically lower in the older cohort (69.7% versus 79.6%) (34).Confirmed hypoglycemia was infrequent; the incidence was 0.5% and 0% with saxagliptin in younger and older patients, respectively, and 0.3% and 0.7% with placebo, respectively. This analysis shows that saxagliptin 5 mg is a safe and effective option for older patients with T2DM.

Other post-hoc pooled analyses

Two additional pooled analyses were conducted utilizing the three add-on saxagliptin trials. One explored the influence of base-line HbA_1c on the reduction in HbA_1c and the proportion of patients achieving an HbA_1c <7.0% without experiencing hypoglycemia (35). Reductions in HbA_1c were greatest in patients with higher base-line HbA_1c(≥8.0%). For patients close to target HbA_1c at base-line (<7.5%), >50% achieved target HbA_1c without associated hypoglycemia over 24 weeks. The latter finding suggests the potential role of saxagliptin as an early add-on treatment option. The second analysis assessed whether various demographic or base-line clinical characteristics influenced the HbA_1c reduction with saxagliptin 5 mg versus placebo. Reductions in mean HbA_1c were greater in patients with longer duration of T2DM (≥5 and ≥10 y), lower base-line CL_CR (<80 mL/min), and lower base-line HOMA-2β (at or below the median of 58.6%) with saxagliptin treatment. The HbA_1c reductions appeared independent of age, gender, or BMI (36).The potential effects of race remain unknown at this time; although a comparison of white versus non-white (six groups) populations revealed no differential effects (10), the majority of patients in these analyses were white. Results may have differed in other ethnic populations, such as Asians, owing to underlying differences in BMI, insulin levels, and β-cell function. Nonetheless, these results suggest that saxagliptin is effective in a broad range of patients with T2DM, including those with a longer duration of disease, and regardless of age, gender, and BMI.

In a meta-analysis of pooled data from a total of eight phase II and phase III trials, which included 3,356 patients treated with saxagliptin and 1,251 patients from the control groups (4), there was no evidence of increased cardiovascular risk in T2DM patients exposed to saxagliptin for >1 year. An independent clinical events committee reviewed and reported on major adverse clinical cardiovascular events (MACE), consisting of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. MACE was confirmed by an independent clinical events committee in 0.7% of patients in all saxagliptin treatment groups compared with 1.4% of patients in the comparator groups (4). The Cox proportional hazards ratio for MACE adjudicated by the independent committee was 0.43 (95% CI 0.23–0.80), which raises the hypothesis that saxagliptin may reduce cardiovascular risk in patients with T2DM. An outcome study (ClinicalTrials.gov identifier NCT01107886) is in progress, which is designed to test the hypothesis that saxagliptin has potential cardioprotective effects and to fulfill the FDA's requirement for excluding increased cardiovascular risk (37).

Extension studies

All phase III pivotal trials included a double-blind, placebo-controlled follow-up for up to 4 years. Patients who completed the 24-week pivotal trial of saxagliptin add-on to metformin were eligible to enter a 42-month extension study (38). Patients who required rescue therapy with pioglitazone during the initial 24-week period entered the extension receiving blinded study medication plus open-label pioglitazone, whereas those patients who did not require rescue continued in the extension period with unchanged blinded medication (38). Pioglitazone rescue was also mandated during the extension study according to progressively stringent glycemic criteria (HbA_1c >8.0% at weeks 30, 37, or 50; >7.5% at weeks 63 or 76; >7.0% after week 89). Saxagliptin added to metformin produced durable, clinically meaningful glycemic improvements in an interim analysis after 102 weeks (Table V) (38). From a mean base-line HbA_1c of 8.1%, the adjusted mean changes corrected for placebo were –0.62% and –0.72% for saxagliptin 2.5 and 5 mg, respectively. The proportion of patients who discontinued for insufficient glycemic control or who received rescue therapy for meeting the pre-specified glycemic criteria was lower for add-on saxagliptin 2.5 mg (58.3%) and 5 mg (51.8%) compared with add-on placebo (71.5%). Small reductions in mean body-weight from base-line to week 102 were observed before any rescue therapy; in a last-observation-carried-forward analysis, the mean changes were –1.0 kg and –0.4 kg with saxagliptin 2.5 and 5 mg, respectively, versus –0.8 kg with placebo (38). Saxagliptin plus metformin was generally well tolerated (Table VI)(38). The frequency of adverse events was 89.6% and 78.0% among patients receiving saxagliptin 2.5 and 5 mg plus metformin, respectively, versus 78.8% among those receiving placebo plus metformin. It should be noted, however, that patients receiving saxagliptin 2.5 and 5 mg had a longer mean duration of exposure to study treatment than those receiving placebo (78 and 75 weeks, respectively, versus 68 weeks). The incidence of reported hypoglycemia was comparable across groups (10.4% and 8.9% versus 10.1%), as was the incidence of confirmed hypoglycemia (1.0% and 1.0% versus 0.6%). Saxagliptin plus metformin was not associated with an increased incidence of infections, localized edema, or cardiovascular events compared with placebo plus metformin, although skin-related adverse events occurred more frequently (15.6% and 13.6% for saxagliptin 2.5 and 5 mg versus 11.2% for placebo). This interim analysis illustrates the long-term efficacy and safety of adding saxagliptin to metformin in patients inadequately controlled by metformin alone.

Table V. Glycemic parameters in long-term extension studies with saxagliptin 5 mg (38–41).

	102-week LTE: Add-on to MET		76-week LTE: Add-on to GLY		76-week LTE: Add-on to TZD		76-week LTE: Initial combination with MET
	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Mean base-line HbA1c, %	8.1	8.1	8.5	8.4	8.4	8.2	9.41	9.42
Δ HbA1c, %	−0.40	0.32	0.03	0.69	−1.09	−.20	−2.3	−1.8
Δ FPG, mg/dL	−11.3	6.8	7.9	4.2	−21.4	−4.5	−53.9	−40.3
Δ 2-hour PPG, mg/dL	−31.5	6.1	−19.5	19.1	−75.2	−20.7	−137.0	−85.8
HbA1c <7%, % of patients	30.4	11.6	9.6	5.3	41.3	24.4	51.1	34.7
HbA1c ≤6.5%, % of patients	18.5	8.1	5.2	1.5	22.8	13.9	38.4	20.1

Δ = adjusted mean change from base-line; FPG = fasting plasma glucose; GLY = glyburide; HbA_1c = glycated hemoglobin; LTE = long-term extension; MET = metformin; PBO = placebo; PPG = postprandial glucose; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide.

Table VI. Incidence of hypoglycemia and adverse events (incidence ≥ 5%) occurring more frequently in patients treated with saxagliptin 5 mg than in those receiving control treatment in the long-term extension studies (38–41).

Events, reported as n (%)	102-week LTE: Add-on to MET		76-week LTE: Add-on to GLY		76-week LTE: Add-on to TZD		76-week LTE: Initial combination with MET
	SAXA + MET n = 191	PBO + MET n = 179	SAXA + GLY n = 253	PBO + UP-GLY n = 267	SAXA + TZD n = 186	PBO + TZD n = 184	SAXA + MET n = 320	PBO + MET n = 328
Nasopharyngitis	21 (11.0)	19 (10.6)	26 (10.3)	29 (10.9)	15 (8.1)	15 (8.2)	29 (9.1)	19 (5.8)
Influenza	22 (11.5)	23 (12.8)	19 (7.5)	27 (10.1)	6 (3.2)	4 (2.2)	20 (6.3)	19 (5.8)
Headache	17 (8.9)	20 (11.2)	25 (9.9)	23 (8.6)	15 (8.1)	12 (6.5)	31 (9.7)	18 (5.5)
Pharyngitis	2 (1.0)	4 (2.2)	19 (7.5)	15 (5.6)	7 (3.8)	5 (2.7)	7 (2.2)	9 (2.7)
Peripheral edema	11 (5.8)	9 (5.0)	6 (2.4)	11 (4.1)	26 (14.0)	19 (10.3)	8 (2.5)	6 (1.8)
URTI	17 (8.9)	14 (7.8)	24 (9.5)	25 (9.4)	24 (12.9)	19 (10.3)	15 (4.7)	10 (3.0)
Urinary tract infection	15 (7.9)	12 (6.7)	42 (16.6)	32 (12.0)	20 (10.8)	17 (9.2)	13 (4.1)	25 (7.7)
Bronchitis	18 (9.4)	11 (6.1)	11 (4.3)	8 (3.0)	7 (3.8)	9 (4.9)	14 (4.4)	4 (1.2)
Sinusitis	10 (5.2)	9 (5.0)	5 (2.0)	5 (1.9)	5 (2.7)	3 (1.6)	–	–
Diarrhea	14 (7.3)	23 (12.8)	16 (6.3)	27 (10.1)	10 (5.4)	14 (7.6)	26 (8.1)	30 (9.1)
Arthralgia	16 (8.4)	9 (5.0)	20 (7.9)	20 (7.5)	10 (5.4)	13 (7.1)	7 (2.2)	6 (1.8)
Musculoskeletal pain	4 (2.1)	9 (5.0)	5 (2.0)	9 (3.4)	12 (6.5)	6 (3.3)	7 (2.2)	4 (1.2)
Dizziness	8 (4.2)	9 (5.0)	3 (1.2)	11 (4.1)	7 (3.8)	14 (7.6)	3 (0.9)	8 (2.4)
Cough	7 (3.7)	9 (5.0)	15 (5.9)	17 (6.4)	5 (2.7)	13 (7.1)	9 (2.8)	5 (1.5)
Toothache	8 (4.2)	11 (6.1)	9 (3.6)	8 (3.0)	5 (2.7)	3 (1.6)	5 (1.6)	6 (1.8)
Back pain	15 (7.9)	16 (8.9)	16 (6.3)	18 (6.7)	12 (6.5)	7 (3.8)	13 (4.1)	11 (3.4)
Pain in extremity	6 (3.1)	13 (7.3)	15 (5.9)	19 (7.1)	6 (3.2)	2 (1.1)	5 (1.6)	10 (3.0)
Hypertension	9 (4.7)	12 (6.7)	23 (9.1)	15 (5.6)	11 (5.9)	12 (6.5)	27 (8.4)	17 (5.2)
Reported hypoglycemia^a	17 (8.9)	18 (10.1)	58 (22.9)	55 (20.6)	9 (4.8)	11 (6.0)	15 (4.7)	19 (5.8)
Confirmed hypoglycemia^b	2 (1.0)	1 (0.6)	8 (3.2)	9 (3.4)	0 (0.0)	1 (0.5)	0 (0.0)	2 (0.6)

^aEvents consistent with symptoms of hypoglycemia with or without documented blood glucose levels.

^bFingerstick glucose < 50 mg/dL with associated symptoms.

GLY = glyburide; LTE = long-term extension; MET = metformin; PBO = placebo; SAXA = saxagliptin; TZD = thiazolidinedione; UP-GLY = up-titrated glyburide; URTI = upper respiratory tract infection.

Long-term extensions of the pivotal trials in which saxagliptin was added to a thiazolidinedione or glyburide were also conducted. Patients who completed the initial 24-week treatment period entered a 52-week long-term extension, for a total treatment duration of 76 weeks (39,40). Rescue therapy with open-label metformin 500 mg/d with titration to a maximum of 2,500 mg/d was mandated in the extension period according to glycemic criteria (HbA_1c > 8.0% at weeks 30, 37, or 50, and > 7.5% at week 63). In the glyburide trial, patients assigned to the placebo group who had not been rescued previously were allowed further up-titration of the glyburide dose to 15 or 20 mg/d providing HbA_1c was ≥ 7.0% at week 30 and the open-label glyburide dose had not been previously reduced because of hypoglycemia (40).

Saxagliptin added to a thiazolidinedione provided sustained incremental efficacy compared with add-on placebo over 76 weeks (Table V)(39). The adjusted mean changes in HbA_1c from base-line to week 76 (repeated measures analysis) were –0.59% and –1.09% with saxagliptin 2.5 and 5 mg, respectively, versus –0.20% with placebo. The between-group comparisons were statistically significant for both saxagliptin doses: –0.39% (95% CI –0.64% to –0.14%; P = 0.0019) for saxagliptin 2.5 mg versus placebo and –0.89% (95% CI –1.14% to –0.64%; P < 0.0001) for saxagliptin 5 mg versus placebo. The sustained efficacy of saxagliptin plus a thiazolidinedione was further demonstrated by the lower rate of rescue therapy: 35.9% and 24.7% with add-on saxagliptin 2.5 and 5 mg, respectively, versus 74.9% with add-on placebo.Combination therapy with saxagliptin plus a thiazolidinedione was generally well tolerated over 76 weeks, with no associated increases in risk of hypoglycemia, cardiovascular events, or significant weight gain compared with placebo plus a thiazolidinedione (39).

The efficacy of adding saxagliptin to a submaximal dose of glyburide compared with glyburide up-titration was maintained in the extension study (40). Adjusted mean changes from base-line HbA_1c (repeated measures analysis) at week 76 for saxagliptin 2.5 and 5 mg were 0.11% (95% two-sided CI − 0.05 to 0.27) and 0.03% (− 0.14 to 0.19), respectively, versus 0.69% (0.47 to 0.92) for up-titrated glyburide (Table V). Between-group comparisons favored both saxagliptin doses relative to up-titrated glyburide: –0.6% (95% CI –0.9% to –0.3%; P < 0.0001) for saxagliptin 2.5 mg and –0.7% (–0.9% to –0.4%; P < 0.0001) for saxagliptin 5 mg. At week 76, the percentage of patients who were rescued or discontinued for lack of efficacy was lower with add-on saxagliptin 2.5 and 5 mg than with glyburide up-titration (63.3% and 62.1% versus 74.9%). Saxagliptin add-on to glyburide was generally well tolerated over the study period, with similar rates of adverse events and hypoglycemic events across treatment groups (Table VI)(40).

A 52-week extension period was also included in the trial evaluating initial therapy with saxagliptin plus metformin in treatment-naive patients with T2DM (41). Pioglitazone 15 mg/d titrated up to 45 mg/d was used as rescue according to the progressively stringent glycemic criteria previously listed for the other extension studies. Patients who did not achieve a reduction in FPG ≥ 30 mg/dL within 8 weeks of starting rescue therapy were discontinued. Initial combination therapy with saxagliptin plus metformin produced sustained glycemic control for 76 weeks, with greater improvements compared with metformin alone. The adjusted mean change in HbA_1c from base-line to week 76 (repeated measures analysis) was –2.31% with saxagliptin 5 mg plus metformin versus –1.79% for metformin alone, comparable to the changes seen at week 24. The between-group comparison at week 76 favored the combination regimen: –0.52% (95% CI –0.71% to –0.33%; P < 0.0001). The proportion of patients requiring rescue therapy or discontinuation for insufficient glycemic control by week 76 was lower in patients receiving saxagliptin plus metformin than in those receiving metformin alone (27.8% versus 41.9%). Initial therapy with saxagliptin plus metformin was well tolerated over 76 weeks (Table VI). The proportion of patients with adverse events was similar across treatment groups (65.9% of patients receiving saxagliptin plus metformin versus 68.3% of those receiving metformin alone), as were the rates of treatment-related adverse events (14.1% versus 20.4%), discontinuations due to adverse events (4.4% versus 4.3%), and reported hypoglycemic events (4.7% versus 6.1%) (41). These results support saxagliptin plus metformin as an attractive first-line option for patients with T2DM.

While long-term saxagliptin extension studies have demonstrated a favorable tolerability profile with no attenuation of efficacy relative to placebo, the results of the long-term glycemic parameter analyses should be interpreted with caution as only relatively small numbers of patients were available for assessment at the end of the extension periods.

Impact of saxagliptin on current treatment regimens

Although metformin continues to be recommended as first-line therapy for patients with T2DM, DPP-4 inhibitors are increasingly being recognized in treatment algorithms as initial and add-on treatment options because of their efficacy in lowering HbA_1c and preferential targeting of PPG, as well as their safety and tolerability profile (2). Key benefits of saxagliptin and other DPP-4 inhibitors include their ability to improve glycemic control, weight neutrality, and low risk of hypoglycemia (1). As such, these agents—particularly when used in combination therapy—provide a validated therapeutic alternative to other classes of OADs.

In summary, saxagliptin is a once-daily DPP-4 inhibitor currently approved in the United States, Europe, Canada, and other countries for patients with T2DM who are not able to maintain glucose control with diet and exercise. The long-term efficacy and tolerability of saxagliptin have been demonstrated when used as initial combination therapy with metformin (41), and when used as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione in studies up to 102 weeks (38–40). Moreover, the efficacy and tolerability of saxagliptin has been demonstrated in special populations including those with moderate or severe renal impairment (28), and post-hoc analyses have established the safety and efficacy of saxagliptin across demographic subgroups including the elderly (34,36). Head-to-head studies showed that saxagliptin plus metformin was non-inferior to glipizide plus metformin in providing sustained HbA_1c reduction over 52 weeks along with reduced body-weight and significantly lower risk of hypoglycemia (26). Saxagliptin plus metformin was also non-inferior to sitagliptin plus metformin (27). A meta-analysis showed no evidence of increased cardiovascular risk in patients with T2DM exposed to saxagliptin, and the reduction in events raised the hypothesis that saxagliptin may have potential cardioprotective effects (4).

Saxagliptin monotherapy or in combination with metformin, a thiazolidinedione, or a sulfonylurea provides a clinically validated therapeutic alternative that offers relatively comparable efficacy to other options without compromising tolerability (e.g. weight neutrality and low risk for hypoglycemia). If sustained glycemic control and cardiovascular risk reduction are confirmed in long-term studies, saxagliptin may emerge as the drug of choice for use in combination in most patients with T2DM.

Declaration of interest: Dr Schwartz has received funds from the following pharmaceutical companies that are involved in the diabetes therapeutic area: Abbott Laboratories; Alteon, Inc.; Amgen, Inc.; Amylin Pharmaceuticals, Inc.; Arena Pharmaceuticals; AstraZeneca (Omnicare); Avanir Pharmaceuticals; Becton, Dickinson and Company; Bertek Pharmaceuticals, Inc. (Covalent); BioRexis Pharmaceutical Corporation; BioStratum, Inc. (PPD); Bristol-Myers Squibb; Covalent Group, Inc.; DexCom, Inc.; E.R. Squibb & Sons, LLC; Eli Lilly and Company; Equidyne Systems, Inc. (JB & Associates); Esperion Therapeutics, Inc.; Exocell, Inc.; Galileo Health Partners; Generex Pharmaceuticals, Inc.; Glaxo; GlaxoSmithKline PLC; Innovex Biosciences; Institute for Diabetes Discovery (Covance); Johnson & Johnson; LifeScan, Inc.; LXN Corporation; Mayo Clinic; MediSense, Inc.; Medtronic MiniMed, Inc.; Merck & Co., Inc.; Metabolex, Inc.; Mitsubishi Pharma Corporation; Nastech Pharmaceutical; Neurobiological Technologies, Inc.; Novartis Pharmaceuticals Corporation; Novo Nordisk; Palatin Technologies, Inc. (Protocare); Pfizer Inc.; Quigley Pharma, Inc.; R.W. Johnson Pharmaceutical Research Institute; Regeneron Pharmaceuticals, Inc.; sanofi-aventis; SmithKline Beecham; Solvay Pharmaceuticals; Squibb-Novo; Takeda Pharmaceutical Company, Ltd.; TheraSense, Inc.; Vivus, Inc.; and Xoma Corporation.

Funding for this review was provided by Bristol-Myers Squibb and AstraZeneca. Technical and editorial support for this manuscript was provided by Diane Kwiatkowski, PhD, Paul Ruest, PhD, and Jennifer Ciafullo, MPH, Quintiles Medical Communications, Parsippany, NJ; and Steven Tiger, PA, and Erica Wehner, RPh, Complete Healthcare Communications, Chadds Ford, PA. Dr Schwartz independently drafted, critically revised and approved the final manuscript.