Ingrid Gause-Nilsson
email: ingrid.gause-nilsson@astrazeneca.com

Burkhard Göke

Baptist Gallwitz

Johan Eriksson

Asa Hellqvist

Å Hellqvist

Saxagliptin is non

Keywords: dipeptidyl peptidase-4, DPP-4, HbA 1c, incretin, non-inferiority, sulphonylurea, glipizide, saxagliptin, type 2 diabetes mellitus

What's known (70 words max; current word count: 57 words)

• Due to insulin resistance and the progressive beta-cell failure that characterises type 2 diabetes mellitus, most patients will eventually require combination therapy to achieve and maintain adequate glycaemic control.

• Combination therapy with metformin and a sulphonylurea is a common therapeutic strategy; however, sulphonylureas are associated with treatment-limiting side effects, such as weight gain and hypoglycaemia.

What's new (70 words max; current word count without data slug: 68 words)

• This non-inferiority trial assessed the efficacy and safety of saxagliptin 5 mg vs. glipizide, as add-on therapy to metformin for 52 weeks in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone.

• Saxagliptin provided a sustained HbA 1c reduction over 52 weeks and was non-inferior to glipizide in lowering HbA 1c with reduced body weight and significantly lower risk of hypoglycaemia compared with glipizide.

Introduction

Failure to achieve and maintain adequate glycaemic control is due to the progressive nature of type 2 diabetes mellitus (T2DM) [START_REF] Matthaei | Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association[END_REF] and the limitations of current therapies [START_REF] Gallwitz | Future perspectives for insulinotropic agents in the treatment of type 2 diabetes-DPP-4 inhibitors and sulphonylureas[END_REF][START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF][START_REF] Barnett | DPP-4 inhibitors and their potential role in the management of type 2 diabetes[END_REF]. Achieving glycaemic goals can substantially reduce morbidity, making effective treatment of hyperglycaemia a high priority [START_REF] Stratton | Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study[END_REF].

Insulin resistance and a decreasing number of functional insulin-producing beta-cells contribute to the pathophysiology of T2DM and, thus, most patients eventually require combination therapy [START_REF] Donath | Mechanisms of β-cell death in type 2 diabetes[END_REF][START_REF] Butler | β-Cell deficit and increased βcell apoptosis in humans with type 2 diabetes[END_REF][START_REF] Turner | Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49)[END_REF].

Treatments targeting the beta-cell dysfunction that characterises T2DM, as well as other underlying disease mechanisms are necessary to achieve and maintain normal glucose levels over time [START_REF] Butler | β-Cell deficit and increased βcell apoptosis in humans with type 2 diabetes[END_REF].

Moreover, some current therapies have treatment-limiting side effects, including hypoglycaemia and weight gain [START_REF] Uk Prospective | Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)[END_REF]. Combining therapeutic agents that differ in their mechanism of action and tolerability profiles can address some of these treatment challenges [START_REF] Asche | Association between oral and antidiabetic use, adverse events and outcomes in patients with type 2 diabetes[END_REF].

Metformin is standard first-line pharmacotherapy for patients with T2DM [START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF][START_REF] Asche | Association between oral and antidiabetic use, adverse events and outcomes in patients with type 2 diabetes[END_REF]. Metformin is inexpensive, generally well tolerated and infrequently associated with hypoglycaemia, though dosing may be limited by transient gastrointestinal effects [START_REF] Matthaei | Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association[END_REF][START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF]. The major non-glycaemic benefit of metformin is weight stability or modest weight loss, in contrast with many other blood glucose-lowering medications, such as sulphonylurea or insulin [START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF][START_REF] Uk Prospective | Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)[END_REF]. As monotherapy, metformin typically results in glycated haemoglobin (HbA 1c ) reductions of 1.0% to 2.0% depending on baseline HbA 1c [START_REF] Matthaei | Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association[END_REF][START_REF] Bailey | Metformin[END_REF][START_REF] Defronzo | Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group[END_REF]; however, metformin alone is frequently insufficient to maintain glycaemic goals over time [START_REF] Turner | Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49)[END_REF][START_REF] Kahn | Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy[END_REF].

Sulphonylureas are commonly used as add-on therapy in patients with inadequate glycaemic control on metformin alone and represent current standard therapy in most T2DM treatment algorithms [START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF][START_REF]Chapter 9: Glucose control: oral therapy[END_REF][START_REF] Korytkowski | Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride[END_REF].

Sulphonylureas are also inexpensive and initially demonstrate strong HbA 1c -lowering effects [START_REF] Nathan | Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes[END_REF][START_REF]Chapter 9: Glucose control: oral therapy[END_REF]. Their use, however, is associated with limitations, which include multiple titration steps, the potential for betacell failure [START_REF] Donath | Mechanisms of β-cell death in type 2 diabetes[END_REF][START_REF] Maedler | Sulfonylurea induced ß-cell apoptosis in cultured human islets[END_REF], weight gain [START_REF] Korytkowski | Sulfonylurea treatment of type 2 diabetes mellitus: focus on glimepiride[END_REF] and increased risk of hypoglycaemia [START_REF] Krentz | Oral antidiabetic agents: current role in type 2 diabetes mellitus[END_REF]. Hypoglycaemia in particular affects morbidity and quality of life for patients with T2DM and is a major obstacle to medication adherence [START_REF] Barnett | Key considerations around the risks and consequences of hypoglycaemia in people with type 2 diabetes[END_REF][START_REF] Amori | Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis[END_REF].

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of oral antidiabetic agents (OADs) and augment glucose homoeostasis by preventing degradation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) [START_REF] Matthaei | Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association[END_REF][START_REF] Barnett | DPP-4 inhibitors and their potential role in the management of type 2 diabetes[END_REF]. The former hormone accounts for the majority of the incretin effect and is a key component in regulating both fasting plasma glucose (FPG) and postprandial glucose (PPG) by stimulating glucose-dependent insulin secretion, and attenuating glucagon secretion by the pancreatic alpha-cells to decrease glucose production by the liver [START_REF] Matthaei | Medical antihyperglycaemic treatment of type 2 diabetes mellitus: update of the evidence-based guideline of the German Diabetes Association[END_REF][START_REF] Barnett | DPP-4 inhibitors and their potential role in the management of type 2 diabetes[END_REF][START_REF] Drucker | Enhancing incretin action for the treatment of type 2 diabetes[END_REF]. DPP-4 inhibitors demonstrate a low propensity for hypoglycaemia and are generally weight neutral, making them suitable candidates for combination therapy [START_REF] Barnett | DPP-4 inhibitors and their potential role in the management of type 2 diabetes[END_REF][START_REF] Amori | Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis[END_REF]. Further, metformin works through pathways complementary to DPP-4 inhibitors, and combination therapy may improve glycaemic control by targeting multiple mechanisms [START_REF] Hinke | Metformin effects on dipeptidylpeptidase IV degradation of glucagon-like peptide-1[END_REF] without increasing the risk of hypoglycaemia or inducing weight gain.

Saxagliptin is a selective DPP-4 inhibitor approved as an adjunct to diet and exercise for the management of glycaemic control in adults with T2DM [START_REF] Augeri | Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes[END_REF]23). Saxagliptin, either as add-on therapy to metformin or given with metformin as initial therapy for 24 weeks was well tolerated and led to statistically significant improvements in glycaemic indices vs. placebo and metformin, respectively, in patients with T2DM and inadequate glycaemic control [START_REF] Defronzo | The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone[END_REF][START_REF] Jadzinsky | Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial[END_REF]. Hypoglycaemic events were comparable across treatment groups and there were no increases in weight observed in the saxagliptin plus metformin groups in either study [START_REF] Defronzo | The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone[END_REF][START_REF] Jadzinsky | Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial[END_REF]. Additionally, saxagliptin and metformin combination therapy improved indices of beta-cell function [START_REF] Defronzo | The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone[END_REF]. Combination therapy with saxagliptin and metformin may offer several advantages compared with the current standard practice of metformin-sulphonylurea combination therapy. This 52-week trial assessed the efficacy and safety of saxagliptin vs. the sulphonylurea, glipizide, as addon therapy to metformin in patients with T2DM and inadequate glycaemic control on a stable dose of metformin alone. A non-inferiority trial design was chosen to investigate the clinical equivalence of saxagliptin plus metformin therapy as compared with the current standard treatment of sulphonylurea plus metformin.

F

Patients and methods

Patients

Eligible study participants were men and women age ≥ 18 years with T2DM and HbA 1c >

Study end-points

The primary efficacy end-point was change from baseline to week 52 in HbA 1c and was used to assess if saxagliptin plus metformin was non-inferior to glipizide plus metformin. Key secondary end-points were the proportion of patients reporting ≥ 1 event of hypoglycaemia over 52 weeks, the change from baseline body weight at week 52 and the mean slope of regression of change from week 24 to week 52 in HbA 1c .

Other secondary end-points included change from baseline FPG, fasting insulin, C-peptide, glucagon and proinsulin; the proportion of patients achieving a therapeutic glycaemic response defined as HbA 1c ≤

Statistical analyses

The primary efficacy analysis and key secondary efficacy analyses involving HbA 1c were conducted on a per-protocol (PP) analysis set. The PP analysis set included patients who completed the 52-week randomised treatment period, had both a baseline and week 52 HbA 1c measurement and no significant protocol deviations. The full analysis set, which included all patients who received at least 1 dose of randomised study medication and had at least 1 non-missing baseline and 1 post-baseline efficacy data assessment, was used for confirmatory analysis of the primary end-point and for all other efficacy analyses.

Efficacy analyses for continuous variables were performed using an analysis of covariance (ANCOVA) model, with treatment as an effect and baseline HbA 1c as the covariate. Within the framework of the ANCOVA model, point estimates and 95% confidence intervals (CIs) for the mean change within each treatment group, as well as for the differences in mean change between the saxagliptin plus metformin group and the glipizide plus metformin group were estimated. Saxagliptin plus metformin was considered non-inferior to glipizide plus metformin if the upper limit of the 95% CI of the difference in change in HbA 1c from baseline to week 52 between the 2 treatment groups was < 0.35%. A fixed-sequence test was employed for primary and key secondary efficacy end-points to control the overall type I error rate of the study. All comparisons were 2-sided at the 5% significance level. The proportion of patients reporting ≥ 1 hypoglycaemic event and the percentage of patients achieving a targeted glycaemic response were analysed using the Fisher exact test. A mixed model with patient-specific slopes using observed values assessed the durability of the HbA 1c effect.

Demographic and other baseline characteristics were summarised using descriptive statistics With 419 patients per treatment group, there was a 95% power to establish the non-inferiority comparison on change from baseline to week 52 in HbA 1c at the 5% level, assuming that the standard deviation (SD) of change from baseline in HbA 1c was 1.1%, with a non-inferiority limit set at 0.35% and a zero true difference between the 2 randomised treatments. The sample size assumed that 35% of randomised patients would be excluded from the PP analysis set.

Results

Disposition, baseline demographics, clinical characteristics, and drug exposures

A total of 858 patients were randomised and treated with double-blind therapy; 633 (73.8%) completed the 52-week treatment period, with comparable completion percentages between groups (72.9% for saxagliptin plus metformin, 74.7% for glipizide plus metformin) (Figure 1). Demographic and baseline A total of 59 patients were enrolled for an OGTT; however, the number of evaluable OGTT results was low (35 patients).

Primary end-point

At 52 weeks, saxagliptin plus metformin was non-inferior to glipizide plus metformin in lowering HbA 1c (primary analysis of the PP analysis set). Adjusted mean changes from baseline HbA 1c were -0.74% vs. -0.80% with saxagliptin vs. glipizide, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%) (Figure 2A, Table 2). Confirmatory analysis of the full analysis set yielded consistent results (adjusted mean change from baseline HbA 1c -0.57% vs. -0.66% for saxagliptin plus metformin vs.

glipizide plus metformin, respectively). Mean HbA 1c values over time for the PP analysis set are shown in Figure 2B.

Key secondary end-points

The proportion of patients reporting ≥ 1 hypoglycaemic event over 52 weeks was low in the saxagliptin plus metformin group (3.0%), and was significantly lower compared with the glipizide plus metformin 3).

Treatment with saxagliptin vs. glipizide was associated with a divergent impact on body weight at week 52; mean body weight decreased in the saxagliptin plus metformin group and increased in the glipizide plus metformin group. Adjusted mean changes from baseline were -1.1 kg vs. 1.1 kg, with saxagliptin vs.

glipizide respectively; the between-group difference was -2.2 kg (95% CI, -2.7 to -1.7; p < 0.0001) (Figure 4).

The PP analysis demonstrated a small rise per week in HbA 1c during weeks 24 to 52 in both treatment groups (mean changes per week 0.001% for saxagliptin and 0.004% for glipizide). The rise per week was statistically significantly smaller with saxagliptin vs. glipizide (-0.002% difference, 95% CI, -0.0046% to -0.0001%; p = 0.04) indicating a more sustained effect on glycaemic control beyond week 24.

Other secondary end-points

Changes in other secondary efficacy variables from baseline to week 52 are listed in [95% CI, 0.31% to 1.04%]). and is likely to be the source of the significant interaction.

Patients treated with glipizide plus metformin had a greater mean increase in HOMA-2β vs. saxagliptin plus metformin. For the small OGTT patient subset, the saxagliptin plus metformin group demonstrated numerically greater decreases from baseline in 120-minute PPG vs. the glipizide plus metformin group (data not shown).

Fifty-nine (13.8%) patients in the saxagliptin plus metformin group and 47 (10.9%) patients in the glipizide plus metformin group met prespecified glycaemic discontinuation criteria and discontinued from the study by week 52. A small but greater number of patients in the saxagliptin plus metformin group discontinued due to high FPG up to week 24 vs. the glipizide plus metformin group (3.5% vs. 1.2%, respectively). Post 24 weeks, when criteria were based on HbA 1c levels, discontinuation rates were similar (10.3% for the saxagliptin group vs. 9.8% for the glipizide group).

Safety and tolerability

Overall, saxagliptin plus metformin was generally well tolerated (Table 3). Excluding hypoglycaemia, the proportion of patients with AEs was similar between groups (60.0% saxagliptin vs. 56.7% glipizide).

Treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%) due to the higher frequency of hypoglycaemia in patients receiving glipizide. The majority of AEs in both treatment

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Discussion

This study demonstrated that in patients with T2DM not achieving glycaemic control on stable doses of metformin, the addition of saxagliptin 5 mg/day to metformin provided HbA 1c reduction that was sustained over 52 weeks. The HbA 1c reduction at week 52 was non-inferior to adding glipizide to metformin, with a decrease in body weight and statistically significantly lower proportion of patients with hypoglycaemia vs. glipizide. Both saxagliptin and titrated dosages of glipizide added to metformin improved glycaemic control, as assessed by decreases from baseline HbA 1c and FPG, as well as the proportion of patients achieving a therapeutic response. As is frequently observed with antihyperglycaemic agents, greater reductions in HbA 1c were seen in patients with higher HbA 1c values at baseline. Although both treatment groups showed a small rise in HbA 1c from week 24 to week 52, a smaller rise per week in HbA 1c during this time period was observed for saxagliptin plus metformin vs.

glipizide plus metformin indicating a longer period of sustained glycaemic control with saxagliptin treatment. The findings that glipizide-treated patients had a transient greater decrease in HbA 1c at some time points in the first half of the study as well as a greater mean increase in HOMA-2β may be explained by the mechanism of action of a sulphonylurea agent to directly stimulate insulin secretion and is in agreement with findings in other studies [START_REF] Nauck | Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial[END_REF][START_REF] Ferrannini | Fifty-two-week efficacy and safety of vildagliptin vs. glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy[END_REF].

While the importance of long-term glycaemic control has been repeatedly demonstrated, achievement of treatment goals may be limited by adverse drug effects, most notably hypoglycaemia and weight gain associated with some OADs used to treat T2DM [START_REF] Krentz | Oral antidiabetic agents: current role in type 2 diabetes mellitus[END_REF]. The increased number of patients experiencing hypoglycaemia is particularly relevant for treatment combinations that include sulphonylureas and/or insulin; however, treatment with saxagliptin provided added efficacy without safety issues (hypoglycaemia or weight gain). Specifically, treatment with glipizide resulted in 12 times as many patients with hypoglycaemic events relative to saxagliptin-treated patients.

Despite the fact that weight gain has been observed with intensive glycaemic control (9), saxagliptin treatment resulted in a small weight loss, compared to weight gain with sulphonylurea therapy. Results from 24-week studies of saxagliptin and metformin combination therapy have also demonstrated reductions from baseline body weight from-0.87 kg to -1.8 kg [START_REF] Defronzo | The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone[END_REF][START_REF] Jadzinsky | Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial[END_REF]. Because a majority of patients with T2DM are overweight or obese, therapeutic regimens that have a neutral or beneficial impact on weight are important in clinical practice.

Although firm conclusions cannot be drawn from comparisons between studies performed in different patient populations with different designs, the present results were comparable to those of a similar 52week study by Nauck et al using a DPP-4 inhibitor (sitagliptin) added to metformin compared with glipizide added to metformin. Sitagliptin 100 mg/day plus metformin was noninferior to glipizide plus metformin (HbA 1c change from baseline -0.67%, both groups); proportion of patients experiencing hypoglycaemia was significantly higher with glipizide vs. sitagliptin. Sitagliptin also demonstrated a small decrease in weight compared with with glipizide [START_REF] Nauck | Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial[END_REF]. Two-year study results were recently published and demonstrated similar glucose-lowering efficacy between completers in the 2 treatment groups, but with lower risk of hypoglycaemia and weight loss compared with weight gain with sitagliptin vs glipizide [START_REF] Seck | Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study[END_REF]. Another DPP-4 inhibitor, vildagliptin, was also studied as an add-on to metformin therapy vs. the sulphonylurea glimepiride added on to metformin. Two year results indicated vildagliptin 50 mg twice daily was noninferior to glimepiride (HbA 1c change from baseline -0.1%, both groups), with fewer patients experiencing hypoglycaemia and a beneficial effect on body weight for vildagliptin vs glimepiride, respectively [START_REF] Matthews | Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study[END_REF]. In all studies, a greater proportion of patients treated with a DPP-4 inhibitor achieved target HbA 1c goals. These results, in addition to those of the current study, support the utility of DPP-4 inhibitor therapy added to metformin and suggest greater tolerability with comparable efficacy vs. the current standard practice of metformin-sulphonylurea combination therapy.

Given the common and increasing use of OADs, the relative impact on CV health is also of critical importance and a matter of much debate. Studies assessing the association of combination therapy of metformin and sulphonylureas on all-cause and/or cardiovascular mortality risk in T2DM are not consistent. There has been reported both a neutral CV risk [START_REF] Gulliford | Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study[END_REF][START_REF] Kahler | Impact of oral antihyperglycemic therapy on all-cause mortality among patients with diabetes in the Veterans Health Administration[END_REF], a decreased CV risk [START_REF] Johnson | Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes[END_REF], and an increased CV risk [START_REF] Evans | Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin[END_REF][START_REF] Rao | Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?[END_REF][START_REF] Fisman | A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease[END_REF][START_REF] Tzoulaki | Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database[END_REF]. A recent evaluation of total CV death/myocardial infarction/stroke events in the pooled phase 2/3 clinical trials of saxagliptin demonstrated no evidence of increased risk [START_REF] Frederich | A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes[END_REF].

Retrospective studies of other DPP-4 inhibitors (sitagliptin, vildagliptin) as monotherapy or in combination treatment suggest no increased risk of CV events [START_REF] Kothny | Cardiovascular safety profile of vildagliptin, a new DPP-4 inhibitor for the treatment of type 2 diabetes[END_REF][START_REF] Williams-Herman | Safety and tolerability of sitagliptin, a selective DPP-4 inhibitor, in patients with type 2 diabetes: pooled analysis of 6139 patients in clinical trials for up to 2 years[END_REF][START_REF] De | Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis[END_REF]. This favourable tolerability profile suggests that the addition of DPP-4 inhibitors to metformin may be appropriate and preferable for certain patients, including those who are overweight or at higher risk of hypoglycaemia.

There were some limitations to this study; it included mostly patients with uncomplicated T2DM at the time of metformin failure, thus limiting the ability to generalise safety findings across the broad range of patients with T2DM. However, the characteristics of the patient population recruited as well as the degree of HbA 1c reduction are well in line with other studies in patients with failure on metformin monotherapy and support the external validity of the study findings [START_REF] Phung | Effect of noninsulin antidiabetic drugs added to metformin therapy on glycemic control, weight gain, and hypoglycemia in type 2 diabetes[END_REF]. The small sample size of the OGTT patient subset precluded definitive conclusions about PPG effects in this study. Reduction of PPG with saxagliptin in combination with metformin has been demonstrated in other studies [START_REF] Defronzo | The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone[END_REF][START_REF] Jadzinsky | Saxagliptin given in combination with metformin as initial therapy improves glycemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial[END_REF].

In summary, achieving specific glycaemic goals can substantially reduce diabetes-related morbidity, making the effective treatment of hyperglycaemia a high priority. By using agents that differ in their mechanism of action and side effect profiles, combination regimens can better address the numerous *AE defined as any new or worsening illness, sign, symptom or clinically significant laboratory test abnormality as noted by the investigator during the course of the study, regardless of the investigator's attribution of the event to study treatment. †AEs are included up to the last of: 1) the last treatment day +1 day or, 2) the last visit day in the 52-week treatment period. ‡Includes hypoglycaemia events. §SAE defined as an AE that was fatal, life threatening, required in-patient hospitalisation or prolonged an existing hospitalisation, resulted in persistent or significant disability or incapacity, a cancer, a congenital anomaly/birth defect, resulted in the development of drug dependency or drug abuse or was an important medical event that jeopardised the patient or required intervention to prevent a serious outcome.

¶SAEs are included up to the last of: 1) the last treatment day +30 days or 2) the last visit day +30 days in the 52-week treatment period. **Excludes hypoglycaemia events. ‡In patient and event incidences, a patient could contribute to more than 1 column. In event incidences, a patient could experience more than 1 event corresponding to the same column. §Event percent = 100*(number of events of the column)/total number of events. ¶Patient percent = 100*(number of patients with events of the column)/N.

SAXA + MET GPZ + MET

  Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial

6 .

 6 5%; HbA 1c change from baseline in patients with baseline HbA 1c ≥ 7.0%; the proportion of patients achieving a therapeutic glycaemic response defined as HbA 1c < 7.0% in patients with baseline HbA 1c ≥ 7.0%, and change from baseline beta-cell function (as measured by homeostasis model assessment [HOMA-2β]). Change from baseline to week 52 in 120-minute PPG during an oral glucose tolerance test (OGTT) was also assessed in a subset of patients.Safety and tolerability assessments included adverse events (AEs), serious AEs (SAEs), related AEs, discontinuations from study medication due to AEs and deaths, as well as AEs of special interest, specifically hypoglycaemia, lymphopenia, thrombocytopenia, skin disorders, localised oedema, infections and CV AEs. Laboratory values, electrocardiograms, vital signs, physical examination and body weight were also assessed.

Figure 1

 1 Figure 1 Patient disposition. Recruitment period ran from December 11, 2007 through August 5, 2008, and the last visit in the 52-week treatment period was August 28, 2009. *The category of "No longer metstudy criteria" corresponds to the category of "Development of study specific discontinuation criteria." †Patients were only included in this category if the study investigator checked adverse event (AE) as the primary reason for discontinuation. A patient may have experienced an AE that resulted in discontinuation and was summarised as an AE leading to discontinuation that was not counted here as a reason for discontinuation if the study investigator checked an alternative primary reason for discontinuation. ‡Per study investigator's opinion. GPZ, glipizide; MET, metformin; SAXA, saxagliptin.

Figure 2

 2 Figure 2 Composite figure. (A) Primary end-point: Adjusted mean change from baseline HbA 1c at week 52: SAXA + MET vs. GPZ + MET. (B) Mean HbA 1c values over time: SAXA + MET vs. GPZ + MET.*Per-protocol analysis set GPZ, glipizide; MET, metformin; SAXA, saxagliptin.

Figure 3

 3 Figure 3 Proportion of patients with at least 1 hypoglycaemic episode over 52 weeks. *Safety analysis set. †p < 0.0001.

Figure 4 32 Figure 2 33 ( 34 Figure 3 35 Figure 4

 432233343354 Figure 4 Adjusted mean change from baseline body weight (kg) to week 52. *Safety analysis set. †p < 0.0001.

of 37 International Journal of Clinical Practice International Journal of Clinical Practice

  [START_REF] Donath | Mechanisms of β-cell death in type 2 diabetes[END_REF].5% -10.0% on a stable dose of metformin monotherapy ≥ 1500 mg/day for at least 8 weeks prior to enrollment. KeyThe study protocol was approved by the Institutional Review Board/Independent Ethics Committee for each participating site, and carried out in accordance with the Declaration of Helsinki and International Conference on Harmonisation/Good Clinical Practice guidelines. Patients were informed of the study purpose and potential risks, and gave written informed consent.

	Manuscript ID IJCP-07-10-0351.FX5
	5 mg/day (morning dose) and titrated in 3-week intervals to a maximum of 20 mg/day using a double-
	dummy technique to ensure blinding. Titration steps were 10 mg/day (morning dose), followed by 15
	mg/day (10 mg morning dose, 5 mg evening dose) and 20 mg/day (10 mg morning dose, 10 mg evening
	dose). Initial titration assessment was at week 3; subsequent re-assessment for titration occurred at weeks
	6, 9, 12, 15 and 18. During the titration period, glipizide could be down-titrated once if hypoglycaemic
	Study design events occurred and could thereafter be up-titrated once. Evaluation at each titration visit and final
	This was a 52-week, phase 3b, international, multicenter, randomised, parallel-group, active-controlled, decision by the investigator on dose increase or decrease took into account patient glucose measurements
	F o r P e e r R e v i e w double-blind, non-inferiority trial, with a 52-week extension period (ongoing). Eligible patients enrolled in a 2-week, single-blind, placebo-controlled lead-in period that included advice on diet and exercise. All patients received open-label metformin at 1500, 2000, 2500 or 3000 mg daily based on individual metformin dose at enrollment for the duration of the study; the dose remained stable throughout the study. Patients were assigned a glucometer and patient diary for the course of the initial 52-week treatment period and instructed to monitor their fingerstick glucose level regularly. Information about hypoglycaemic events (list of symptoms, fingerstick value if obtained) was to be entered into the patient diary. At screening, patients were assigned a unique identifier to be used throughout the study. Following the lead-in period, eligible patients were randomised (1:1) via an interactive Web-response system using a balanced block randomisation schedule to 1 of 2 treatment groups: saxagliptin 5 mg/day plus open-label metformin or glipizide up-titrated as needed from 5 to 20 mg/day plus open-label metformin. Blinding was ensured using a double-dummy technique. Study medication was taken orally, immediately before or F o r P e e r R e v i e w made before visits, hypoglycaemic events recorded in the patient diary and investigator's measurements at titration visits. Following the titration period, medication doses remained stable except for instances of glipizide down-titration to mitigate recurrent hypoglycaemia at the discretion of the study investigator; no up-titration was allowed. Patients were instructed to monitor their fingerstick glucose levels at least once a week and continue documenting hypoglycaemic events in their patient diaries. Throughout the study, patients were discontinued if they failed to meet prespecified, progressively more stringent glycaemic control criteria. Patients with FPG > 270 mg/dl (> 15.0 mmol/l), > 240 mg/dl (> 13.3 o r P e e r mmol/l), > 220 mg/dl (> 12.2 mmol/l) or > 200 mg/dl (11.F R e v i e w
	normal (ULN) and/or alanine aminotransferase (ALT) > 2 × ULN and/or total bilirubin > 2.0 mg/dL (> 34 µmol/L)] or any clinically significant laboratory abnormality upon screening. O n with a meal. Patients assigned to saxagliptin plus metformin remained on saxagliptin 5 mg throughout the study. For O n O n
	l y patients assigned glipizide plus metformin, glipizide was titrated to an optimal effect (FPG ≤ 110 mg/dl [≤ 6.1 mmol/l]) or the highest tolerated dose during an 18-week titration period. Glipizide was initiated at l y l y
	8

exclusion criteria included type 1 diabetes; history of diabetic ketoacidosis or hyperosmolar non-ketotic coma; insulin therapy within 1 year of enrollment; treatment with a thiazolidinedione within the 12 weeks prior to enrollment; treatment with systemic glucocorticoids other than replacement therapy; previous DPP-4 inhibitor treatment; donation of blood, plasma or platelets within the 3 months prior to enrollment; congestive heart failure defined as New York Heart Association class III or IV and/or known left ventricular ejection fraction ≤ 40%; significant cardiovascular (CV) history within the past 6 months defined as myocardial infarction, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, transient ischaemic attack or cerebrovascular accident; history of haemoglobinopathies; significant alcohol or drug abuse within the year prior to enrollment; treatment with human immunodeficiency virus/antiviral drugs or cytochrome P450 3A4 (CYP450 3A4) inducers; serum creatinine ≥ 1.5 mg/dL [≥ 133 µmol/L (men)]; ≥ 1.4 mg/dL [≥ 124 µmol/L (women)]; active liver disease and/or significant abnormal liver function [aspartate aminotransferase (AST) > 2 × upper limit of 1 mmol/l) at weeks 3, 12, 18 or 24, respectively, or HbA 1c > 8.0% at week 30 or 39 were discontinued. Assessments took place at each visit to determine if study discontinuation criteria were met.

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  All patients who received at least 1 dose of study medication during the 52-week treatment period were included in the safety analysis (safety analysis set). Patients were assessed for safety according to the actual treatment taken. AEs were tabulated; other safety-related variables were summarized using descriptive statistics, tabulations and/or listings. AEs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 at the preferred term (PT) level and grouped by system organ class (SOC). AEs of special interest were identified by matching reported AEs to a predefined list of PTs or lowest level terms (localised oedema only) reflective of that particular diagnosis. AE intensity was defined as mild (awareness of event but easily tolerated), moderate (discomfort enough to cause some interference with usual activity), severe (inability to carry out usual activity) or very severe (debilitating, significantly incapacitates patient despite symptomatic therapy). Reported hypoglycaemia events were a

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  clinical characteristics were generally well balanced across treatment groups in both the randomised and PP analysis sets and representative of patients with uncontrolled T2DM treated with metformin monotherapy (Table1). For the overall study population, mean age, HbA 1c , weight, body mass index (BMI), metformin dose and duration of T2DM were 57.6 years, 7.7%, 88.7 kg, 31.4 kg/m 2 , 1910 mg/day and 5.4 years, respectively. Mean final glipizide total daily dose (TDD) was 14.7 mg/day (range, 0-20 mg); more than two-thirds of patients in the glipizide plus metformin group underwent 2 or more dose titrations, and approximately 50% of the patients in the glipizide plus metformin group reached a final glipizide TDD of 20 mg/day. Median exposure to study medication was 363 days for the saxagliptin plus metformin group and 364 days for the glipizide plus metformin group.

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	Manuscript ID IJCP-07-10-0351.FX5
	group (36.3%) (difference vs. glipizide plus metformin -33.2% (95% CI, -38.1% to -28.5%; p < 0.0001)
	(Figure
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Table 2

 2 The proportion of patients achieving HbA 1c ≤ 6.5% was similar (35.9% vs. 34.3% for saxagliptin vs. glipizide, respectively). The proportion of patients achieving HbA 1c < 7.0% (with or without hypoglycaemic events) in patients whose baseline HbA 1c ≥ 7.0% was similar (42.6% vs. 47.8% for saxagliptin vs. glipizide, respectively). When patients with hypoglycaemic events were excluded, 41.4%

	Deleted: 3

. Both treatment groups demonstrated improved glycaemic control as assessed by decreases from baseline FPG, with a numerically greater decrease with glipizide plus metformin vs. saxagliptin plus metformin. There were small and generally similar increases from baseline in both treatment groups in mean values for fasting insulin and fasting C-peptide. Numerical reductions in fasting proinsulin and numerically smaller increases in fasting glucagon were demonstrated for saxagliptin vs. glipizide.

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  (saxagliptin) vs.[START_REF] Gulliford | Mortality in type 2 diabetic subjects prescribed metformin and sulphonylurea drugs in combination: cohort study[END_REF].9% (glipizide) of patients achieved HbA 1c < 7.0%. Greater decreases were associated with categories of higher baseline HbA 1c in each treatment group. Adjusted mean changes from baseline for saxagliptin vs glipizide, respectively, were -0.32 vs. -0.30 for HbA 1c < 7.0%; -0.45 vs. -0.58 for HbA 1c ≥ 7.0% to < 8.0%; -0.84 vs. -0.81 for HbA 1c ≥ 8.0% to < 9.0%; and -1.05 vs. -1.72 for HbA 1c ≥

	9.0%. An interaction of treatment with baseline category was observed (p = 0.0179). The smallest
	subgroup analysed, ie, those with baseline HbA 1c ≥ 9.0%, (n = 79) demonstrated numerically greater
	reductions with glipizide plus metformin vs. saxagliptin plus metformin (between-group difference 0.67%
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 2 groups were mild or moderate in intensity and discontinuation rates due to AEs were similar for saxagliptin vs. glipizide. Four deaths occurred during the study period (cardiac failure and head injury in the saxagliptin plus metformin group; ischaemic stroke and myocardial infarction in the glipizide plus metformin group), none of which was considered by study investigators to be treatment related.

	Hypoglycaemic events are listed in Table 4. A total of 13 (3.0%) patients in the saxagliptin plus
	metformin group experienced 19 hypoglycaemic events and 156 (36.3%) patients in the glipizide plus
	metformin group experienced 750 hypoglycaemic events over the 52-week treatment period. No patients F o (0%) experienced a hypoglycaemic event with fingerstick glucose ≤ 50mg/dL [2.8 mmol/l] or a
	r confirmed hypoglycaemic event (defined as fingerstick glucose value ≤ 50 mg/dl [2.8 mmol/l] with
	associated symptoms) in the saxagliptin plus metformin group vs. 38 (8.8%) and 35 (8.1%) of the patients P r e e in the glipizide plus metformin group, respectively. Most hypoglycaemic events were mild in intensity.
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One (0.2%) patient in the saxagliptin plus metformin group and 62 (14.4%) patients in the glipizide plus metformin group had hypoglycaemic events that were moderate in intensity. No (0%) patients in the saxagliptin plus metformin group and 7 (1.6%) patients in the glipizide plus metformin group had hypoglycaemic events that were severe. No patients in the saxagliptin plus metformin group required medical assistance for a hypoglycaemic event; 4 (0.9%) patients experienced a non-serious hypoglycaemic AE requiring medical assistance in the glipizide plus metformin group.

Two or fewer patients in either treatment group had AEs of lymphopenia, thrombocytopenia, skin disorders or localised oedema. The proportion of patients with CV AEs was comparable for saxagliptin vs. glipizide (8 [1.9%] vs 9 [2.1%], respectively). A total of 3 patients had hypersensitivity AEs: 1 patient in the saxagliptin plus metformin group (SAE of hypersensitivity) and 2 patients in the glipizide plus metformin group (AE of drug hypersensitivity [ciprofloxacin] and SAE of laryngeal oedema). There were no AEs of pancreatitis in the saxagliptin plus metformin group; 1 (0.2%) patient in the glipizide plus metformin group had 2 SAEs of pancreatitis. Small mean decreases from baseline in systolic and diastolic Page

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  blood pressure, respectively, occurred in the saxagliptin plus metformin (-4.1 and -2.7 mm Hg) and glipizide plus metformin (-1.2 and -1.1 mm Hg) treatment groups. There were no apparent differences between the saxagliptin plus metformin and glipizide plus metformin groups in change from baseline in mean values for fasting lipid parameters. There were no clinically relevant changes in electrocardiograms or clinically meaningful drug effects on any laboratory safety parameter.

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  Combination therapy with saxagliptin and metformin provided similar HbA 1c lowering efficacy with a reduction in weight compared with weight gain and a lower proportion of hypoglycaemia vs. glipizide plus metformin. Based on this overall profile, saxagliptin plus metformin may be preferable to adding a sulphonylurea to metformin in patients with inadequate glycaemic control with metformin monotherapy.

	Page 19 of 37	International Journal of Clinical Practice
	pathophysiologic abnormalities that characterise T2DM while reducing safety and tolerability issues.
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Table 1

 1 Demographic and baseline clinical characteristics*

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		SAXA + MET	GPZ + MET
	Characteristic	(n = 428)	(n = 430)
	Age, years, mean (SD)	57.5 (10.26)	57.6 (10.37)
	Aged ≥ 65 years, n (%)	106 (24.8)	113 (26.3)
	Aged ≥ 75 years, n (%)	21 (4.9)	21 (4.9)
	Gender, n (%)
	Male	212 (49.5)	232 (54.0)
	Female	216 (50.5)	198 (46.0)
	Race, n (%)
	Asian	73 (17.1)	65 (15.1)
	Black/African American	1 (0.2)	0
	White	352 (82.2)	362 (84.2)
	Other	2 (0.5)	3 (0.7)
	Geographical region, n (%)
	Asia	68 (15.9)	63 (14.7)
	Europe	360 (84.1)	367 (85.3)
	Weight, kg, mean (SD)	88.7 (18.61)	88.6 (19.64)
	BMI, kg/m 2 , mean (SD)	31.5 (5.70)	31.3 (6.17)
	Duration of diabetes, years, mean (SD)	5.5 (4.5)	5.4 (4.7)
	HbA 1c , %, mean (SD)	7.7 (0.9)	7.7 (0.9)
	< 7.0%, n (%)	99 (23.1)	105 (24.4)
	≥ 7.0% to < 8.0%, n (%)	190 (44.4)	186 (43.3)
	≥ 8.0% to < 9.0%, n (%)	93 (21.7)	105 (24.4)
	≥ 9.0%, n (%)	46 (10.7)	34 (7.9)
	FPG, mg/dl, mean (SD)	163 (41.2)	161 (39.2)
	MET dose, mg, mean (SD) †	1938 (484.8)	1883 (453.7)
	≥ 1500 to < 2000, n (%) †	193 (45.1)	209 (48.6)
	≥ 2000 to < 2500, n (%) †	131 (30.6)	143 (33.3)
	≥ 2500 to < 3000, n (%) †	66 (15.4)	48 (11.2)
	≥ 3000, n (%) †	37 (8.6)	30 (7.0)
	Not reported, n (%) †	1 (0.2)	0
	BMI, body mass index; FPG, fasting plasma glucose; GPZ, glipizide; HbA 1c , glycated haemoglobin;
	MET, metformin; SAXA, saxagliptin.
	* Randomized analysis set.
	†At randomization.

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Table 3

 3 Safety and tolerability during the 52-week treatment period AE, adverse event; GPZ, glipizide; MET, metformin; SAE, serious adverse event; SAXA, saxagliptin.

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	Manuscript ID IJCP-07-10-0351.FX5
	Adverse events, n (%)* † ‡	(n = 428)	(n = 430)
	≥ 1 AE	260 (60.7)	293 (68.1)
	≥ 1 related AE	42 (9.8)	134 (31.2)
	Deaths	2 (0.5)	2 (0.5)
	≥ 1 SAE § ¶	39 (9.1)	32 (7.4)
	≥ 1 related SAE	0	1 (0.2)
	Discontinuation from study medication due to AE	18 (4.2)	19 (4.4)
	Discontinuation from study medication due to SAEs	8 (1.9)	8 (1.9)
	Adverse events (≥ 5%)**
	Nasopharyngitis	41 (9.6)	37 (8.6)
	Diarrhoea	22 (5.1)	16 (3.7)
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Table 4

 4 All reported hypoglycaemic events by fingerstick plasma glucose concentration during 52-week treatment period* †

			Plasma Glucose Level (mg/dL) [mmol/L]
			≤ 50	> 50 -< 63	≥ 63 -<70	≥ 70	No fingerstick	Total
			[≤ 2.8]	[> 2.8 -< 3.5]	[≥ 3.5 -< 3.9]	[≥ 3.9]	value obtained
	Treatment group
	SAXA + MET, N = 428 Events, n (%) ‡, §	0 (0.0)	5 (26.3)	2 (10.5)	3 (15.8)	9 (47.4)	19 (100.0)
		Patients, n (%) ‡, ¶	0 (0.0)	4 (0.9)	2 (0.5)	2 (0.5)	6 (1.4)	13 (3.0)
	GPZ + MET, N = 430	Events, n (%) ‡, §	66 (8.8)	283 (37.7)	146 (19.5)	151 (20.1)	104 (13.9)	750 (100.0)
		Patients, n (%) ‡, ¶	38 (8.8)	103 (24.0)	72 (16.7)	51 (11.9)	44 (10.2)	156 (36.3)
	GPZ, glipizide; MET, metformin; SAXA, saxagliptin.

*Safety analysis set. †Reported hypoglycaemia events is a combination of reports of either signs or symptoms consistent with hypoglycaemia or reported low glucose levels.

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	PPG at 120 min † (mg/dl)
	N	18	17
	BL mean (SE)	285 (11.7)	280 (16.1)
	Adjusted mean change from BL (SE)	-49 (16.6)	-28(17.1)
	Mean difference vs. GPZ + MET (SE)	-21 (23.8)
	95% CI	-69.3 to 27.8
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International Journal of Clinical PracticeInternational Journal of Clinical Practice

Acknowledgements

This study was funded, designed and supervised by scientists at Bristol-Myers Squibb and AstraZeneca, discoverers and developers of saxagliptin. The authors gratefully acknowledge the study participants, CRAs, and site staff who assisted with this research. Technical and editorial assistance for this manuscript was provided by Jennifer Ciafullo, MPH, of Quintiles Medical Communications, Parsippany, NJ, USA.

boards for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, Novartis,

Author Contributions

Drs Göke, Gallwitz and Eriksson contributed to the data acquisition, drafting and critical revision of the manuscript content. Dr Gause-Nilsson and Åsa Hellqvist, MSc, contributed to the study design, data analysis/interpretation, drafting and critical revision of the manuscript content. All authors approved the final manuscript.