ONGLYZA® (saxagliptin)

How do you choose the right DPP-4 inhibitor for your patients with type 2 diabetes?

Study details: De Fronzo et al. 2009

This was a 24-week, randomised, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1500 —2500 mg) in 743 patients (HbA1c ≥ 7.0 and ≤ 10.0%). The aim of the trial was to assess the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycaemic control with metformin alone.

Of the 1,462 patients screened, 743 were randomly assigned and received study treatment and 73% (543 of 743) completed 24 weeks of treatment.

Patients completing the 24-week treatment period or those who met the rescue criteria could enter the 42-month long-term extension.
The primary efficacy outcome was change from baseline in A1C to week 24. Secondary end-points included change from baseline to week 24 in fasting plasma glucose (FPG), the percentage of patients at the glycaemic target (defined as A1C <7.0%), and postprandial glucose (PPG) 3-h area under the curve (AUC) during a 75-g oral glucose tolerance test (OGTT). 

Study details: Nowicki et al. 2011

This was a 12-week, phase 3, randomised, parallel-group, placebo-controlled, double-blind international, multi-centre trial with a 40-week extension period.The aim of the study was to assess the efficacy and safety of saxagliptin vs. placebo in adults with type 2 diabetes mellitus and inadequate glycaemic control (HbA1c 7-11%) and moderate or severe renal impairment, or end-stage renal disease (ESRD).

Using CrCI estimated by the Cockcroft-Gault equation, eligible patients (n=170) were stratified based on degree of renal impairment, and randomised (1:1) in balanced blocks within each renal impairment category to double-blind treatment with saxagliptin 2.5 mg (n=85) or placebo (n=85) once daily. Other antidiabetic drugs in use at enrolment were continued, subject to adjustment as needed to prevent hypoglycaemia through the 52-week study or to improve glycaemic control during the 40-week extension; addition of new drugs except thiazolidinediones, glucagon-like peptide 1 (GLP-1) agonists, metformin and other DPP-4 inhibitors was allowed.

Efficacy was assessed by absolute changes from baseline to week 12 HbA1c (primary end-point) and FPG (secondary end-point).The percentage of patients achieving a therapeutic glycaemic response (defined as >0.5% decrease in HbA1C) in each treatment group was also determined.

The primary efficacy end-point was absolute HbA1c change from baseline to week 12. Secondary end-points included assessment of efficacy at 52 weeks using absolute change from baseline in HbA1c and fasting plasma glucose and changes from baseline in the type and/or daily doses of background oral antidiabetic drug therapy and insulin.
A total of 170 patients were randomised. Of these, 129 (76%) completed the 12-week short-term treatment period and 92 (54%) completed the 52-week study (saxagliptin, 49%; placebo, 59%). 

Study details: Ott et al. 2013

This was a randomised, double-blind, placebo-controlled investigator sponsored cross-over trial. The aim was to analyse the impact of saxagliptin on early microvascular changes due to type 2 diabetes by noninvasively measuring the retinal circulation, documenting haemodynamic changes and assessing early vascular remodeling. 

Patients of either gender and age between 18 and 75 years were eligible for inclusion into the study given they were diagnosed with T2D (defined by fasting glucose ~7.0 mmol/L or HbA1c ~ 6.5% (48 mmol/mol) or receiving anti-diabetic pharmacotherapy). Patients with micro- or macrovascular complications such as diabetic retinopathy, macroalbuminuria, an acute cardiovascular event, unstable angina or stroke within 6 months prior to enrolment were excluded. 

Patients (n=42) were randomly assigned to either 5 mg of saxagliptin once daily or matching placebo. At 6 weeks patients' treatment was switched (cross-over) and treatment continued for another 6 weeks without a washout between treatment phases.The total treatment duration was 12 weeks. 

Retinal arteriolar structure and retinal capillary flow (RCF) at baseline and during flicker-light exposure was assessed by scanning laser Doppler flowmetry. Central hemodynamies were assessed by pulse wave analysis. 

Study details: Goke et al. 2010 and Goke et al. 2013

This was a 52-week, phase 3b, international, multicentre, randomised, parallel-group, active-controlled, double-blind, non-inferiority trial with a 52-week extension period. The aim of this study was to assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone.

Adults with HbA1c > 6.5-10% (on stable metformin >1500 mg/day) were randomised to saxagliptin 5 mg/day (n=428; per protocol n=293) or glipizide titrated from 5 to 20 mg/day (mean total daily dose 15 mg/day; n=430; per protocol n=293) for 52 weeks with a 52-week extension. Patients assigned to saxagliptin plus metformin remained on saxagliptin 5 mg throughout the study. For patients assigned to 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. The mean metformin dose was approximately 1900 mg in each treatment group.

The primary efficacy end-point was HbA1c, change from baseline at 52 weeks and was used to assess if saxagliptin plus metformin was non-inferior to glipizide plus metformin. The primary efficacy analysis was 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 HbA1C measurement and no significant protocol deviations. Onglyza 5 mg + metformin was considered non-inferior to glipizide + metformin if the upper confidence limit of the estimate was <0.35 at 1 year. After 52 weeks, the saxagliptin and glipizide groups had similar mean reductions from baseline in HbA1c, in the per protocol analysis (-0.74% vs. -0.8%, respectively, mean baseline HbA1C of 7.5% for both groups). The difference (95% confidence interval) between the two treatment arms, based on the per-protocol analysis, was 0.06 (-0.05 to 0.16) at 52 weeks, hence establishing non-inferiority.

Key secondary safety and efficacy end-points include the proportion of patients reporting event of hypoglycaemia over 1 year and the change from baseline body weight at 1 year. Assessment of the long-term safety, tolerability and efficacy of add-on saxagliptin vs. glipizide after 104 weeks was a tertiary objective of the initial 52-week study. End-points included the proportion of patients reporting at least one hypoglycaemic event during 104 weeks of treatment. Confirmed hypoglycaemia was defined as a finger-stick glucose value ≤ 2 8 mmol/l with associated symptoms. 

Study details: Scirica et al. 2013

This was a multi-centre, randomised, double-blind, placebo-controlled, phase 4 trial conducted at 788 sites in 26 countries.

Eligible patients had a history of documented type 2 diabetes, a HbA1c, of 6.5% to 12.0%, and either a history of established cardiovascular disease or multiple risk factors for vascular disease. To meet the criteria for established cardiovascular disease, patients had to be at least 40 years old and have a history of a clinical event associated with atherosclerosis involving the coronary, cerebrovascular, or peripheral vascular system. To meet the criteria for the multiple risk factors, patients had to be at least 55 years of age (men) or 60 years of age (women) with at least one of the following additional risk factors: dyslipidaemia, hypertension, or active smoking.

Eligible patients were randomly assigned (1:1 ratio), to receive saxagliptin at a dose of 5 mg daily (or 2.5 mg daily in patients with an estimated glomerular filtration rate [GFR] of ~50 ml per minute) or matching placebo. Stratification was according to the qualifying cardiovascular disease state (established cardiovascular disease vs. multiple risk factors only) and renal function (normal function or mild renal impairment [estimated GFR, >50 ml per minute] vs. moderate renal impairment [estimated GFR, 30 to 50 ml per minute] vs. severe renal impairment [estimated GFR, <30 ml per minute]). Patients in whom renal impairment (an estimated GFR of ~50 ml per minute) developed during the study period had a single dose adjustment to 2.5 mg daily.

The primary efficacy and safety end-point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal ischemic stroke.The secondary efficacy end-point included the primary composite end-point plus hospitalisation for heart failure, coronary revascularisation, or unstable angina. 

Study details: Fu et al. 2016

This observational cohort study used a U.S. insurance claims database to compare the risk of hospitalisation for heart failure (hHF) between patients with type 2 diabetes mellitus treated with DPP-4i vs. SU and between those treated with saxagliptin vs. sitagliptin.

Secondary analyses compared the aforementioned groups with respect to other CV outcomes: risk of hospitalisation for acute myocardial infarction (AMI), hospitalisation for stroke, hospitalisation for unstable angina, coronary revascularisation, and a composite of all outcomes together, including hHF.

Methods followed the FDAs Mini-Sentinel protocol for active surveillance of antidiabetic agents.

Patients initiated treatment between 8/1/2010 and 8/30/2013 and had no use of the comparator treatments in the prior 12 months (baseline). Each comparison consisted of patients matched 1:1 on a propensity score (nearest neighbour; caliper=0.01). Analyses were stratified by presence of baseline CVD. Time to hHF was compared between matched groups using Cox models. 

 

Veeva code: GB-7993

Date of preparation: August 2017