27th July 2009,
A phase III, 24 week randomised controlled trial has assessed the efficacy and short-term safety of saxagliptin 2.5, 5 and 10mg versus placebo as add-on therapy to metformin in 743 people with type 2 diabetes mellitus who had an HbA1c ≥ 7.0% and ≤ 10.0% and a BMI ≤ 40kg/m2. All doses of saxagliptin plus metformin produced greater changes in HbA1c from baseline than placebo plus metformin.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Saxagliptin has not yet been marketed, but should this occur then local decision making bodies will need to consider its place in therapy. Recent NICE guidance suggests that the marketed dipeptidyl peptidase-4 (DPP-4) inhibitors, sitagliptin▼ and vildagliptin▼, may be second-line options in certain people with type2 diabetes mellitus (T2DM) (see our blog). Importantly, no evidence has yet been published that shows of the effect of these agents on macrovascular or microvascular disease, including cardiovascular events.
What is the background to this?
In June 2009 the DPP-4 inhibitor saxagliptin received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of T2DM. It is recommended for use in adults as add-on therapy with either metformin, a thiazolidinedione or a sulphonylurea. The product will be available as a 5mg tablet under the trade name Onglyza®.
What does this study claim?
All doses of saxagliptin plus metformin were statistically significantly more effective than placebo plus metformin at reducing HbA1c. Adjusted mean changes from baseline to week 24 were −0.59% (standard error [SE] 0.07) for 2.5mg, −0.69% (SE 0.07) for 5mg and −0.58% (SE 0.07) for 10mg (all P < 0.0001 vs. placebo).
How does this relate to other studies?
The NICE clinical guideline on the management of T2DM was published in May 2009. This covers other DPP-4 inhibitors but not saxagliptin, which did not receive a positive opinion in time to be included. Saxagliptin is not yet part of NICE’s work programme. We have previously blogged about the launch of vildagliptin. Several other gliptins are in clinical trials. A short trial of saxagliptin versus sitagliptin in patients already taking metformin has recently been completed.
We have previously highlighted that the evidence for the use of hypoglycaemic agents to achieve tight blood glucose control in people with type 2 diabetes mellitus may well be of less benefit to individuals than other interventions to reduce cardiovascular risk. In many patients priority should still be given to the important lifestyle interventions such as support for smoking cessation, eating healthily, increasing excercise, controlling blood pressure, and taking a statin.
No evidence has yet been published that shows of the effect of the gliptins on macrovascular or microvascular disease, including cardiovascular events.
NICE suggests setting an individualised target for HbA1c in people with type 2 diabetes mellitus. With certain provisos, a DDP-4 inhibitor may be considered at an HbA1c of 6.5% for people on one glucose-lowering drug and 7.5% for people on two or more oral glucose-lowering drugs or taking insulin (or higher levels if agreed with the individual). In this trial, HbA1c was reduced to < 7.0% with saxagliptin 2.5, 5 and 10mg plus metformin vs. placebo and metformin in 37%, 44% and 44% vs. 17% of patients, respectively. NICE also recommends that DPP-4 inhibitors should be continued only if the person has a beneficial metabolic response to therapy (a reduction of at least 0.5% in HbA1c in six months). In this trial, saxagliptin plus metformin decreased HbA1c by slightly more than 0.5%.
Saxagliptin will have the same licensed indications as vildagliptin as add-on therapy with metformin, a thiazolidinedione or a sulphonylurea. Sitagliptin can be used as dual or triple therapy.
More information on T2DM can be found on the cardiovascular floors of NPC.
DeFronzo RA, Hissa MN, Garber AJ et al for the Saxagliptin 014 Study Group. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes on metformin alone. Diabetes Care published online May 28, 2009 DOI: 10.2337/dc08-1984
Design: phase III, 24-week randomised, double-blind, placebo-controlled study.
Patients: 743 patients aged between 18 and 77 years with T2DM on a stable dose of metformin (1500 to 2550mg/day) for at least 8 weeks. Patients were required to have an HbA1c ≥ 7.0% and ≤ 10.0% and a BMI ≤ 40kg/m2.
Intervention and comparison: oral saxagliptin 2.5, 5 or 10mg or placebo once daily plus stable dose of metformin. Eligible patients were enrolled into a 2-week, single-blind, dietary and exercise placebo lead-in period and received open-label metformin.
Outcomes and results: the primary endpoint was change in HbA1c. Adjusted mean HbA1c changes from baseline to week 24 were −0.59% (SE 0.07), −0.69% (SE 0.07) and −0.58% (SE 0.07) with saxagliptin 2.5mg, 5mg and 10mg, respectively (all P < 0.0001 vs. placebo). Levels rose by + 0.13% (SE 0.07) in patients on placebo plus metformin.
The risk of hypoglycaemic adverse events was similar in each group. All events were of mild to moderate intensity and did not require treatment or medical intervention. The percentage of patients who had at least one adverse effect was 74.3% in the saxagliptin plus metformin patients and 64.8% in the metformin plus placebo group, without evidence of a dose-response relationship.
Sponsorship: Bristol-Myers Squibb and AstraZeneca
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