Saxagliptin

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Onglyza (Bristol-Myers Squibb)
5 mg tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook section 10.1.3

Incretins help to lower blood glucose after a meal. This effect can be prolonged by inhibiting their metabolism. Sitagliptin and saxagliptin are drugs which do this by inhibiting the enzyme dipeptidyl peptidase 4 (DPP4) (see 'Incretin mimetics and enhancers' Aust Prescr 2008;31:102-8).

Saxagliptin is taken once a day. After absorption, the drug suppresses DPP4 activity for 24 hours. Saxagliptin is metabolised by cytochrome P450 3A4 to a less potent active metabolite. The pharmacokinetics of saxagliptin can therefore be affected by other drugs which act on P450 3A4. For example, inhibition by ketoconazole increases the concentration of saxagliptin and decreases the concentration of its active metabolite. Saxagliptin has a half-life of 2.5 hours and its main metabolite has a half-life of 3.1 hours. The drug and its metabolites are mainly excreted in the urine. It should not be used in patients with moderate or severe renal impairment.

Saxagliptin has been studied as an add-on treatment for patients with type 2 diabetes that had not been controlled by a single drug. It was added to metformin in a placebo-controlled study of 743 patients. After 24 weeks of treatment, the 191 patients who took metformin with saxagliptin 5 mg had a reduction of 0.69% in their concentrations of glycated haemoglobin (HbA1c). There was a rise of 0.13% in the patients who added a placebo to metformin. Saxagliptin also significantly reduced fasting blood glucose.¹

The relative benefits of increasing the dose of a sulfonylurea or adding saxagliptin were assessed in a study of 768 patients. All the patients were given glibenclamide 7.5 mg daily for four weeks. Patients whose diabetes was not controlled were then randomised to increase the dose to 10 mg daily or add saxagliptin 2.5 or 5 mg. After 24 weeks the mean HbA1c concentration had increased by 0.08% in the glibenclamide group, but decreased by 0.54% in patients who added saxagliptin 2.5 mg and by 0.64% in those who added 5 mg. The combination of treatments had a statistically significantly greater effect on fasting blood glucose than increasing the dose of glibenclamide.² The mean reduction from baseline was 0.4 mmol/L with compared with an increase of 0.04 mmol/L with glibenclamide.

Saxagliptin has also been added to the treatment of patients whose diabetes has not been controlled by a thiazolidinedione. In this study, 565 patients taking pioglitazone or rosiglitazone were randomised to add saxagliptin 2.5 mg, 5 mg or a placebo. After 24 weeks the HbA1c concentration had fallen by 0.66% with 2.5 mg, 0.94% with 5 mg and 0.3% with placebo. The reductions in fasting blood glucose were also significantly greater with saxagliptin.³

One study used saxagliptin and metformin in 1306 patients who were starting treatment for the first time. After 24 weeks the combination reduced the concentrations of HbA1c and fasting blood glucose more than either drug alone. Metformin with saxagliptin 5 mg reduced HbA1c by 2.5% compared to 2.0% with metformin and 1.7% with saxagliptin 10 mg alone.⁴

During the trials 3.3% of the patients discontinued saxagliptin 5 mg because of adverse effects compared with 1.8% of the placebo groups. Reasons for stopping treatment included lymphopenia, rashes and increased creatinine concentrations. Hypoglycaemia was reported by 5.2% of patients when saxagliptin 5 mg was added to metformin,¹ 14.6% when added to glibenclamide² and 2.7% when added to a thiazolidinedione.³ In the thiazolidinedione study 8.1% of the patients developed peripheral oedema when saxagliptin 5 mg was added to their treatment.³

Saxagliptin's main role is likely to be as an add-on therapy. Its modest efficacy will not bring every patient's diabetes under control. The proportion of patients achieving HbA1c concentrations under 7% after adding saxagliptin 5 mg was 43.5% with metformin,¹ 22.8% with glibenclamide² and 41.8% with a thiazolidinedione.³ Continuing diet and exercise is therefore important. Although saxagliptin has been approved for use with metformin as an initial drug treatment, it is not usual practice to begin treatment with a combination of drugs. As diabetes is a chronic disease, it will be years before the clinical effectiveness and safety of saxagliptin can be confirmed.

manufacturer provided the AusPAR

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, a scientific discussion about this drug was available on the website of the European Medicines Agency (www.emea.europa.eu).