Sitagliptin

Januvia (Merck Sharp & Dohme)
25 mg, 50 mg and 100 mg tablets
Approved indication: type 2 diabetes
Australian Medicines Handbook section 10.1

Incretins stimulate the release of insulin after meals. They are rapidly metabolised by dipeptidyl peptidase 4 (DPP4) so inhibiting this enzyme prolongs their effect (see Experimental and clinical pharmacology articles: Aust Prescr 2008;31:102-4 and Aust Prescr 2008;31:104-8).

Sitagliptin is an inhibitor of DPP4 which can be given once a day. The drug is rapidly absorbed and its action leads to lower blood glucose concentrations. Its half-life is approximately 12 hours and most of the dose is excreted unchanged in the urine. While people with liver disease may be able to take sitagliptin, it is not recommended for patients with renal impairment.

Several doses of sitagliptin were compared to placebo and glipizide in 743 patients with type 2 diabetes. The patients' mean glycated haemoglobin (HbA1c) at the start of the study was 7.9%. After 12 weeks a total daily dose of sitagliptin 100 mg had reduced the HbA1c by 0.54%, while there had been a 0.23% increase with placebo. Glipizide reduced HbA1c by 0.76%.¹

Another placebo-controlled study gave sitagliptin to 741 patients for 24 weeks. The mean HbA1c was reduced from 8.0% to 7.39% in the patients who took sitagliptin 100 mg. It fell below 7% in 41% of those taking this dose, compared with 17% of the placebo group.²

A trial involving patients whose type 2 diabetes was inadequately controlled by metformin randomised 464 to add sitagliptin and 237 to add a placebo. The HbA1c declined in the first 12 weeks of sitagliptin therapy then plateaued. After 24 weeks the mean HbA1c had declined from 7.96% to 7.26% with sitagliptin while it was almost unchanged in the placebo group. The HbA1c fell below 7% in 47% of the sitagliptin group, but in only 18% of the placebo group.³

Another study tried starting the treatment of 1091 patients with sitagliptin, metformin or a combination of both. The drugs were given in a variety of doses all of which significantly reduced the mean HbA1c (8.8%) over 24 weeks. The reductions were 0.66% with sitagliptin 100 mg, 0.82% with metformin 500 mg twice daily and 1.13% with metformin 1 g twice daily. In combination therapy, sitagliptin 50 mg twice daily reduced HbA1c by 1.4% with metformin 500 mg twice daily and by 1.9% with metformin 1 g twice daily.⁴

Patients whose diabetes was not controlled by metformin were enrolled in a trial comparing sitagliptin with a sulfonylurea. Glipizide was added to the treatment of 584 patients while 588 added sitagliptin. After a year the average HbA1c declined by 0.56% with glipizide, and 0.51% with sitagliptin. There was a difference in the effect of treatment on the patients' weights. People taking glipizide gained 1.1 kg while those taking sitagliptin lost 1.5 kg.⁵

Sitagliptin has also been added to the treatment of 353 patients taking pioglitazone. At the start of the placebo-controlled trial these patients had mean HbA1c concentrations of approximately 8%. In the 175 randomised to add sitagliptin 100 mg daily for 24 weeks the HbA1c fell by 0.85%. The fall in the placebo group was 0.15%. By the end of the trial 45% of the patients taking sitagliptin and pioglitazone had HbA1c concentrations below 7% compared with 23% of the patients taking pioglitazone and a placebo.⁶

During the trials of sitagliptin the main adverse events were gastrointestinal upsets and musculoskeletal complaints. There were slightly more infections in the patients given sitagliptin. This could be a concern as DPP4 is found in T lymphocytes. Serious hypersensitivity reactions have also been reported. Hypoglycaemia can occur, but is more likely to happen if sitagliptin is used in combination with a sulfonylurea. Approximately 12% of patients reported hypoglycaemia when sitagliptin was used in combination with glimepiride, with or without metformin.

Sitagliptin has little effect on lipids and its influence on cardiovascular disease in diabetes is unknown. It has an effect on the surrogate outcome of HbA1c, but its role in therapy is currently unclear. In the comparison with glipizide more patients taking sitagliptin discontinued treatment, mainly because of a lack of efficacy.⁵ Although sitagliptin has a greater effect than placebo, it has not been approved for monotherapy in Australia. It is also not approved as an add-on therapy when a patient's diabetes has not been controlled by the standard therapy of metformin and a sulfonylurea.

manufacturer did not respond to request for data

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).