Sitagliptin 100mg tablets (Januvia^®▼) - type 2 diabetes mellitus

SMC recommendations

7th September 2007
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5th September 2008
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4th June 2010
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Tayside recommendation
Formulary – restricted use. Restricted to use as add-on combination therapy with metformin, when metformin alone with diet and exercise does not provide adequate glycaemic control and only in patients when the addition of a sulphonylurea is not appropriate. Sitagliptin is the 1^st line choice of DPP-4 inhibitor in Tayside.

Tayside recommendation
Non-formulary

Vildagliptin 50mg/metformin hydrochloride 850g film coated  tables and vildagliptin 50mg/metformin hydrochloride 1000mg film coated tablets (Eucreas^® ▼50mg/850mg and 50mg/1000mg) - type 2 diabetes mellitus

Tayside recommendation
Non-formulary (dual therapy in combination with metformin)

Not recommended (monotherapy or triple therapy)

The Gliptins’: Sitagliptin, Saxagliptin and Vildagliptin

·         The gliptins are a novel class of oral antidiabetic agents known as the dipeptidyl peptidase type 4 (DPP-4) inhibitors.  DPP-4 inhibitors increase levels of incretin hormones and thus stimulate insulin release and reduce glucagon secretion, thereby reducing blood glucose levels.

·         Sitagliptin has the broadest SMC recommendations of all the gliptins. Gliptins are 2^nd or 3^rd line treatment options for management of glycaemic control in patients with type 2 diabetes. Locally the addition of a gliptin may be considered as an alternative option to the addition of a thiazolidinedione in patients with type 2 diabetes who are inadequately controlled on metformin alone and either have not tolerated sulphonylureas or who are considered unsuitable for treatment with sulphonylureas.

·         Efficacy. In a Cochrane systematic review the HbA1c reduction seen with these agents was 0.6 – 0.7%.  In a 52-week randomised trial, sitagliptin added to metformin has been shown comparable to glipizide added to metformin.  Further data indicate that sitagliptin added to metformin has similar efficacy to a thiazolidinedione plus metformin.  In a 24-week RCT vildagliptin added to metformin showed non-inferiority, in terms of Hba1c reduction, to pioglitazone added to metformin.  An active-controlled 18-week study demonstrated non-inferiority, in terms of HbA1c reduction, with saxagliptin plus metformin compared to sitagliptin plus metformin. No trials have compared linagliptin with other DDP-4 inhibitors. Long-term studies are needed to assess whether the glitptins reduce disease-related morbidity and mortality.

·         Side effects.  Unlike thiazolidinediones and sulphonylureas the gliptins do not cause weight gain.  The gliptins are generally well tolerated.  Vildagliptin should be used cautiously in NYHA I & II heart failure, and is contraindicated in NYHA III & IV heart failure (due to limited data on these groups). Saxagliptin has limited experience in NYHA I & II heart failure, and no experience in clinical studies in NYHA III & IV heart failure. Vildagliptin should not be used in hepatic impairment and when the ALT or AST is > 3 times the upper limit of normal and requires 3 monthly LFT monitoring for the first year. Vildagliptin may be used at a reduced dose of 50mg once daily in moderate or severe renal impairment or with end-stage renal disease. Sitaglitpin at a reduced dosage may be used in moderate or severe renal impairment, or with end-stage renal disease (25mg once daily or 50mg once daily depending on renal function). With sitagliptin, liver function test monitoring is not required and heart failure is not a contraindication. Saxagliptin has a licence for use in moderate and severe renal impairment, when 2.5mg once daily should be used. Saxagliptin should be used with caution in patients with moderate hepatic impairment and should not be used in severe hepatic impairment. Linagliptin does not require dose adjustment in renal impairment or hepatic impairment, however clinical experience in patients with hepatic impairment is limited. Acute pancreatitis has been reported with all of the gliptins. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, gliptins and other potentially suspect medicines should be discontinued. Hypersensitivity reactions have also been reported with the gliptins, if a hypersensitivity reaction is suspected the gliptin should be discontinued. Saxagliptin is contraindicated if the patient has a history of any serious hypersensitivity reaction to a gliptin.

·         Cost.  Sitagliptin 100mg once daily (£432 per patient per year) , saxagliptin 5mg daily (£411 per patient per year) , linagliptin 5mg daily (£432 per patient per year) and vildagliptin 50mg twice daily (£413 per patient per year) are a similar price to the thiazolidinediones and considerably more expensive than sulphonylureas.

·          Comparison of sitagliptin, saxagliptin, linagliptin and vildagliptin. Sitagliptin, saxagliptin, linagliptin and vildagliptin appear to have similar efficacy although have not been compared in a head-to-head study.  Change from baseline in HbA1c achieved with saxagliptin added to metformin was non-inferior to that achieved with sitagliptin added to metformin in an active-controlled 18-week study of 801 patients. Sitagliptin is taken once daily and is not contraindicated in heart failure or mild to moderate hepatic impairment. Saxagliptin is also taken once daily and is not contraindicated in heart failure, however should be used with caution in moderate hepatic impairment. Linagliptin is taken once daily and may be used in renal or hepatic impairment. Linagliptin is only recommended by SMC for dual therapy in combination with metformin, as is saxagliptin (although both have additional licensed indications which are different). Vildagliptin is taken twice daily, and is contraindicated in heart failure and hepatic dysfunction and liver function monitoring is required in the first year. Sitagliptin is the formulary 1^st line choice of gliptin, saxagliptin is an alternative to sitagliptin, restricted to use as add-on combination therapy with metformin (when metformin alone with diet and exercise does not provide adequate glycaemic control) where the addition of a sulphonylurea is not appropriate. Linagliptin and Vildaglitptin are non-formulary in Tayside.

·         Preparations in Tayside Area Formulary. Sitagliptin – 25mg, 50mg, 100mg tablets. Saxagliptin – 2.5mg, 5mg tablets. In combination with metformin – sitagliptin 50mg/metformin 1000mg.

·         The NHS Tayside Diabetes MCN Pharmacological management of type 2 diabetes guidance incorporates the DPP-4 inhibitors and other oral hypoglycaemic agents.

October 2008, Updated August 2010 and April 2012.