Approved indication: type 2 diabetes
Trajenta (Boehringer Ingelheim)
5 mg tablets
Australian Medicines Handbook section 10.1.3
Patients with diabetes produce less of the peptide hormones known as incretins. Their concentration can be increased by inhibiting the enzyme (dipeptidyl peptidase 4) which metabolises them. This increases insulin secretion and lowers glucose concentrations. Saxagliptin, sitagliptin, vildagliptin and now linagliptin are all inhibitors of the enzyme (see: Incretin mimetics and enhancers, Aust Prescr 2008;31:104-8 ).
Linagliptin is taken once a day. Its bioavailability is only 30% and this can be reduced by drugs, such as rifampicin, which induce the P-glycoprotein transporter. The metabolism of the drug involves cytochrome P450 3A4, but this may not be clinically important. Most of the dose is excreted unchanged in the faeces. The terminal half-life of the drug exceeds 100 hours.
Several thousand patients have been involved in trials of linagliptin. These studies included combinations with other treatments for type 2 diabetes as well as monotherapy. In 503 patients with inadequately controlled diabetes, 24 weeks of monotherapy had a significantly greater effect than placebo. From a baseline mean of 8%, the mean glycated haemoglobin (HbA1c) reduced by 0.44% with linagliptin 5mg, but increased by 0.25% with placebo.1 In Australia however, linagliptin is only approved in combination with metformin, a sulfonylurea or both.
Another 24-week trial randomised 701 patients whose diabetes was not controlled by metformin. A group of 523 patients took linagliptin and 177 took placebo. From a baseline of 8.09%, the HbA1c reduced by 0.49% with linagliptin 5 mg and increased by 0.15%, from 8.02%, with placebo. A target HbA1c of 7% or less was achieved by 26% of the linagliptin group and 9% of the placebo group.2
In a similar group of 333 patients, another placebo-controlled trial studied three different doses (1 mg, 5 mg and 10 mg) of linagliptin and also included a glimepiride arm. All the patients continued to take metformin during the trial. After 12 weeks the active treatments had significantly reduced HbA1c from similar baseline values ( see Table ).3 A longer term comparison found that after a year linagliptin 5 mg reduced HbA1c by 0.38% and glimepiride reduced it by 0.6%.
An 18-week trial studied linagliptin in combination with a sulfonylurea. Compared with placebo, the mean treatment difference was 0.47%.
Linagliptin has also been studied, in 1058 patients, as an addition to treatment with metformin and a sulfonylurea. While adding a placebo reduced the mean HbA1c by 0.1% after 24 weeks, linagliptin reduced it by 0.72%.4
Adding a drug which increases insulin secretion to the treatment of patients with diabetes increases the risk of hypoglycaemia. In patients taking metformin and a sulfonylurea, hypoglycaemia was reported in 22.7% when linagliptin was added and in 14.8% when a placebo was added.4
During monotherapy the adverse events in patients taking linagliptin included musculoskeletal problems, hypertension and headache.1 Some patients may have increases in triglycerides and uric acid concentrations. Rare adverse events include hypersensitivity reactions and pancreatitis. A meta-analysis of cardiovascular events found no increased risk associated with linagliptin.
Animal studies have shown that linagliptin crosses the placenta and is excreted in breast milk.
Linagliptin adds to the choice of drugs which can be considered when a patient's diabetes is not controlled by metformin and sulfonylureas. There seems little difference between the inhibitors of dipeptidyl peptidase, but linagliptin does not require a dose adjustment in patients with renal impairment.
Table - Effect of adding linagliptin, glimepiride or placebo to the treatment of patients with type 2 diabetes inadequately controlled by metformin
1 mg, 2 mg or 3mg
|Number of patients||71||65||66||66||65|
|Baseline HbA1c %||8.4||8.2||8.5||8.4||8.2|
|Change in HbA1c % after 12 weeks||+0.24||–0.14||–0.5||–0.42||–0.68|
|Source: Reference 3|
The Transparency Score is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.
- Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab 2011;13:258-67.
- Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:65-74.
- Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med 2010;27:1409-19.
- Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med 2011;28:1352-61 .
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.