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Linagliptin: A new DPP-IV inhibitor
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Linagliptin was recently approved by the FDA, representing the third DPP-IV inhibitor to reach the US market for the treatment of type 2 diabetes.
DPP-IV is the enzyme responsible for the rapid degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP). Patients with type 2 diabetes demonstrate reduced GLP-1 concentrations after meals compared with healthy patients. GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells and slows gastric emptying time.
Clinical trials
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Forst and colleagues conducted a randomized, double blind study in 333 patients with type 2 diabetes who were uncontrolled on metformin monotherapy. Patients were randomly assigned to receive linagliptin (Tradjenta, Boehringer Ingelheim) in a 1-mg, 5-mg or 10-mg dose once daily; placebo; or open-label glimepiride (1 mg to 3 mg once daily) besides continuing metformin. After 12 weeks, mean changes in HbA1c for placebo and linagliptin 1 mg, 5 mg and 10 mg were +0.25%, –0.15%, –0.48%, –0.42%, respectively. Similarly, mean changes in fasting plasma glucose were +12.6 mg/dL, –6.4 mg/dL, –22 mg/dL and –16.2 mg/dL. All of these were statistically significant reductions compared with placebo. Weight loss was comparable and insignificant for placebo and all linagliptin-treated participants. Adverse effects were similar across all groups, and there were no hypoglycemic episodes associated with placebo or linagliptin treatment.
Taskinen and colleagues conducted a similar study in 701 patients who received linagliptin 5 mg once daily or placebo, besides existing metformin therapy. Mean adjusted HbA1c and FPG were reduced by 0.49% and 10.6 mg/dL, respectively, in the linagliptin-treated participants compared with placebo. Weight was essentially unchanged in both groups and hypoglycemia was rare. The researchers also said there was a trend toward improvement in markers of beta-cell function. More specifically, fasting C-peptide was significantly lower in the linagliptin-treated participants, and there was a significant change in homeostasis model assessment of beta-cell function from baseline.
In placebo-controlled monotherapy studies of 18- to 24-week duration, the manufacturer reports mean HbA1c reductions of 0.4% with linagliptin 5 mg once daily. They also reported a mean HbA1c reduction of 0.5% when linagliptin was combined with metformin, sulfonylurea or pioglitazone (Actos, Takeda), and a reduction of 0.7% when added to existing metformin and sulfonylurea therapy.
Dosing
Linagliptin is indicated as monotherapy or combined with other drugs used to treat type 2 diabetes. The recommended dose is 5 mg by mouth once daily. No dose adjustment is needed for renal or hepatic impairment. It has not been studied in combination with insulin.
Adverse effects
Linagliptin is generally well-tolerated. Adverse effects more commonly seen with linagliptin than placebo include nasopharyngitis, hyperlipidemia, cough and weight gain. Increases in uric acid were also more commonly reported with linagliptin compared with placebo. The overall incidence of hypoglycemia in patients treated with linagliptin was similar to the incidence in patients taking placebo monotherapy. Note that the addition of linagliptin, or any other DPP-IV inhibitor, to existing antihyperglycemic medications can increase risk for hypoglycemia.
Place in therapy
Linagliptin appears to significantly reduce HbA1c and fasting glucose when used as monotherapy and combined with other agents. At this point, there is no evidence that it affects cardiovascular disease risk, and it is generally well-tolerated.
Efficacy and tolerability are comparable to the existing DPP-IV inhibitors sitagliptin (Januvia, Merck) and saxagliptin (Onglyza, Bristol-Myers Squibb). At this point, the only clinically relevant difference is that linagliptin does not require dose adjustment in renal impairment, whereas sitagliptin and saxagliptin do. To date, no head-to-head clinical trials have been conducted.
James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida, Gainesville.
For more information:
- Forst T. Diabet Med. 2010;27:1409-1419.
- Taskinen MR. Diabetes Obes Metab. 2011;13:65-74.
Disclosure: Taylor reports no relevant financial disclosures.