Pharmacology Update

Linagliptin Tablets (Tradjenta™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.

A third dipetdyl peptidase-4 (dpp-4) inhibitor has been approved by the FDA. Linagliptin follows sitagliptin and saxagliptin to the market. It is marketed by Boehringer Ingelheim as Tradjenta.

Indications

Linagliptin is indicated for the treatment of type 2 diabetes mellitus as an adjunct to diet and exercise.1

Dosage

The recommended dose is 5 mg once daily. It may be taken without regard to meals.1 Linagliptin is available as 5 mg tablets.

Potential Advantages

Linagliptin is excreted mainly unchanged in the feces via the enterohepatic system with minimal metabolism and renal excretion. No dosage adjustment is required for renal or hepatic impairment.1

Potential Disadvantages

Similar to the other DPP-4 inhibitors, drug levels or effects may be reduced by CYP3A4 or p-glycoprotein inducers.1

Comments

Linagliptin is a reversible, potent, selective DPP-4 inhibitor. This inhibition reduces the degradation of the incretin hormones glucagon-like peptide and glucose-dependent insulinotropic polypeptide. This results in enhanced insulin secretion, lowers inappropriate postprandial glucagon secretion, and reduces gastric emptying. The efficacy and safety of linagliptin was shown in eight double-blind, placebo-controlled studies as monotherapy or in combination with other antihyperglycemic agents.1 In two monotherapy studies (n = 730), subjects with baseline mean HbA1c of 8.0-8.1 were randomized to linagliptin 5 mg or placebo for 18 weeks or 24 weeks.1,2 Linagliptin treatment resulted in a reduction (difference from placebo) of -0.6 % (95% confidence interval [CI]: -0.9, -0.30) for the 18-week study and -0.7% (95% CI: -0.9, -0.5) for the 24-week study. Linagliptin when added on to metformin (1500 mg or higher),3 pioglitazone (30 mg),4 a sulfonylurea, or metformin + a sulfonylurea showed a placebo-adjusted reduction of -0.6% to -0.5% at 24 weeks. In a 52-week, active controlled study, linagliptin showed comparable reduction in HbA1c to glimepiride (mean dose 3 mg/day) when added to metformin with a lower incidence of hypoglycemia (5.4% vs 31.8%, P < 0.001). Linagliptin is generally well tolerated with frequency of nasopharyngitis occurring more often than placebo (4.3% vs 1.2%).1 Pancreatitis was reported in 1 per 538 person years compared to 0 in 433 person years for the comparator.

Clinical Implications

Linagliptin is the third DPP-4 inhibitor to enter the market. Its primary advantage over the other inhibitors is it nonrenal excretion, thus dose adjustment is not required for patients with impaired renal function.

References

1. Tradjenta Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; May 2011.

2. Del Prato S, et al. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2011; 13:258-267.

3. Taskinen MR, 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.

4. Gomis R, et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes Metab 2011;13:653-661.