Gemigliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor developed by Novartis and LG Life Sciences for the treatment of type 2 diabetes. Its chemical name is (2R)-4-oxo-4-triazolopyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. Gemigliptin has an empirical formula of C18H13F6N5O with a molecular weight of 447.32 g/mol. It exists as a yellow crystalline solid at room temperature. Gemigliptin has good aqueous solubility and is stable across a wide range of pH conditions from 1-9. These favorable physicochemical properties contribute to its once-daily oral dosing.

Mechanism of Action

Like other DPP-4 inhibitors, Gemigliptin works by inhibiting the DPP-4 enzyme. DPP-4 is responsible for the breakdown of incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) released after meals from the intestinal L and K cells respectively. By inhibiting DPP-4, the levels of active GLP-1 and GIP are increased resulting in higher insulin secretion and lower glucagon secretion in a glucose-dependent manner. This enhances glucose-dependent insulin release and suppresses glucagon release leading to better glycemic control. Gemigliptin exerts its anti-diabetic effects mainly via this incretin-based mechanism of action.

Pharmacokinetics and Metabolism 

When administered orally, it is rapidly absorbed with peak plasma concentrations occurring 1-2 hours post-dosing. The mean absolute bioavailability of it is 59%. It undergoes minimal metabolism with less than 10% of the absorbed dose undergoing biotransformation. The major metabolic pathways involve dehydrogenation, hydroxylation and glucuronidation. It is predominantly excreted unchanged in feces (51%) and urine (43%). The mean plasma elimination half-life is 24 hours enabling once-daily dosing.

It displays linear pharmacokinetics across the clinically relevant dose range of 25-200 mg. Steady state levels are achieved within 8 days of daily dosing with no drug accumulation. Pharmacokinetics of it is similar between healthy subjects and patients with type 2 diabetes. No dose adjustments are required based on age, sex, and race, mild to moderate renal or hepatic impairment.

Clinical Efficacy and Safety Studies

The efficacy and safety of it have been evaluated in multiple Phase 2 and 3 randomized controlled trials. In a 12-week monotherapy trial, once-daily 50mg and 100mg produced greater reductions from baseline in HbA1c compared to placebo. In another 24-week add-on trial with metformin, addition of its 50mg or 100mg provided additional glycemic control over metformin alone.

Long term efficacy and safety was assessed in a 52-week extension study. Glycemic control was maintained with no new safety issues observed. 100mg was non-inferior to sitagliptin 100mg when added to metformin over 24-weeks. In a cardiovascular outcomes trial, it did not increase the risk of major adverse cardiovascular events compared to placebo when added to standard of care over 3 years in patients with high cardiovascular risk.

Overall it was generally well tolerated in clinical trials. The most common adverse events reported were upper respiratory tract infection, nasopharyngitis and headache. No clinically significant changes were noted in vital signs, ECG or laboratory parameters. It does not carry an increased risk of hypoglycemia when used as monotherapy or in combination with other agents not known to cause hypoglycemia such as metformin.

Regulatory Approval and Dosage

Based on the positive results of the Phase 3 trials, it received regulatory approval in South Korea in 2013 and in several other Asian countries subsequently for the treatment of type 2 diabetes. The recommended therapeutic dose of Gemigliptin is 50mg or 100mg administered orally once daily with or without food. Dosage adjustment is not required based on renal or hepatic impairment. It is available as 25mg, 50mg and 100mg film-coated tablets

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