Sojourn of Gemigliptin: A Hidden Gem?

Gemigliptin (LC15-0444) is a competitive, reversible (fast association and slow dissociation), selective (> 3000-fold against DPP-8/9), and long-acting (halflife 30.8 hours) dipeptidyl peptidase-4 (DPP-4) inhibitor, first approved for clinical use by the Korean Food and Drug Administration (FDA) in 2012. It has been approved to be taken orally, with or without food, at a dose of 50 mg once daily, either as monotherapy or in combination with other drugs, and no dose adjustment is required in patients with renal or hepatic impairment. While DPP-4 inhibition with gemigliptin in experimental animal studies was found to be 80%, the fast association and slow dissociation kinetics of DPP-4 inhibition with gemigliptin were found to be albeit different compared with sitagliptin (fast on and fast off rate) and vildagliptin (slow on and slow off rate). Although the originator LG Life Sciences initially signed a licensing agreement with developers such as Sanofi (France) and Stendhal (Mexico) for 104 countries, gemigliptin has been currently approved in 11 countries including India, Columbia, Costa Rica, Panama, Ecuador, Russia, Mexico, and Thailand beside South Korea. In this issue of Clinical Diabetology, a real-world, 12-week, small study (n = 60), of gemigliptin by Sarkar et al. [1] from the Eastern part of India conducted during 2016–2017, reported a robust –1.25% (95% confidence interval, –1.59 to –0.92) HbA1c reduction with gemigliptin in people with type 2 diabetes (median age 52.2 years with a mean HbA1c of 9.5% and duration of diabetes of 8.6 years) on a background antidiabetic (mono, dual, triple combination) therapy but majorly (65%) on background metformin monotherapy. Moreover, 57% of patients achieved a target HbA1c of < 7% with the addition of gemigliptin. The larger HbA1c lowering effect of gemigliptin in this real-world study could be due to a higher baseline mean HbA1c of 9.5% but this appears to be > 2-fold higher than the HbA1c lowering effect observed in the randomized controlled trials (RCTs) conducted in Indian patients. In the subgroup analysis of a double-blind RCT [2], the HbA1c lowering effect of gemigliptin was lower in 108 Indian patients compared with 74 Korean patients (–0.55% vs. –0.94%, respectively) against placebo, despite a higher mean baseline HbA1c (including a higher percentage of patients with baseline HbA1c of > 8.5%) in Indians compared to the Koreans. This suggests real-world studies could often overestimate the effect size related to its inherent bias. Interestingly, the sojourn of gemigliptin did not last long (launched in India in April 2016) and it was withdrawn from India in July 2018 by the Sanofi for unknown or perhaps commercial reasons related to its cost. Notably, the cost of gemigliptin (not approved by the USA FDA and with no cardiovascular (CV) outcome trial (CVOT) conducted) was nearly similar to another DPP-4 inhibitor sitagliptin (US FDA-approved) with clean cardiovascular (CV) safety data shown in CV outcome trial TECOS (2015). Nevertheless, from the glucose lowering efficacy perspective, eleven RCTs of gemigliptin have been conducted to date either against placebo or active This Editorial accompanies a Research Paper, see page 151