Vol 11, No 3 (2022)
Editorial
Published online: 2022-06-30

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Sojourn of Gemigliptin: A Hidden Gem?

Awadhesh Kumar Singh
Clin Diabetol 2022;11(3):131-134.

Abstract

Not available

EDITORIAL

ISSN 2450–7458
e-ISSN 2450–8187

Sojourn of Gemigliptin: A Hidden Gem?

Awadhesh Kumar Singh1
1G.D Hospital & Diabetes Institute, Kolkata, India

This Editorial accompanies a Research Paper, see page 151

Address for correspondence:

AK Singh

G.D Hospital & Diabetes Institute

Kolkata, 700013, India

phone:091 9831020428

e-mail: draksingh_2001@yahoo.com

Clinical Diabetology 2022, 11; 3: 131–134

DOI: 10.5603/DK.a2022.0027

Received: 25.06.2022 Accepted: 26.06.2022

Gemigliptin (LC15-0444) is a competitive, reversible (fast association and slow dissociation), selective (> 3000-fold against DPP-8/9), and long-acting (half-life 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).

Table 1: HbA1c Lowering with Gemigliptin Against Placebo or Active Comparator in Randomized Controlled Trials

Trial eponym; first author, year

Countries
involved
(n)

Background therapy

Duration of T2DM [yrs.]

Comparator
groups

Each
arm
(n)

Baseline HbA1c
[%]

Duration of study
[weeks]

Primary
outcome

∆ HbA1c [%]

∆ HbA1c (95% CI)
between two groups, P value

Drug-related adverse event rates; Hypo’s

HbA1c lowering studies

Rhee et al. [3], 2010

Korea (145)

LSM

3

GEMI 50 mg

35

8.24

12

HbA1c change

–0.98

–0.92 (–1.29, –0.56),

p < 0.0001

Similar in both groups including hypo’s
(0% in both groups)

PBO

34

8.20

–0.06

Yang et al. [2], 2013

Korea (74),

India (108)

LSM

≈ 3

GEMI 50 mg

87

8.20

24

HbA1c change

NR

–0.71 (–1.04, –0.37),

p < 0.0001

Similar; Hypo’s: 2.3%

PBO

87

8.30

NR

Hypo’s: 0%

GUARD; Yoon et al. [4], 2017

Korea (132)

Renal impaired, INS ± SU

16.7

GEMI 50 mg

64

8.30

12

HbA1c change

–0.82

–1.20 (–1.53, –0.87),
p < 0.001

Similar; Hypo’s: 11%

15.9

PBO

66

8.40

+0.38

Hypo’s: 8%

GUARD Extension; Han et al. [5], 2018

Korea (102)

Renal impaired, INS ± SU

15.4

GEMI 50 mg

48

8.4

40

HbA1c change

–1.00

–0.35 (–0.84, 0.13),
p = 0.15

Similar, including
Hypo’s

16.5

LINA 5 mg

52

8.4

–0.65

INICOM; Lim et al. [6], 2017

Korea (357)

Thailand (76)

8–week wash out of prior 1 OAD

4.2

A. GEMI 50 mg + MET

136

8.65

24

HbA1c change

–2.06

A minus B:

–0.62 (–0.82, –0.41),
p < 0.001;

A minus C:

–0.82 (–1.02, –0.63),
p <0.001

Similar;

Hypo: 2.1%

4.1

B. PBO + MET

148

8.73

–1.47

Hypo: 1.3%

3.5

C. PBO + GEMI 50 mg

140

8.66

–1.24

Hypo: 0%

TROICA; Ahn et al. [7], 2017

Korea (219)

MET, GLIM

13.0

GEMI 50 mg

107

8.20

24

HbA1c change

–0.88

–0.87 (–1.09, –0.64),
p < 0.001

Hypo: 9.4%

12.8

PBO

109

8.20

–0.01

Hypo: 2.7%

ZEUS II; Cho et al. [8], 2020

Korea (44),

Thailand (239)

INS ± MET

16.3

GEMI 50 mg

188

8.10

24

HbA1c change

–0.8

–0.7 (–0.9, –0.4),

p < 0.0001

Similar including

Hypo’s: 5.7%

16.5

PBO

95

8.10

–0.1

Hypo’s: 5.2%

Rhee et al. [9], 2010

Korea (296),

India (129)

MET

6.1

GEMI 50 mg

135

7.93

24

HbA1c change

–0.77

0.004 (–0.15, 0.16),

p = NS

Similar, hypo’s were
not reported

6.4

SITA 100 mg

133

8.05

–0.80

Jung et al. [10], 2018

Korea (94),

India (63)

MET

6.1

GEMI 50 mg

55

7.9

52

HbA1c change

–1.06

Groups not compared

Similar, hypo’s were
not reported

6.4

SITA 100 mg switched to GEMI 50 mg

44

8.08

–0.99

Glycemic variability studies

Primary outcome

∆ MAGE

(mg/dL)

∆ MAGE (95% CI) between two groups (mg/dL), P value

Drug–related adverse event rates; hypo’s

STABLE; Park et al. [11], 2017

Korea (69)

LSM

0.63

A. GEMI 50 mg

24

9.5

12

Change in MAGE

–42

A minus B:

–0 (–20, 19),

p = NR;

A minus C:

–20 (–39, –2),

p = 0.03;

B minus C:

–20 (–38, –3),

p = 0.02

Similar; hypo’s: 0%

2.0

B. SITA 100 mg

21

9.1

–42

Hypo’s: 0%

1.47

C. GLIM 2 mg

21

9.7

–21

Hypo’s: 9.0%

STABLE II; Kwak et al.. [12], 2020

Korea (71)

LSM or MET

2.2

GEMI 50 mg

34

7.9

12

Change in MAGE

–27.2

–19.2 (–31.3, –7.2),

p = 0.002

Similar; hypo’s 0%
in both groups

3.5

DAPA 10 mg

36

7.9

–7.9

Nevertheless, from the glucose lowering efficacy perspective, eleven RCTs of gemigliptin have been conducted to date either against placebo or active comparators including two extension studies that varied in duration from 12 to 52 weeks (Tab. 1) [2–12]. Of the eleven RCTs, six were exclusively conducted in South Korea, three were conducted in India and two were conducted in Thailand in addition to South Korea. Change in HbA1c reduction was the primary objective in nine RCTs, whereas the change in glycemic variability [mean amplitude of glucose excursion (MAGE)] was the primary outcome in two RCTs. Gemigliptin was compared with placebo (six RCTs), sitagliptin 100 mg (3 RCTs), linagliptin 5 mg (1 RCT), glimepiride 2 mg (1 RCT), dapagliflozin 10 mg (1 RCT) and metformin up to 2000 mg (1 RCT). Summarily, in RCTs, gemigliptin was found to reduce HbA1c by –0.7 to –1.2% in monotherapy studies against placebo in a baseline HbA1c of mean 8–8.5%. A larger reduction of HbA1c of –2.0% was also observed with gemigliptin in combination with metformin in a mean baseline HbA1c of 8.7% in one RCT (INICOM). Similarly, the reduction of HbA1c was quite pronounced at the top of background metformin and sulfonylurea (SU) combination therapy (TROICA; –0.9%) or background insulin therapy (ZEUS II; –0.7%) even in a long-standing type 2 diabetes of >10 years duration. In a 24-week head-to-head study, HbA1c reduction with gemigliptin (–0.77%) was comparable to sitagliptin (–0.8%) with background metformin therapy and the 28-week extension of the same study showed switching to gemigliptin 50 mg from sitagliptin 100 mg yielded a similar efficacy outcome. Importantly, while gemigliptin was shown to reduce glycemic variability (MAGE) similar to the sitagliptin but significantly better than glimepiride, reduction in standard deviation (SD) of mean glucose was more effective with gemigliptin compared to both sitagliptin and glimepiride, in head-to-head RCT (STABLE). Interestingly, reduction in MAGE was significantly better with gemigliptin compared to dapagliflozin in a head-to-head RCT (STABLE II) of 12 weeks duration. Gemigliptin was also studied in patients with chronic renal disease (CKD, with a mean eGFR of 33.3 mL/min/1.73 m2) in one RCT (GUARD) and was found to significantly lower HbA1c by –0.8% against placebo in background insulin (with or without SU) therapy, without provoking significant hypoglycemia. Moreover, the HbA1c lowering with gemigliptin was similar to linagliptin (–1.0% vs. –0.65%; Difference -0.35%; 95% CI, –0.84, 0.13; p = 0.15) in 28-week extension of GUARD study. Importantly, there was a significant decrease in urinary albumin creatine ratio (UACR) with gemigliptin at 12-weeks, in patients having both micro- and macro-albuminuria (–41.9 mg/g, p = 0.03; –528.9 mg/g, p < 0.001; respectively) regardless of the change in HbA1c, systolic blood pressure and use of renin-angiotensin system blockers. However, this reduction in albuminuria was no longer significant in a further 28-weeks extension of GUARD (40-week) study. Overall, gemigliptin was well tolerated in all RCTs and drug-related adverse events were similar compared to placebo or active comparators. Table 1 summarizes the glucose lowering potential of gemigliptin compared to placebo or active comparators.

Conflict of interest

None declared.

References

  1. Sarkar T, Sanyal D, Samanta A, et al. Real World Study of Effectiveness of Gemigliptin Add-On Therapy in Type 2 Diabetes Mellitus. Clinical Diabetology. 2022, doi: 10.5603/dk.a2022.0014.
  2. Yang SJ, Min KW, Gupta SK, et al. A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes. Diabetes Obes Metab. 2013; 15(5): 410–416, doi: 10.1111/dom.12042, indexed in Pubmed: 23170990.
  3. Rhee EJ, Lee WY, Yoon KH, et al. A multicenter, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15-0444 in patients with type 2 diabetes. Diabetes Obes Metab. 2010; 12(12): 1113–1119, doi: 10.1111/j.1463-1326.2010.01303.x, indexed in Pubmed: 20977584.
  4. Yoon SA, Han BG, Kim SG, et al. Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: A 12-week, double-blind randomized study (the GUARD Study). Diabetes Obes Metab. 2017; 19(4): 590–598, doi: 10.1111/dom.12863, indexed in Pubmed: 28019072.
  5. Han SY, Yoon SAe, Han BG, et al. Comparative efficacy and safety of gemigliptin versus linagliptin in type 2 diabetes patients with renal impairment: A 40-week extension of the GUARD randomized study. Diabetes Obes Metab. 2018; 20(2): 292–300, doi: 10.1111/dom.13059, indexed in Pubmed: 28719008.
  6. Lim S, Han KAh, Yu J, et al. INICOM Study Group. Efficacy and safety of initial combination therapy with gemigliptin and metformin compared with monotherapy with either drug in patients with type 2 diabetes: A double-blind randomized controlled trial (INICOM study). Diabetes Obes Metab. 2017; 19(1): 87–97, doi: 10.1111/dom.12787, indexed in Pubmed: 27619558.
  7. Ahn CHo, Han KAh, Yu JM, et al. Efficacy and safety of gemigliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus inadequately controlled with combination treatment of metformin and sulphonylurea: a 24-week, multicentre, randomized, double-blind, placebo-controlled study (TROICA study). Diabetes Obes Metab. 2017; 19(5): 635–643, doi: 10.1111/dom.12866, indexed in Pubmed: 28026912.
  8. Cho YM, Deerochanawong C, Seekaew S, et al. Efficacy and safety of gemigliptin as add-on therapy to insulin, with or without metformin, in patients with type 2 diabetes mellitus (ZEUS II study). Diabetes Obes Metab. 2020; 22(1): 123–127, doi: 10.1111/dom.13873, indexed in Pubmed: 31478335.
  9. Rhee EJ, Lee WY, Min KW, et al. Gemigliptin Study 006 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Obes Metab. 2013; 15(6): 523–530, doi: 10.1111/dom.12060, indexed in Pubmed: 23320436.
  10. Jung CH, Rhee EJ, Lee WY, et al. Gemigliptin Study 006 Group. A 52-week extension study of switching from gemigliptin vs sitagliptin to gemigliptin only as add-on therapy for patients with type 2 diabetes who are inadequately controlled with metformin alone. Diabetes Obes Metab. 2018; 20(6): 1535–1541, doi: 10.1111/dom.13256, indexed in Pubmed: 29436761.
  11. Park SeE, Lee BW, Kim JH, et al. STABLE Study Group. Effect of gemigliptin on glycaemic variability in patients with type 2 diabetes (STABLE study). Diabetes Obes Metab. 2017; 19(6): 892–896, doi: 10.1111/dom.12869, indexed in Pubmed: 28058753.
  12. Kwak SH, Hwang YC, Won JC, et al. Comparison of the effects of gemigliptin and dapagliflozin on glycaemic variability in type 2 diabetes: A randomized, open-label, active-controlled, 12-week study (STABLE II study). Diabetes Obes Metab. 2020; 22(2): 173–181, doi: 10.1111/dom.13882, indexed in Pubmed: 31502749.