Title

Pharmacokinetics and Safety of Fixed Dose Combination Oral Tablet of Remogliflozin

Etabonate 100 mg and Teneligliptin 10 mg in Healthy Indian Adult Male Subjects Under Fed
Conditions.

OR

An Open-Label, Randomized, Three-way Crossover, Bioavailability Study of Fixed Dose

Combination Oral Tablet of Remogliflozin Etabonate 100mg and Teneligliptin 10 mg in Healthy
Indian Adult Male Subjects Under Fed Conditions.

Running Title: Fixed Dose Combination Oral Tablet of Remogliflozin Etabonate 100mg and
Teneligliptin 10 mg
Abstract
Aim: To characterize the pharmacokinetic (PK) and safety profile of a fixed dose combination
(FDC) oral tablet of remogliflozin etabonate 100 mg and teneligliptin 10 mg and to compare its
bioavailability with oral remogliflozin etabonate 100 mg and teneligliptin 10 mg monotherapy in
healthy, adult, male subjects under fed conditions.
Methods: Healthy, adult, male subjects were enrolled in an open-label, randomized, three-way
crossover, and bioavailability study. FDC oral tablet of remogliflozin etabonate 100mg and
teneligliptin 10 mg was given under fed conditions as a single oral dose. The plasma
concentrations of remogliflozin and teneligliptin were analyzed by liquid chromatography–
tandem mass spectrometry (LC–MS/MS) method. Pharmacokinetic parameters determined were
Cmax, AUC0-t, AUC0-∞, AUCextrapolated, Kel, Tmax and T½. Safety and tolerability was assessed through
monitoring of clinical laboratory parameters, vital signs and monitoring for adverse events.
Descriptive statistics were calculated for all parameters and statistical analysis was performed
using SAS 9.4.
Results: The mean age of the study subjects was 31.58 ± 5.61 years with a mean BMI of 24.39 ±
2.96 kg/m2. Remogliflozin test group (T) showed slightly lower Cmax and Kel but higher AUC0-t ,
AUC0-∞ , AUCextrapolated, Tmax and T½ compared to the reference group (R1). Teneligliptin test group
(T) showed slightly lower Cmax and Kel but higher AUC0-t , AUC0-∞ , AUCextrapolated, and T½
compared to the reference group (R2). Tmax was same in both the groups for teneliglitin. The 90%
confidence intervals (CI) for the ratios of geometric least square means (LSMs) were within 80%
- 125% for all the drugs with a power of more than 87.76%, thus establishing the bioequivalence.
Only one adverse event was reported, unlikely to be related to the study drug. No serious adverse
events or death were reported.
Conclusion: FDC oral tablet of remogliflozin etabonate 100 mg and teneligliptin 10 mg was
found to be bioequivalent to remogliflozin etabonate 100mg and teneligliptin 10 mg
monotherapy in healthy, adult, male subjects under fed conditions. It is safe and well tolerated
when administered to healthy subjects.
Key words: pharmacokinetics, dipeptidyl peptidase-4 (DPP), DPP-4 inhibitor, remogliflozin,
remogliflozin etabonate, SGLT2 inhibitor, sodium glucose transporters (SGLTs), teneligliptin,
type 2 diabetes mellitus.
1.0 Introduction

Type 2 diabetes mellitus (T2DM) is a chronic, metabolic, non-communicable disease which is

one of the major contributors of morbidity and mortality worldwide. Despite the availability of a
wide range of anti-diabetic drugs, management of T2DM remains challenging with two thirds of
patients unable to reach their HbA1c targets1. The UK Prospective Diabetes Study (UKPDS)
reported that more than 50% of newly diagnosed T2DM patients required a second anti-
hyperglycemic agent within 3 years of initiation of monotherapy2. But patient compliance is
questionable when more than one drug is being prescribed. A systematic review by Hutchins et
al (2011) indicated that fixed-dose combination (FDC) therapy users have improved adherence,
higher satisfaction, and lower direct medical costs, compared to T2DM patients treated with
loose pill combination therapy3. Several FDC combinations of metformin and dipeptidyl
peptidase-4 (DPP-4) inhibitors are currently available. However, their efficacy deteriorates with
time, necessitating the addition of another anti-hyperglycemic agent4.

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a newer class of anti-diabetic drugs.
Glucose reabsorption by the SGLT2 receptors is considered the main mechanism through which
renal glucose is reabsorbed5. Thus, inhibition of this pathway by SGLT2 inhibitors leads to an
increased urinary glucose excretion, thereby reducing the blood glucose levels.

Remogliflozin etabonate, a prodrug of remogliflozin, is a potent and highly selective SGLT2

inhibitor6. Unlike other drugs which inhibit SGLT1 receptors (present in both the gut and
kidney), causing impaired intestinal glucose absorption and diarrhea, remogliflozin does not
show any gastrointestinal side effects as it selectively inhibits SGLT2 receptors (present in
proximal tubules of kidney)7. When administered orally, a dose-dependent increase in the urinary
glucose excretion has been found6,8. Additionally, a statistically significant trend in the dose–
response relationship towards decreased HbA1c concentrations was observed at dosages
>100mg9,10. Remogliflozin has also shown to lower the mean arterial and systemic blood
pressure when prescribed along with antihypertensive drugs11. It causes decrease in blood
pressure and body weight, with a very low risk of hypoglycemia12. Therefore, remogliflozin
seems to be a promising add-on therapy in the treatment of T2DM.
Incretins are a group of metabolic hormones released from the endocrine cells of the gut. They
are involved in stimulation of insulin secretion13. DPP-4 enzyme rapidly inactivates incretins,
thereby reducing insulin secretion, causing hyperglycemia. DPP-4 inhibitors increase the levels
of incretins, namely glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP) by inhibiting DPP-4 enzymatic activity. These inhibitors act in a glucose-
dependent manner by increasing serum insulin and decreasing serum glucagon levels14. Multiple
trials have been conducted evaluating the effect of DPP-4 inhibitors on the glycemic control of
diabetic patients when administered as monotherapy or in combination with other anti-diabetic
drugs14. Teneligliptin, a DPP-4 inhibitor, is currently being used in cases where there is poor
glycemic control even after diet control, exercise, and sulfonylurea or thiazolidine drug therapy15.

The aim of the present study is to characterize the pharmacokinetic (PK) and safety profile of a
FDC oral tablet of remogliflozin etabonate 100 mg and teneligliptin 10 mg and to compare its
bioavailability with oral remogliflozin etabonate 100 mg and teneligliptin 10 mg monotherapy in
healthy, adult, male subjects under fed conditions.

2.0 Methods

2.1 Subjects

Normal, healthy, adult male subjects, 18 to 45 years of age, with a body mass index (BMI) in the
range of 18.5 to 29.9 kg/m2 and a body weight not less than 50 kgs were eligible for the study.
Only subjects in normal health as determined by the medical history, clinical examination, vital
signs and clinically acceptable results of laboratory examinations were recruited. Subjects with
evidence of hypersensitivity to remogliflozin or teneligliptin, clinically significant disorders and
abnormal findings during screening were excluded from the study along with other standard
criteria for exclusion. Subjects willing to adhere to the protocol requirements and provide written
informed consent were checked-in for the study.
2.2 Study Design

This was an open-label, balanced, randomized three-treatment, three-sequence, three-period,

three-way crossover, and single dose oral comparative bioavailability study in healthy, adult,
male subjects under fed conditions. The study protocol, informed consent form and other related
documents were reviewed and approved by Suraksha Ethics Committee. It was conducted in
compliance with the approved protocol, National Ethical Guidelines for Biomedical and Health
Research involving Human Participants (Indian Council of Medical Research - 2017), Guidelines
for Good Clinical Practice ICH E6 R2 (Step 4), New Drugs and Clinical Trials Rules 2019
G..S.R. 227 (E) of Central Drugs Standard Control Organization (CDSCO), Good Clinical
Laboratory Practice (GCLP), Declaration of Helsinki (Fortaleza, October 2013) and CDSCO
Regulatory Guidelines. All subjects provided written informed consent for the study procedures
before screening. The trial protocol was prospectively registered in the Clinical Trial Registry–
India (Identifier number).

The study subjects were randomized to receive either test drug (T) or reference drug (R1or R2) in
three different sequences (i) TR1R2 (ii) R1R2T (iii)R2T R1(Figure 1). The test drug was a fixed
dose combination oral tablet of remogliflozin etabonate 100 mg and teneligliptin 10 mg.
Reference drug R1 was Remo® 100 (remogliflozin etabonate) 100 mg tablet and R2 was
teneligliptin 10 mg tablet (all the drugs were manufactured by Glenmark Pharmaceuticals Ltd.,
India). There were three study periods – period I, period II and period III for each subject with a
washout period of 10 days between each consecutive dosing period. The analysts were blinded to
the sequence of administration of test (T) and reference (R1or R2) drugs until the completion of
bio-analysis.

Screening of the subjects was carried out within 28 days prior to study drug administration. Pre-
study screening included a medical history, physical examination, vital signs recording, clinical
laboratory tests, 12-lead ECG and a chest X-ray (posterior-anterior view). Clinical laboratory
tests for hematology, biochemistry, urine analysis, and serological tests for HIV, HbsAg, HCV
and VDRL were performed. After screening, a total of 36 subjects were selected for the study, 12
subjects randomly allotted to the three study sequences. They were instructed to be fasting
overnight for at least 10 hours, after which they consumed a high-calorie, non-vegetarian
breakfast. The investigational drugs were administered orally 30 minutes after consumption of
breakfast in a sitting posture with 240 mL of drinking water at ambient temperature. The tablets
were swallowed whole without chewing or crushing.

Laboratory assessments were performed at the time of screening and post study safety
assessment (at or after the last blood sample of the study). Vital signs and well-being
questionnaire were recorded at the time of screening, before check-in, prior to dosing (within 2
hours) and check-out (144 hours) during each study period.

2.3 Pharmacokinetic Evaluations

Plasma concentrations of remogliflozin etabonate (GSK189075), remogliflozin (GSK189074),

the metabolite (GSK279782), and teneligliptin were measured. The blood samples were
collected at pre-dose 0.00 hour and at 0.17, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50,
4.00, 5.00, 6.00, 8.00, 12.00, 16.00, 20.00, 24.00, 48.00, 72.00, 120.00 and 144.00 hours post
dose. These sampling time-points were planned based on the reported PK of the drug for the
assessment of bioequivalence. Plasma samples were stored at -70°C or lower before and after
analysis. The primary PK parameters assessed were maximum concentration (Cmax), area under
the plasma concentration–time curve (AUC) from time 0 hours to the last measurable
concentration (AUC0-t), AUC from time 0 hours to infinity (AUC0-∞), and secondary PK
parameters were time taken to reach Cmax (Tmax), elimination rate constant (Kel), half-life (T1/2)
and AUC from time 0 extrapolated to infinite time (AUCextrapolated). The plasma concentrations of
the drugs were measured by a validated analytical method (SOP: MS-286-02, MS-307-02) using
liquid chromatography–tandem mass spectrometry (LC–MS/MS).

2.4 Safety Evaluations

Safety was assessed from the screening period to the end of the study at periodic intervals. The
safety measurements included clinical laboratory parameters, vital signs and monitoring for
adverse events (AEs). For post study safety assessment, blood sample was collected at 144.00
hrs post dose in period III, along with recording of the ECG.

2.5 Statistical Analysis

Based on the available literature, an intra subject variability of 18%, T/R ratio of 90.0 to
110.10%, bioequivalence limits 80 to 125%, at a significance level of 5% and power of ≥80%, a
sample size of 30 subjects was found sufficient to establish the bioequivalence between the
formulations. However, considering the withdrawals and dropouts, a sample size of 36 was
considered for the study.

Descriptive statistics were calculated and reported for all the PK parameters of remogliflozin
etabonate (GSK189075), remogliflozin (GSK189074), the metabolite (GSK279782) and
teneligliptin. Phoenix® WinNonlin Version 8.1 was used for the evaluation of primary parameters
Cmax, AUC0-t and AUC0-∞and secondary parameters Tmax, Kel, T½ and AUCextrapolated. The Ln-
transformed PK parameters Cmax, AUC0-t and AUC0-∞were subjected to Analysis of Variance
(ANOVA) using PROC GLM at a significance level of 5 % (alpha =0.05).The ANOVA model
included Sequence, Treatment and Period as fixed effects and Subject (Sequence) as a random
effect. The power of ANOVA test to detect 20% mean difference between test and reference
formulations was calculated. The ratio of Geometric least square means (LSM) of test and
reference formulations was computed and reported for Ln-transformed PK parameters Cmax,
AUC0-t and AUC0-∞. If the confidence intervals for the ratio of geometric LSM (test/reference)
were within 80% - 125%, the drugs were considered to be bioequivalent. Statistical analysis was
carried out using SAS® Version 9.4 (SAS Institute Inc.). Data for remogliflozin etabonate
(GSK189075) and the metabolite (GSK279782) were supportive only.

3.0 Results

3.1 Demographic data

A total of 36 subjects for remogliflozin etabonate, remogliflozin and GSK279782 and 35

subjects for teneligliptin (36 in period I and period II and 35 in period III), were considered for
PK and statistical analysis. The mean age of the study subjects was 31.58 ± 5.61 years with a
mean BMI of 24.39 ± 2.96 kg/m2. All the subjects were of normal health based on general
physical examination and laboratory test reports. None of them had any relevant or significant
previous medical history that could affect the study results.
3.2 Pharmacokinetics

The summary of various primary and secondary PK parameters for remogliflozin etabonate,
remogliflozin, GSK279782 and teneligliptin in test and reference groups are shown in Table 1.
Remogliflozin showed the highest Cmax, AUC0-t , and AUC0-∞ compared to the prodrug and the
metabolite, GSK279782. Among the test and reference groups of remogliflozin, the test group
(T) showed slightly lower Cmax and Kel but higher AUC0-t , AUC0-∞ , AUCextrapolated, Tmax and T½
compared to the reference group (R1). Similar findings were found for teneligliptin, wherein the
test group (T) showed slightly lower Cmax and Kel but higher AUC0-t , AUC0-∞ , AUCextrapolated, and
T½ compared to the reference group (R2). Tmax was same in both the groups for teneliglitin. The
mean plasma concentration time curves of the study drugs are presented in Figure 2, 3, 4 and 5
respectively.

The test to reference log-transformed geometric LSM ratios (T/R1 or R2) and 90% confidence
interval obtained for Cmax, AUC0-t and AUC0-∞ are represented in Table 2. The 90% confidence
intervals for the ratios of geometric LSMs were within 80% - 125% for all the drugs with a
power of more than 87.76%. Hence the test and reference drugs of remogliflozin and
teneligliptin are considered to be bioequivalent.

Table 3 shows the p-values obtained from ANOVA for sequence, period, and treatment effects
for Cmax, AUC0-t and AUC0-∞. The Cmax, AUC0-t and AUC0-∞ for teneligliptin were statistically
significant for the treatment effect (p<0.05). For remogliflozin, the treatment effect was
statistically significant for AUC0-t and AUC0-∞ only (p<0.05).

3.3 Safety data

During the course of the study one (01) AE of wound was reported by a subject which was
unlikely to be related to the study drug and was mild in nature. The AE was resolved without
sequel after treatment. No serious AEs or death were reported. No subject was withdrawn from
the study due to a safety related concern. Both the test and reference drugs were found to be safe
and well tolerated.
4.0 Discussion

This is the first study to evaluate the PK and safety profile of FDC oral tablet of remogliflozin
etabonate 100 mg and teneligliptin 10 mg. Bioequivalence of the above combination was
compared with that of remogliflozin etabonate 100 mg and teneligliptin 10 mg monotherapy in
healthy adult male subjects under fed conditions. The primary parameters under study were Cmax,
AUC0-t and AUC0-∞ and the secondary parameters were Tmax, Kel, T½ and AUCextrapolated. The study
results showed similar values in the test and reference groups for both remogliflozin and
teneligliptin. Markham et al (2019) reported that the Cmax and AUC0-t for remogliflozin were
around 559 ng/mL and 1798 ng·h/mL, respectively, at a dose of 100 mg in Indian patients with
T2DM16. Joshi et al (2019) demonstrated the Cmax and AUC0-last for remogliflozin to be 536.18
ng/mL and 1259.54 ng·h/mL respectively17. These results are in agreement with our study results
(Table 1). The prodrug, remogliflozin etabonate was readily converted into its active form,
remogliflozin and its active metabolite, GSK279782. CYP3A4 is mainly responsible for the
metabolism of remogliflozin etabonate and teneligliptin8,15,16.

GSK 279782 has a shorter half life compared to other SGLT2 inhibitors such as dapagliflozin,
canagliflozin, and empagliflozin, necessitating twice daily administration5,12. The T1/2 of
GSK279782 was found to be 2.7 hours in this study, which is similar to studies by Joshi et al
(2019) and Kapur et al (2013), wherein it was 2.37 hours and 2.28 hours at a dose of 100mg and
150mg respectively17,18. The slight difference may be due to the slightly higher dosage of the
latter. In this study the median Tmax for teneligliptin was found to be 2.5 hours and the mean T1/2
was 35.5 and 31.5 hours for test and reference groups respectively. Kishimoto et al (2013)
reported a Tmax of 1.0 hour at a dose of 10 and 20 mg and a mean T1/2 of 20.8 and 18.9 hours,
respectively for teneligliptin15. Any differences observed are potentially due to the presence of a
small sample size and variability rather than differences in absorption or metabolism.

In this study, the dosage of remogliflozin was 100 mg. There is a linear proportional increase in
its plasma concentration with an increase in the dosage17. Kapur et al (2013) reported that the
plateau in glucose excretion is observed at single doses of 150 mg and 500 mg of remogliflozin,
suggesting maximal inhibition of the SGLT2 transporter within this dose range. Moreover,
subjects with T2DM showed increased glucose excretion with increasing doses of remogliflozin
etabonate over 24 hours18. Kishimoto et al (2013) found that in adults, teneligliptin is orally
administered at a dosage of 20 mg up to 40 mg per day once daily. The maximum percentage of
the inhibition in plasma DPP-4 activity was reached within 2 hours after administration of
teneligliptin and was 81.3% and 89.7% at 10 and 20 mg dosages respectively15. We suggest
further investigations to be carried out at higher dosages of remogliflozin and teneligliptin FDC.

The test product was considered to be bioequivalent to the reference product, if the 90% CI for
ratio (test/reference) of geometric LSM for Ln-transformed Cmax, AUC0-t and AUC0-∞ were within
80.00% - 125.00%.The 90% CI for the ratios of test and reference log-transformed geometric
LSMs for Cmax, AUC0-t and AUC0-∞, were 82.54 - 107.32%, 101.56 - 113.65%, 101.63 - 113.63%
for remogliflozin and 86.53 - 98.09%, 102.07 - 110.56%, 102.41 - 110.77% for teneligliptin
respectively (Table 2). Therefore both the test and reference drugs of remogliflozin and
teneligliptin were observed to be bioequivalent.

The safety and tolerability of remogliflozin and teneligliptin has been well established in
previous studies15,17,18. Remogliflozin etabonate was first approved in India for the treatment of
adults with T2DM in April 201916. As remogliflozin is a highly selective SGLT2 inhibitor, it
does not cause gastrointestinal side effects shown by SGLT1 inhibitors. Data from this study
demonstrates that both the test and the reference products were well tolerated. There were no
deaths or serious adverse events reported during the study. The most common adverse effects of
remogliflozin monotherapy are genital fungal infections, urinary tract infections, and dizziness12.
However, further studies are needed to establish its long-term safety and efficacy.

Remogliflozin shows other benefits as well, such as weight loss and reduction in blood
pressure7,11. Additionally, SGLT2 inhibitors work by an insulin-independent mechanism, which
is of value in patients with diminished pancreatic function and insulin resistance18. In view of the
several advantages of SGLT2 inhibitors, they can be used as an adjuvant drug after treatment
failure with metformin and DPP-4 inhibitors4.

Our study has some limitations; firstly, the PK and safety parameters were considered in healthy
subjects only. Second, the drug-dose response, drug-drug interactions and drug-disease
interactions in patients with T2DM were not studied. Hence, further studies are required in these
areas.
5.0 Conclusion

FDC oral tablet of remogliflozin etabonate 100 mg and teneligliptin 10 mg was found to be
bioequivalent to remogliflozin etabonate 100mg and teneligliptin 10 mg monotherapy in healthy,
adult, male subjects under fed conditions. It did not produce any serious AE or death, and is safe
and well tolerated when administered to healthy subjects.

References

1. Dobbins R, Hussey EK, O’Connor-Semmes R, et al. Assessment of safety and tolerability

of remogliflozin etabonate (GSK189075) when administered with total daily dose of 2000
mg of metformin. BMC Pharmacol Toxicol. 2021;22(1):1-11. doi:10.1186/s40360-021-
00502-0

2. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic Control With Diet, Sulfonylurea,
Metformin , or Insulin in Patients With Type 2 Diabetes Mellitus. JAMA.
1999;281(21):2005-2012.

3. Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of

adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2
diabetes. Curr Med Res Opin. 2011;27(6):1157-1168. doi:10.1185/03007995.2011.570745

4. De Buitléir C, O’ Connor E, Satti MM, Shaw J, Liew A. Efficacy and safety of a sodium-
glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with
type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4
inhibitor: a systematic review and meta-analysis of ran. Diabet Med. 2021;38(2):0-2.
doi:10.1111/dme.14409

5. Dharmalingam M, Aravind SR, Thacker H, et al. Efficacy and Safety of Remogliflozin

Etabonate, a New Sodium Glucose Co-Transporter-2 Inhibitor, in Patients with Type 2
Diabetes Mellitus: A 24-Week, Randomized, Double-Blind, Active-Controlled Trial.
Drugs. 2020;80(6):587-600. doi:10.1007/s40265-020-01285-0

6. Fujimori Y, Katsuno K, Nakashima I, Ishikawa-Takemura Y, Fujikura H, Isaji M.

Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose
 cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J
Pharmacol Exp Ther. 2008;327(1):268-276. doi:10.1124/jpet.108.140210

7. Abdul-Ghani MA, Norton L, DeFronzo RA. Efficacy and safety of SGLT2 inhibitors in
the treatment of type 2 diabetes mellitus. Curr Diab Rep. 2012;12(3):230-238.
doi:10.1007/s11892-012-0275-6

8. Atal S, Fatima Z, Singh S, Balakrishnan S, Joshi R. Remogliflozin: the new low cost
SGLT-2 inhibitor for type 2 diabetes mellitus. Diabetol Int. 2021;12(3):247-253.
doi:10.1007/s13340-020-00472-4

9. Sykes AP, Kemp GL, Dobbins R, et al. Randomized efficacy and safety trial of once-daily
remogliflozin etabonate for the treatment of type 2 diabetes. Diabetes, Obes Metab.
2014;17(1):1-4. doi:10.1111/dom.12393

10. Sykes AP, O’Connor-Semmes R, Dobbins R, et al. Randomized trial showing efficacy and
safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes.
Diabetes, Obes Metab. Published online 2014:1-4. doi:doi:10.1111/dom.12391

11. Roy S. A case series of five hypertensive type 2 diabetes patients showing reduction in
blood pressure and mean arterial pressure reduction in ambulatory blood pressure
monitoring with remogliflozin etabonate 200 mg coprescribed with recent onset anti-
hypertensi. Clin Diabetol. 2019;8(5):254-257. doi:10.5603/DK.2019.0020

12. Mikhail N. Remogliflozin etabonate: A novel SGLT2 inhibitor for treatment of diabetes
mellitus. Expert Opin Investig Drugs. 2015;24(10):1381-1387.
doi:10.1517/13543784.2015.1061501

13. Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest.
2007;117(1):24-32. doi:10.1172/JCI30076

14. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for
the treatment of patients with type 2 diabetes: A review of recent clinical trials. Curr Med
Res Opin. 2008;24(2):489-496. doi:10.1185/030079908X261069

15. Kishimoto M. Teneligliptin: A DPP-4 inhibitor for the treatment of type 2 diabetes.
 Diabetes, Metab Syndr Obes Targets Ther. 2013;6:187-195. doi:10.2147/DMSO.S35682

16. Markham A. Remogliflozin Etabonate: First Global Approval. Drugs. 2019;79(10):1157-

1161. doi:10.1007/s40265-019-01150-9

17. Joshi S, Gudi G, Menon VCA, et al. An Open-Label, Single-Period, Two-Stage, Single
Oral Dose Pharmacokinetic Study of Remogliflozin Etabonate Tablet 100 and 250 mg in
Healthy Asian Indian Male Subjects Under Fasting and Fed Conditions. Clin
Pharmacokinet. 2020;59(3):349-357. doi:10.1007/s40262-019-00819-4

18. Kapur A, O’Connor-Semmes R, Hussey EK, et al. First human dose-escalation study with
remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2
(SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. BMC
Pharmacol Toxicol. 2013;14(1):1. doi:10.1186/2050-6511-14-26