INTRODUCTION:

The incidence and prevalence of type 2 diabetes mellitus (T2DM) are increasing globally, with about one in 11 adults having diabetes mellitus and 90% of them having T2DM. Asia is emerging as an epidemic area for diabetes, with China and India being epicenters¹.

The aim of the present multinational, randomized, double-blind, placebo- and active-controlled study was to determine the efficacy, safety and tolerability of RE twice daily as a monotherapy for 12 weeks, in drug-naïve subjects with type 2 diabetea²

There are two types of sodium-glucose co transporter: SGLT1, high affinity, low-capacity glucose cotransporter, and SGLT2, low affinity, and high capacity glucose co transporter that were characterized and which demonstrated the renal (proximal tubule) glucose reabsorption.3 Phlorizin, the first natural SGLT inhibitor, came into existence in the year 1835. Phlorizin inhibits both SGLT1 and SGLT2, with low selectivity. SGLT1 inhibition, however, caused several gastrointestinal side effects. Phlorizin has a hydrolytic metabolite, phloretin, which inhibits glucose transporter 1 (GLUT1), obstructing glucose uptake in tissues². Remogliflozin etabonate (RE) is a prodrug of remogliflozin, a selective O-linked glycoside inhibitor of SGLT2. In an earlier clinical study, Remogliflozinetabonate increased urine glucose excretion, reduced plasma glucose concentration and decreased bodyweight^3-4.

Extensive literature review for the quantitative analysis revealed that various analytical methods have been reported for the estimation of REM. Analysis of REM in human plasma and blood has been reported by liquid chromatography coupled with mass spectrometric method⁴. UV spectroscopy and high-performance thin-layer chromatography (HPTLC) method for the estimation of REM in bulk and tablet dosage form has been reported⁵. REM is not official in any pharmacopoeia. The incidence and prevalence of Type 2 diabetes (T2DM) are increasing as the result of a worldwide epidemic of obesity⁶.

Medical management of patients with T2DM includes diet, exercise and weight reduction, together with oral anti-diabetic medications or insulin therapy, when appropriate⁷. Remogliflozin works similarly in mice and rats and exhibits antidiabetic efficacy in animal models and humans⁸. The increase in adverse effects demands a safer anti-diabetic agent. The critical effects under consideration are the drug’s potential for hypoglycemia, weight gain, and long term side Effects⁹.

The main adverse event of clinical concern with metformin is lactic acidosis, apotentially life-threatening side effect that may be associated with high plasma concentrations of metformin and renal insufficiency^10-16. Remogliflozin etabonate is intended for use in the treatment of T2DM as monotherapy.

Given its mechanism of action, it would be a candidate for combination with metformin and other antidiabetic therapies as well. The osmotic diuresis associated with increased urine glucose excretion provides a potential mechanism for pharmacokinetic drug–drug interactions due to the extensive renal clearance of metformin, although treatment with the diuretic hydrochlorothiazide for 2 weeks had no significant effect on the clearance of metformin in subjects with T2DM¹⁷.

The HPTLC method provides accurate and precise results which are comparable to that of liquid chromatographic method. Reduced sample preparation methods, less analysis time, and small quantity of mobile phase required are some of its advantages over liquid chromatography. Densitometric scanning used in HPTLC for quantitative analysis offers advantage of accuracy, precision, and specificity over conventional methods used in TLC. Stability and degradation samples can also be analyzed using a densitometer. HPTLC has become part of many pharmacopoeial monographs for the estimation of the drug and impurities. The method submitted to FDA must have a stability-indicating nature which helps to identify the possible stability issues related to the drug and the degradation pathway. So, the present study involves development and validation of the stability-indicating high-performance thin-layer chromatographic method for the estimation of REM in tablet formulation^18.

Fig.1: Chemical Structure of Remogliflozin Etabonate

Remogliflozinetabonate, chemically ethyl [(2R,3S,4S,5R,6S)-3,4,5-trihydroxy-6-[5-methyl-1-propan-2-yl-4-[(4-propan-2-yloxyphenyl)methyl] pyrazol-3-yl]oxyoxan-2-yl]methyl carbonate 1-3, is an oral selective Sodium-Glucose co-transporter 2 (SGLT2) inhibitor used for the management of type 2 Diabetes Mellitus.¹⁹

The renal glycosuria produced by SGLT2 inhibitors could alter body composition through loss of calories in the urine and by osmotic diuresis. In addition, initial weight changes during negative energy balance could be the result of diuresis caused by glycogen mobilization from the liver. If the sustained weight changes are the result of reduced adipose tissue stores caused by energy excretion as glucose, then this may explain, in part, the metabolic improvement seen with SGLT2 inhibitors.²⁰ In India today, 8.9% of the total population, equivalent to 77 million people, have diabetes.²

The American Association of Clinical Endocrinologists (AACE) provides guidelines for T2DM management, which include lifestyle therapy, medically assisted weight loss, and individual goals of achieving hemoglobin A1C (HbA1C) level of ≤6.5%. The patient characteristics, like glycemic index and weight, lifestyle, comorbidities, and undesirable side effects of pharmaco-therapeutic management, determine the choice of anti-diabetic agents.²¹ The AACE guidelines recommended SGLT2 inhibitors as one of the first-line anti-diabetic agents.5 The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) suggest using SGLT2 inhibitors for patients with diabetic co-morbidities like cardiovascular disease (including heart failure, and atherosclerotic cardiovascular disease) and, chronic kidney disease.^21-22

The population for efficacy analysis was the intent-to-treat population, consisting of all randomized subjects who received at least one dose of study medication, had a baseline assessment and at least one corresponding on-therapy efficacy assessment. The safety population, comprising all participants who received at least one dose of study medication, was used to summarize all safety variables including on-therapy adverse events^23. Tukey’s trend test was used in the analysis of the primary endpoint of change from baseline in week 12 HbA1c with respect to the dose response. Tukey’s trend test was implemented using analysis of covariance, which ensured the protection of the overall two-sided significance level of 5%. The model included terms for treatment group and baseline HbA1c and was also used to estimate the treatment difference (and 95% confidence interval) from placebo for each RE treatment group and for the pioglitazone group.²⁴

In addition, we measured the changes in total body water (TBW) to determine the contribution of fluid loss caused by osmotic diuresis to the overall change in weight seen with these SGLT2 inhibitors. ²⁵ The low-affinity, high-capacity sodium-dependent glucose co-transporter-2 (SGLT2), which is expressed specifically in the renal proximal tubule^25-27, plays a major role in the reabsorption of glucose by the kidney. SGLT2 has recently gained recognition as a potential therapeutic target for reducing hyperglycemia in T2DM, and several selective SGLT2 inhibitors are being evaluated in the clinic^28-34.In diabetic animal models, pharmacological inhibition of SGLT2 leads to glucosuria followed by normalization of plasma glucose levels and consequent improvement in insulin resistance.^35-37This mechanism may provide improvements in both fasting and postprandial hyperglycemia without causing weight gain or other dose-limiting side effects observed with other oral antidiabetic approaches.

Treatment of diabetes mellitus: Treats type 2 diabetes mellitus and contains Remogliflozin Etabonate. It works by reducing blood sugar levels by eliminating excess sugars from the body through urine. REMOGLIFLOZIN ETABONATE also reduces the risk of heart failure in patients with type 2 diabetes and heart disease. Expert advice for Remogliflozin Etabonate.

· It may cause your body to lose too much fluid (dehydration) or you may urinate more often. Drink plenty of water and stay hydrated.

· It can cause genital fungal and/or urinary tract infections (UTIs) in both females and males, so practice good hygiene.

· It may cause hypoglycemia (low blood sugar level) when used with other anti diabetic medicines, alcohol or if you delay or miss a meal.

· Always carry some sugary food or fruit juice with you in case you experience hypoglycemia symptoms such as cold sweats, cool pale skin, tremor and anxiety.

· Inform your doctor immediately if you experience constant dizziness, joint pain, cold-like symptoms or unexplained nausea/vomiting.

· Monitor your blood sugar regularly while taking this medicine. neutralized and diluted up to the mark with methanol.

Pharmocology^38-42

1. Pharmacodynamics:

In vivo, administration of a single oral dose of remoglifozinetabonate to normal mice and rats was associated with a dose-dependent increase in urinary glucose excretion and decreased plasma insulin levels. Administration of and the single oral dose, dose-dependently inhibited the increase in plasma glucose levels seen after glucose loading in normal And streptozotocin-induced diabetic rats, with a markedly enhanced effect observed in the latter ⁸. Administration of a single oral dose of remoglifozinetabonate to db/db mice decreased blood glucose and dose-dependently reduced blood glucose AUC6h. Also in db/db mice, oral administration of remoglifozinetabonate daily for 6 weeks was associated with reduced fasting plasma glucose and glycatedhaemoglobin (HbA1c), and reduced urinary glucose excretion. Goto-Kakizaki rats, oral remoglifozinetabonate administered for 8 weeks was associated with improvements in hyperglycaemia, hyperinsulinaemia, hypertriglyceridemia, and insulin resistance

In a murine model of non-alcoholic fatty liver disease (NAFLD), oral administration of remoglifozinetabonate was associated with 76% and 48% reductions in plasma alanine aminotransferase and aspartate amino transferase levels, respectively, and reduced liver weight by 42% and hepatic triglyceride content by 40% ⁹. Administration of remoglifozinetabonate to volunteers (50–1000mg) and patients with T2DM (50 and 500mg) was associated with a dose-dependent increase in total urine glucose excretion from 0 to 24h in a phase I study.

The increase in urine glucose excretion was less than proportional with increasing doses, however, indicating a plateau of effect. Urinary glucose excretion was higher in patients with T2DM than in volunteers because of higher plasma glucose concentrations in the former. When urine glucose excretion was corrected according to circulating plasma glucose concentrations and creatinine clearance, the percentage filtered glucose load was similar in both groups¹. Fujimori Y, Katsuno K, Nakashima I, et al. Remogliflozinetabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efcacy in rodent models. J Pharmacol Exp Ther. 2008; 327:268 – 76. 9. Nakano S, Katsuno K, Isaji M, et al. Remoglifozinetabonate improves fatty liver disease in diet-induced obese male mice. J Clin Exp Hepatol. 2015; 5(3): 190–8.

2. Pharmacokinetics:

An ester prodrug remogliflozinetabonate is rapidly absorbed and then extensively de-esterifed in the gastrointestinal mucosa to the active moiety remoglifozin, which appears maximally in plasma of animal. Remoglifozin is metabolised to GSK 279782 which is the active metabolite and GSK 333081, predominantly by cytochrome P450 (CYP) 3A4, before undergoing glucuronidation to form inactive glucuronide conjugates. A single dose mass balance study in healthy volunteers indicated >93% of [14C] remoglifozinetabonate was absorbed, and was predominantly excreted in urine as inactive glucuronide conjugates. Both remoglifozinetabonate and remoglifozin are P-glycoprotein (P-gp) substrates but do not inhibit P-gp. However, as remoglifozinetabonate is almost completely absorbed, P-gp inhibitors are not expected to impact the pharmacokinetic profle of remoglifozinetabonate. ⁽⁴⁾.

· Oral bioavailability: low (due to extensive metabolism)

· Protein binding: not reported

· T1/2: 1.5 to 1.9hrs

· Metabolism: liver

· Excretion: urinary glucose (93%)

· Dose: 100mg, 250mg

3. Therapeutic Trials:

· Features and Properties:

a) Alternative names:- Remo TM, Remozen TM, BHV 091009, GSK 189075, KGT-1681

b) Class: Antihyperglycaemics, glucosides hepatoprotectants, pyrans, pyrazole.

c) Mechanism of Action:- Sodium-glucose transporter 2 inhibitor

d) Route of Administration:- Oral route

e) Adverse Effects (Most frequent):- Urinary tract infection, pyrexia, headache, bacteriuria, constipation, diarrhoea, decreased glomerular fltration rate, ketonuria, cough, dyslipidaemia, asthenia, viral upper respiratory tract infection, hypoglycaemia, orthostatic hypotension

f) WHO ATC Code:- A05B-A (liver therapy), A08 (antiobesity preparations, excl. diet products), A10X (other drugs used in diabetes)

g) Chemica names:- Ethyl [(2R,3S,4R,5S)-3,4,5-trihydroxy-6-[4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1H-pyrazol-3-yloxy] tetrahydro-2H-pyran-2-yl]methyl carbonate.

4. Adverse Effect:

The most commonly reported adverse reactions occurring in patients treated with Remoglifozinetabonate in the phase III trial included –

Table 2: Adverse effects with percentage

Sr. No.	Adverse Effect	Percent
1)	Urinary Track Infection	4.9%
2)	Pyrexia	2.7%
3)	Headache	2.5%
4)	Bacterioria	2.3%
5)	Consitpation	1.7%
6)	Diarrhoea	1.7%
7)	Decreased glomereularfilteration rate	1.7%
8)	Ketoneuria	1.7%
9)	Cough	1.5%
10)	Dyslipidaemia	1.5%
11)	Viral Upper Respiratory Tract Infection	1%
12)	Hypoglycaemia	1%
13)	Orthostatic Hypotension	1%

Hypoglycaemia was reported in similar proportions of patients receiving remoglifozin or dapaglifozin as add-on treatment to metformin in the phase III trial in Vulvovaginitis, balanitis and related genital infections, all of which were mild to moderate inseverity and responded to an initial course of standard treatment, were reported in 1.8% and 1.2% of remoglifozinetabonate 100 and 250 mg recipients and in 2.7% of dapaglifozin recipients. Urinary tract infections were reported in 3.1% and 6.6% remoglifozinetabonate 100 and 250 mg recipients and in 2.1% of dapaglifozin recipients. Dehydration or hypovolaemia was not reported in remoglifozin or dapaglifozin recipients ⁴.

Marketed formulation:

Taken sample equivalent to 50 mg of Remogliflozin and 50 mg of Metformin hydrochloride was transferred to a 100 ml volumetric flask, add 60 ml of Mobile phase and Shake for 15 minutes and made up volume up to the mark with mobile phase. The solution was filtered through Whatman filter paper no. 42 and first few drops of filtrate were discarded. 1 ml of this solution was diluted to 10 ml with mobile phase. The solution was injected 20 µl. The areas of resulting peak were measured at 247 nm. Applicability of the proposed method was tested by analyzing the commercially available formulation.

Table 3: Marketed formulation analysis

Formulation	Label claim		Assay (% Of label claims) Mean±S.D.
Formulation	RE	MH	% RE	% MH
Synthetic mixture	100mg	500mg	99.344 0.422	100.25 ±0.142

RE= Remogfliflozin etabonate; MH= Metformin HCl

CONCLUSIONS:

In summary, the findings of this study do not indicate a safety concern when multiple oral doses of remogliflozin etabonate 500 mg are administered with metformin 500 BID in the intended patient population. Because remogliflozin etabonate does not affect the PK profile of metformin, there is a low risk for adverse events resultingfrom a PK drug interaction and increased metformin exposure. The approximate 20% decline in remogliflozin Cmax under conditions of co administration is likely a reflection of the 15% decline in the Cmax of the prodrug (RE) when given with metformin (Table 3). It appears that metformin reduces the Cmax of RE without an effect on RE AUC, suggesting a change in the shape of the 12-hour, steady state, concentration-time profile. Even though the confidence interval is wide for the prodrug Cmax point estimate (0.54, 1.35) and contains 1.0, it is plausible that coadministration of metformin altered GI motility enough to affect the absorption or hydrolysis of RE resulting in a lowerCmax of RE. The lower Cmax values for remogliflozin andGKS279782 following dosing with metformin collectively support this conclusion since they are downstream metabolites of RE. Although administration with metformin resulted in a21% reduction in Cmax, the PD properties of remogliflozin etabonate were not altered when administered with metformin. There was an indication that remogliflozin etabonate alone improves plasma blood glucose by increasing the excretion of urine glucose, and this effect by remogliflozin etabonate was not impaired by the co-administration of metformin. Future studies in a larger patient population are warranted to definitively test the safety and efficacy of remogliflozin etabonate in combination with metformin inpatients with T2DM who have not achieved the desired glycemic target.

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Received on 26.07.2023 Modified on 29.08.2023

Asian J. Pharm. Tech. 2024; 14(1):16-22.

DOI: 10.52711/2231-5713.2024.00005

	Remogliflozin etabonate Pioglitazone once daily
	Placebo N=47 50mg N=44 100mg N=44 250mgN=45 500mgN=47 1000mgN=47 30mgN=47
Number of subjects	43+	45	43	44	47	45	47
At baseline mean (s. d)	8.12(0.76)	8.25(0.62)	8.10(0.71)	8.14(0.68)	8.03(0.68)	8.12(0.63)	8.08(0.56
At week 12,mean(s.d)	7.80(1.06)	7.16(0.83)	7.15(0.76)	7.08(0.89)	6.85(0.73)	6.74(0.64)	7.02(0.80)
Model adjusted change mean(s.e)	-0.31(0.110)	-1.04(0.11)	-0.96(0.11)	-1.05(0.11)	-1.21(0.10)	-1.38(0.10)	-1.07(0.10)
Trend test p values		<0.001	<0.001	<0.001	<0.001	<0.001
Difference from placebo Mean (95%CI)		-0.73(-1.02,-0.44)	-0.64(-0.94,-0.35)	-0.74(-1.03,-0.44)	-0.90(-1.19,0.61)	-1.07(-1.36,-0.77)	-0.76(-1.05,-0.47)
P\|\|		<0.001	<0.001	<0.001	<0.001	<0.001	0.001