INTRODUCTION:

The main energy source for eukaryotic organisms is glucose. It is crucial for maintaining cellular homeostasis and metabolism. Most mammalian cells needed a constant glucose supply to function. This acts as the primary 1,2 source for the creation of adenosine triphosphate (ATP). The control of glucose metabolism is maintained through the coordinated action of three systems. The first is the small intestine's absorption of glucose, and the second is the liver's production of glucose. The third phase is the consumption of glucose by all tissues.

The brain and other tissues require a steady supply of glucose. Seizures, unconsciousness, and irreversible cell damage are the outcomes of low blood glucose concentration. Glucose toxicity, which is caused by high blood glucose levels, can result in blindness, renal failure, heart disease, and neuropathy.

The sodium glucose co-transporter system (SGLT) and facilitative glucose transporters (GLUT) are the two distinct types of transporter proteins that mediate glucose and other sugar transfer across lipid bilayer. Both GLUT and SGLT are members of the solute carrier gene family. A metabolic disorder called diabetes mellitus is characterized by unusually high blood glucose levels. To treat diabetes mellitus, a wide range of medications are available. This class of drugs includes biguanides, meglitinides, alpha glycosidase inhibitors, and sulfonylureas. These drugs reduce blood sugar levels in a number of ways, such as by increasing peripheral glucose consumption, production of insulin, and so forth.

They have several disadvantages, such as hypoglycemia, anemia, and gastrointestinal distress. One SGLT 2 inhibitor that can be used to treat diabetes mellitus is ertugliflozin. It lowers blood glucose levels by blocking the reabsorption of glucose. SGLT2 Inhibitors, or sodium glucose co-transporter type 2 inhibitors, are one such promising class of newly developed drugs for the treatment of diabetes. The production and handling of SGLT2 inhibitor medications have presented difficulties for the pharmaceutical sector. In December 2017, the US Food and Drug Administration authorized ertugliflozin, the most recent medication in the series, for the treatment of type 2 diabetes.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that work by inhibiting sodium-glucose cotransporter 2 in the proximal convoluted renal tubule, which in turn allows glucose to be reabsorbed. A wide range of metabolic benefits, including a drop in body weight, blood pressure, albuminuria, and glycosylated hemoglobin (HbA1c), are brought about by the increase in glycosuria and natriuresis that follows. There is sufficient data to conclude that the oral antidiabetic SGLT2i class of drugs is just as successful in lowering plasma glucose levels as other existing treatment alternatives.

Sodium-glucose co-transporter 2 inhibitors, or SGLT2is, have positive effects on blood pressure and weight in addition to effectively decreasing glycated hemoglobin (HbA1c) levels. As seen by this class of prescription medicine's growing importance in the most recent clinical practice recommendations, these potential benefits have been acknowledged. The most recent SGLT2i to hit the market is ertugliflozin, which is authorized to be used in addition to diet and exercise. to enhance glycemic control in adult patients suffering from type 2 diabetes mellitus (T2DM), including recent regulatory approvals in the EU (March 2018), the USA (December 2017), and other countries. Etugliflozin's regulatory approval was predicated on several Phase III trials that shown its ability to reduce blood pressure, weight, and HbA1c. SGLT2 inhibitors have been shown to improve cardiovascular outcomes in two real-world investigations and three sizable, randomised, placebo-controlled trials that have been reported to date (3-5). SGLT2 inhibitors are advised for usage either alone or in conjunction with other antihyperglycemic medications in accordance with treatment guidelines. Recently, the European Union and the United States approved ertugliflozin, a highly selective SGLT2 inhibitor, to help persons with type 2 diabetic mellitus (T2DM) improve their glycaemic control.

VERTIS Programme:

Several international multicenter clinical studies related to the VERTIS Program Studies (evaluation of ERTugliflozin effIcacy and safety) are now evaluating ertugliflozin. In these investigations, ertugliflozin has been assessed in both monotherapy and as a supplement or combination medication for people with diabetes. When used alone or in conjunction with metformin and/or dipeptidyl peptidase-4 (DPP-4), ertugliflozin improved glycaemic control. A previous open-label Phase I trial found that ertugliflozin is primarily absorbed and metabolized by glucuronidation, with a smaller amount occurring by oxidative metabolism. 90% of the given radioactivity was recovered when radiolabeled material was excreted in the urine and feces.

Sodium Glucose Co-transporters:

The kidneys are essential for the body's energy regulation. In Glomerulus, glucose undergoes filtration and is then reabsorbed. The primary site of reabsorption in the proximal tubules is the S1 segment. Glycosuria is the term for the condition that occurs when excess glucose is discharged in urine after glucose reabsorption reaches saturation. Every day, about 180 g of glucose are filtered. 90% of the glucose is reabsorbed in this way. The remaining 10% is reabsorbed in the distal straight segment of the convoluted proximal tube. The major players in the transport of glucose are SGLT and GLUT. There are six recognized SGLT varieties.

SGLT1 and SGLT2 were studied in great detail among them. SGLT1, which has a higher affinity for glucose, is mostly found in the renal proximal tubule at the S2 site. Moreover, its transport capacity is lower than that of SGLT2. Proximal tubule membranes at the S1 location contain SGLT2. It can transport glucose with a greater capacity and a lower affinity. About 90% of the glucose that is reabsorbed in the proximal tubule is mediated by SGLT2, with SGLT1 accounting for the remaining 10%.

Structure of Ertugliflozin:

The chemical name of ertugliflozin L-pyroglutamic acid is (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo [3.2.1] octane-2,3,4-triol, Compound with (2S)-5 oxopyrrolidine-2-carboxylic acid.

Formula: C₂₇H₃₂ClNO₁₀:

Schedule: Schedule H

Molar mass: 566.00 g/mol

Monoisotopic Weight: 565.171473 Da

Boiling point: 630.5±55.0 °C at 760 mmHg

Vapour Pressure:0.0±1.9 mmHg at 25

Enthalpy of Vaporization:98.0±3.0 kJ/mol

Flash Point:335.1±31.5 °C

Solubility: Soluble in organic solvents such as ethanol, DMSO, and dimethyl formamide. Solubility of Ertugliflozin in these solvents is approximately 30 mg/ml.

Elimination half-life:11-17 hours.

Absorption: Oral bioavailability of Ertugliflozin is 70-90%

Half life: 16.6 hours

Clearance: 11.2 L/hr.

Protein Binding: 94-96%

A white to off-white powder, ertugliflozin L-pyroglutamic acid is soluble in acetone and ethyl alcohol, slightly soluble in acetonitrile and ethyl acetate, and very slightly soluble in water.

Mechanism of Action:

Ertugliflozin inhibits sodium-glucose cotransporter-2 (SGLT2) at the proximal convoluted tubules, preventing the reabsorption of glucose. This causes an excessive amount of glucose to be excreted in urine, which lowers blood glucose levels. As a result, it improves β-cell function, insulin sensitivity, and decreases glucose toxicity. The main transporter that brings glucose back into the bloodstream from the glomerular filtrate is called SGLT2. Ertugliflozin is an SGLT2 inhibitor. Ertugliflozin lowers the renal threshold for glucose and decreases renal reabsorption of filtered glucose by inhibiting SGLT2, which raises urine glucose excretion. Less than 1% of the blood's glucose is expelled in the urine because it is filtered for excretion and then reabsorbed in the glomerulus as part of a regular process. Ninety percent of the glucose that is reabsorbed is handled by the sodium-dependent glucose cotransporter (SGLT), primarily type 2. A modest SGLT2 inhibitor, ertugliflozin's action raises glucose excretion and lowers hyperglycemia without necessitating excessive insulin secretion.

Fig. 1: Mechanism of action of SGLT-2 Inhibitors

Pharmacokinetics:

Ertugliflozin is an oral sodium-glucose cotransporter-2 (SGLT2) inhibitor. It has an oral bioavailability of 70–90% and is well absorbed. Tmax (median) is two hours (after a high-fat meal) and one hour (when fasting). It is mainly metabolized to inactive metabolites by O-glucuronidation mediated by UGT1A9 and UGT2B7. Urine accounts for 50% of elimination, whereas feces make up 41%. Half-Life exceeds sixteen hours. Patients with type 2 diabetes mellitus and healthy persons have comparable ertugliflozin pharmacokinetics.

When 5mg of ertugliflozin was taken once daily, the steady state mean Plasma AUC and Cmax were 398 ng√hr/mL and 81.3ng/mL, respectively; when 15mg of ertugliflozin was taken once daily, the values were 1,193 Ng√hr/mL and 268ng/mL, respectively. Ertugliflozin administered once daily for four to six days results in the onset of the steady-state. Ertugliflozin does not show time-dependent pharmacokinetics, and after several doses, it can accumulate in plasma by 10–40%.

Pharmacodynamics:

Urinary Volume and Glucose Excretion Increases in the amount of glucose expelled in urine that are dose-dependent were seen in patients with type 2 diabetes mellitus and in healthy individuals after receiving both a single and repeated dose of ertugliflozin. Urinary glucose excretion (UGE) is nearly maximal at 5 and 15 mg of ertugliflozin, according to dose-response modeling. Following the delivery of repeated doses, enhanced UGE is maintained. Urine volume also increases when using ertugliflozin in combination with UGE.When ertugliflozin is administered, it increases the excretion of glucose in the urine, causing osmotic diuresis and a negative balance. Therefore, it has been shown that this antidiabetic drug considerably lowers the blood pressure and body weight of diabetic patients.

Cardiac Electrophysiology:

In 42 healthy participants, a Phase 1 Randomized, placebo- and positive-controlled, three-period crossover study was conducted to assess the impact of ertugliflozin on QTc interval. At 6.7 times the doses used for therapy Ertugliflozin does not extend QTc to a clinically significant degree when taken at the maximum advised dose.

Absorption:

According to preclinical research, ertugliflozin has an oral bioavailability of 70–90% and is well absorbed. Tmax was recorded to have happened 0.5–1.5 hours after dose.3. The Cmax and AUC after oral treatment seemed to be dosage proportionate. Following 15 mg administration, Cmax and AUC values were recorded as 268 ng/ml and 1193 ng h/ml, respectively. Peak plasma concentrations (median Tmax) of ertugliflozin occur one hour post-dose in fasting circumstances after single-dose oral administration of 5 mg and 15 mg of the medication. After single doses of 0.5 mg (0.1 times the lowest recommended dose) to 300 mg (20 times the highest recommended dose) and after multiple doses of 1 mg (0.2 times the lowest recommended dose) to 100 mg (6.7 times the highest recommended dose), ertugliflozin's plasma Cmax and AUC increase in a dose-proportional manner. After a 15 mg dose is administered, ertugliflozin's absolute oral bioavailability is almost 100%.

Effect of Food:

When ertugliflozin is administered with a high-fat, high-calorie meal, the Cmax of the drug is reduced by 29% and the Tmax is extended by one hour; however, the AUC remains unchanged when compared to the fasted condition. It is not deemed clinically significant that food has any effect on the pharmacokinetics of ertugliflozin; hence, food can be taken with or without the medication. Ertugliflozin was provided without consideration to meals in Phase 3 clinical studies.

Distribution:

The average steady-state volume of ertugliflozin's dispersion. 85.5 L after an intravenous dosage. Ertugliflozin binds to plasma proteins with a 93.6% binding rate that is unaffected by plasma concentrations of the drug. Patients with hepatic or renal impairment do not significantly change in terms of plasma protein binding. Ertugliflozin has a blood-to-plasma concentration ratio of 0.66. Following ertugliflozin oral dosing, 215.3 L was reported as the apparent volume of distribution. After intravenous etrugliflozin dosing, the steady-state volume of distribution is 85.53 L.

Protein binding:

Ertugliflozin binds strongly to plasma proteins, with a range of 94–96% binding, regardless of the dose that is given.

Metabolism:

Ertugliflozin's principal clearance mechanism is metabolism. Research conducted in vitro revealed that the metabolism of ertugliflozin in hepatocytes and liver microsomes is shaped by the processes of glucuronidation, O-demethylation, and monohydroxylation. It has been postulated that eight distinct metabolites present in plasma, feces, and urine comprise the basis of ertugliflozin metabolism. It was discovered that the majority of the dose provided in plasma was composed of ertugliflozin in its unaltered form.

Route of elimination:

91% of the drug ertugliflozin was recovered in total, and 41% of it was eliminated by feces and 50% of it through urine. About 168 hours after the first dose was taken, the administered dose recovered. Urine was eliminated relatively quickly; after 24 hours, 80% of the dosage was found in the urine. Seven distinct major metabolites and the unaltered minor metabolite ertugliflozin made up the eliminated dosage in urine. Each patient's rate of elimination in feces varied, however after 168 hours of first dosing, 98.5% of the eliminated dose was found in feces. Three other small metabolites and unaltered ertugliflozin made up the majority of this removed dosage. Based on population pharmacokinetic studies, the mean elimination half-life in type 2 diabetes patients with normal renal function was determined to be 16.6 hours.

Half-life:

Etugliflozin has a terminal elimination half-life of 11–17 hours.

Clearance:

Ertugliflozin administered orally has an apparent total plasma clearance rate of 178.7 ml/min, while intravenous administration results in a systemic total plasma clearance of 187.2 ml/min.

Adverse effects:

With a documented prevalence of ≥5%, female genital mycotic infections are the most common side effect related with ertugliflozin. Intravascular volume contraction/depletion, hypotension, diabetic ketoacidosis, acute kidney injury/renal impairment, lower limb amputation, hypoglycemia, and a rise in low-density lipoprotein cholesterol (LDL) are additional cautions and warnings related to ertugliflozin.With an SGLT2 inhibitor or a DPP-4 inhibitor together, hypoglycemia is uncommon unless the patient is already taking an antihyperglycemic medication.Ertugliflozin usage in clinical studies was connected to amputations of the lower leg in 0.2% of patients receiving the 5 mg dose and 0.5% of patients receiving the 15 mg dose.

Toxicity:

According to the results of clinical trials, ertugliflozin is generally well tolerated and does not cause any serious adverse effects. Studies on carcinogenesis have been conducted, and it has been noted that adrenal medullary pheochromocytoma is more common; this may be connected to disturbed calcium homeostasis resulting from malabsorption of carbohydrates. Mutagenesis and reproductive impairment were not documented.

Indication:

An oral sodium-glucose cotransporter (SGLT2) inhibitor called ertugliflozin is recommended as a supplement to diet and exercise in order to improve glycemic control in persons with type 2 diabetes. It is recommended that adult patients with type 2 diabetes who are taking ERTugliflozin as a monotherapy improve their glycemic management. Label When metformin hydrochloride and ertugliflozin are taken together, individuals with type 2 diabetes who are not managed on either medication or who are already receiving both medications can benefit from improved glycemic control.

When treatment with ertugliflozin and sitagliptin is appropriate, the administration of ertugliflozin in combination with sitagliptin is approved to enhance glycemic control in adult patients with type 2 diabetes. It is noted that ertugliflozin usage must be used in conjunction with diet and exercise as an adjunctive treatment. The two main characteristics of type 2 diabetes mellitus are the existence of insulin shortage or insulin resistance in the liver and muscles, which raise blood glucose levels. Insulin resistance is associated with aging, obesity, sedentary lifestyles, and/or hereditary factors. The vascular system, kidneys, and eyes may sustain serious damage as a result of this blood glucose spike.

Drug Interaction:

Drug-drug Interaction:

1. Amoxicillin: Ertugliflozin may increase the excretion rate of Amoxicillin which could result in a lower serum level and potentially a reduction in efficacy.

2. Acetaminophen: Ertugliflozin may increase the excretion rate of Acetaminophen which could result in a lower serum level and potentially a reduction in efficacy.

3. Atenolol: The therapeutic efficacy of Ertugliflozin can be increased when used in combination with Atenolol.

4. Benzthiazide: The therapeutic efficacy of Ertugliflozin can be decreased when used in combination with Benzthiazide.

5. Bisoprolol: The therapeutic efficacy of Ertugliflozin can be increased when used in combination with Bisoprolol.

6. Captopril: The risk or severity of renal failure, hypotension, and hyperkalemia can be increased when Ertugliflozin is combined with Captopril.

Food Interactions:

Avoid excessive or chronic alcohol consumption. Alcohol abuse may increase the risk of ketoacidosis. Take with or without food.

Approved preparations:

Ertugliflozin has been licensed by the US Food and Drug Administration to treat type 2 diabetes both alone and in combination with metformin or sitagliptin.

Warnings And Precautions:

Urinary tract infections, hypotension, ketoacidosis, acute kidney injury/impairing, and elevated low-density lipoprotein-Cholesterol (LDL-C) were all linked to genital infections. Hypoglycemia combined with concurrent insulin administration Concerns about secretagogues arise when using ertugliflozin.

Dosage and Administration:

Ertugliflozin tablets come in 5 mg and 15 mg dosages. 5 mg once daily, taken in the morning with or without meals, is the recommended starting dose. Increase the dosage to 15 mg once daily in those who can tolerate 5 mg of ertugliflozin once daily. For patients with modest renal impairment, there is no need to modify the dosage.

CONCLUSION:

Ertugliflozin provides a special kind of treatment for type 2 diabetes. Ertugliflozin has advantages in blood pressure, body weight, and blood glucose regulation. Fungal infections in the genitalia and sporadic hypoglycemia are observed side effects. There is no evidence of an elevated risk of cardiovascular disease in the early research. But a longer time frame Clinical research is still necessary. Patients with type 2 diabetes mellitus can now receive treatment with this new medication as an alternative. When it comes to reducing HbA1c, ertugliflozin may be more beneficial than dapagliflozin and empagliflozin for patients who are uncontrolled on diet and exercise, as well as those receiving metformin-only therapy.

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Received on 30.07.2024 Revised on 26.08.2024

Accepted on 11.09.2024 Published on 07.12.2024

Available online on December 30, 2024

Res.J. Pharmacology and Pharmacodynamics.2024;16(4):315-320.

DOI: 10.52711/2321-5836.2024.00054

Ertugliflozin: A Novel Drug for Control of Type-2 Diabetes