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Ertugliflozin

Ertugliflozin: A Comprehensive Overview

Introduction

Ertugliflozin, marketed under the brand name Steglatro, is a medication used to manage blood sugar levels in adults with type 2 diabetes mellitus (T2DM). As a member of the sodium-glucose co-transporter 2 (SGLT2) inhibitor class, ertugliflozin offers a unique insulin-independent mechanism to lower blood glucose levels.

Mechanism of Action

Ertugliflozin functions by selectively inhibiting the SGLT2 protein in the proximal renal tubules of the kidneys. Under normal circumstances, SGLT2 reabsorbs approximately 90% of the glucose filtered by the kidneys back into the bloodstream. By blocking this transporter, ertugliflozin reduces glucose reabsorption, leading to increased urinary glucose excretion and, consequently, lower blood glucose levels. This mechanism is independent of insulin secretion or action, making ertugliflozin effective even in patients with diminished β-cell function or insulin resistance.

Clinical Uses

Ertugliflozin is primarily indicated for:

  • Type 2 Diabetes Mellitus (T2DM): As an adjunct to diet and exercise to improve glycemic control in adults.

  • Combination Therapy: Ertugliflozin is available in fixed-dose combinations with:

    • Metformin (brand name: Segluromet)

    • Sitagliptin (brand name: Steglujan)

These combinations offer the convenience of dual therapy in a single tablet, enhancing patient adherence.

Pharmacokinetics

Understanding the pharmacokinetic profile of ertugliflozin is crucial for optimizing its therapeutic use.

  • Absorption: Ertugliflozin is rapidly absorbed after oral administration, with peak plasma concentrations occurring approximately one hour post-dose under fasting conditions.

  • Bioavailability: The drug exhibits high oral bioavailability, ensuring effective plasma concentrations with oral dosing.

  • Distribution: Once in circulation, about 93.6% of ertugliflozin binds to plasma proteins.

  • Metabolism: Ertugliflozin is primarily metabolized via glucuronidation by the enzymes UGT1A9 and UGT2B7. Cytochrome P450 enzymes play a minor role in its metabolism.

  • Elimination: The elimination half-life is approximately 17 hours, supporting once-daily dosing. About 50.2% is excreted in urine (1.5% unchanged), and 40.9% via feces (33.8% unchanged).

  • Food Interaction: Administration with or without food does not have a clinically meaningful effect on the pharmacokinetics of ertugliflozin.

Dosage and Administration

  • Starting Dose: 5 mg orally once daily, taken in the morning with or without food.

  • Dose Adjustment: If additional glycemic control is needed and the initial dose is well-tolerated, the dose may be increased to a maximum of 15 mg once daily.

  • Renal Impairment: Ertugliflozin is not recommended for patients with severe renal impairment, end-stage renal disease, or those on dialysis.

Benefits Beyond Glycemic Control

Ertugliflozin offers several additional benefits:

  • Weight Reduction: By promoting urinary glucose excretion, ertugliflozin leads to calorie loss, contributing to modest weight loss.

  • Blood Pressure Reduction: The osmotic diuretic effect results in mild reductions in systolic and diastolic blood pressure.

  • Cardiovascular Outcomes: While some SGLT2 inhibitors have demonstrated cardiovascular benefits, studies specific to ertugliflozin have shown it to be non-inferior to placebo concerning cardiovascular events.

Adverse Effects

While ertugliflozin is generally well-tolerated, some patients may experience side effects.

Common Side Effects:

  • Increased urination

  • Thirst

  • Dry mouth

  • Headache

  • Genital yeast infections (more common in females)

Serious Adverse Effects:

  • Diabetic Ketoacidosis (DKA): Though rare, cases of DKA have been reported. Patients should be educated on recognizing symptoms such as nausea, vomiting, abdominal pain, fatigue, and difficulty breathing.

  • Hypotension: Due to volume depletion, especially in patients with impaired renal function or those on diuretics.

  • Acute Kidney Injury: Monitor renal function periodically.

  • Hypoglycemia: Particularly when used in combination with insulin or insulin secretagogues.

Drug Interactions

  • Diuretics: Concurrent use may enhance the risk of dehydration and hypotension.

  • Insulin and Insulin Secretagogues: May increase the risk of hypoglycemia; dose adjustments may be necessary.

  • Rifampin: Co-administration can decrease ertugliflozin exposure; monitor glycemic control.

Contraindications

  • Severe Renal Impairment: Not recommended in patients with an eGFR below 30 mL/min/1.73 m².

  • Hypersensitivity: Contraindicated in patients with known hypersensitivity to ertugliflozin or any of its components.

Use in Special Populations

  • Pregnancy: Limited data are available; use only if the potential benefit justifies the potential risk.

  • Lactation: It is unknown whether ertugliflozin is excreted in human milk; caution is advised.

  • Pediatrics: Safety and efficacy have not been established in patients under 18 years of age.

Conclusion

Ertugliflozin represents a valuable addition to the therapeutic arsenal for managing type 2 diabetes mellitus. Its insulin-independent mechanism, once-daily dosing, and additional benefits such as weight and blood pressure reduction make it an attractive option for many patients. However, clinicians must remain vigilant regarding potential adverse effects and contraindications to ensure optimal patient outcomes.