Ertugliflozin

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
  Used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
• Combination Therapy:
  Can be used in combination with metformin, sulfonylureas, DPP-4 inhibitors, or insulin when monotherapy does not provide adequate glycemic control.

Important Off-label or Investigational Uses (Clinically Accepted):

• Cardiovascular Risk Reduction:
  Though not approved specifically for this, SGLT2 inhibitors (including Ertugliflozin) have shown cardiovascular benefits in clinical trials; however, specific labeling for major adverse cardiovascular events (MACE) prevention may differ from other drugs in this class.

Adults:

• Initial dose: 5 mg orally once daily in the morning, with or without food.
• Titration: May increase to 15 mg once daily if additional glycemic control is needed and the patient tolerates it.

Renal Impairment:

• eGFR ≥60 mL/min/1.73 m²: No dose adjustment required.
• eGFR <60 mL/min/1.73 m²: Not recommended due to reduced efficacy.
• End-stage renal disease (ESRD) or dialysis: Contraindicated.

Hepatic Impairment:

• No dose adjustment required for mild to moderate hepatic impairment.
• Caution advised in severe hepatic impairment due to limited data.

Geriatric Use:

• No dose adjustment based on age alone, but monitor renal function closely.

Pediatric Use:

• Safety and efficacy in patients under 18 years have not been established.

Administration:

• Oral route; can be taken with or without food.
• Consider taking in the morning to reduce the risk of nocturia.

Ertugliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor. It works by inhibiting SGLT2 in the proximal renal tubules, which is responsible for reabsorbing the majority of filtered glucose from the tubular lumen. By blocking this reabsorption, Ertugliflozin increases urinary glucose excretion, thereby lowering blood glucose levels. This insulin-independent mechanism also contributes to modest weight loss and mild reductions in blood pressure.

• Absorption: Rapidly absorbed after oral administration; peak plasma concentration (Tmax) occurs within 1 to 2 hours.
• Bioavailability: Approximately 100%.
• Distribution: Volume of distribution is ~85.5 L; plasma protein binding is ~93.6%.
• Metabolism: Primarily metabolized via UGT1A9 and UGT2B7 to inactive glucuronide conjugates; minimal involvement of CYP450 enzymes.
• Elimination:
• Half-life: ~17 hours
• Excretion: ~41% in feces, ~50% in urine (mostly as metabolites)

• Pregnancy:
  No FDA pregnancy category (due to updated labeling regulations). Animal studies have shown adverse effects on the developing kidney during late pregnancy. Should be avoided, especially in the second and third trimesters.
• Lactation:
  It is unknown whether Ertugliflozin is excreted in human milk. Based on animal studies, excretion into milk occurs and could potentially harm a breastfeeding infant. Use is not recommended during breastfeeding.
• Caution:
  Avoid use in pregnancy and lactation unless the potential benefit justifies the potential risk to the fetus or infant.

• Primary Class: Antidiabetic Agent
• Subclass: Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitor
• Generation: Newer generation oral SGLT2 inhibitor

• Hypersensitivity to Ertugliflozin or any component of the formulation
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Patients on dialysis
• Diabetic ketoacidosis (DKA), regardless of type of diabetes
• Type 1 Diabetes Mellitus (increased risk of DKA)

• Diabetic Ketoacidosis (DKA): Can occur even with normal glucose levels (euglycemic DKA); discontinue if suspected.
• Genital Mycotic Infections: Higher incidence, especially in uncircumcised males and females with a history of yeast infections.
• Hypotension: Especially in patients with impaired renal function or elderly on diuretics.
• Acute Kidney Injury: Monitor renal function before starting and during therapy.
• Necrotizing Fasciitis of the Perineum (Fournier’s gangrene): Rare but serious.
• Lower Limb Amputation Risk: Although not definitively proven for Ertugliflozin, a class warning exists.
• Fracture Risk: Consider bone health in at-risk patients.

Common Side Effects (≥5%):

• Genitourinary: Vaginal yeast infections, balanitis, increased urination
• Metabolic: Hypoglycemia (especially with insulin or sulfonylureas)
• Gastrointestinal: Increased thirst, constipation
• Cardiovascular: Hypotension

Serious/Rare Side Effects:

• Diabetic ketoacidosis
• Acute kidney injury
• Fournier’s gangrene
• Urosepsis and pyelonephritis
• Bone fractures
• Increased LDL-C

Timing & Severity:
Most common side effects occur within the first weeks. Severity is usually mild to moderate, but some risks (e.g., DKA or gangrene) can be life-threatening.

• Diuretics: Increased risk of volume depletion and hypotension.
• Insulin/Sulfonylureas: Risk of hypoglycemia increases; dose adjustments may be required.
• UGT Inducers (e.g., Rifampin, Phenobarbital): May reduce Ertugliflozin efficacy.
• Lithium: SGLT2 inhibitors may reduce lithium levels—monitor closely.
• Alcohol: Increases risk of DKA and hypotension.

Enzyme Systems Involved:

• Metabolized mainly via UGT1A9 and UGT2B7
• Minimal CYP450 involvement, reducing potential for major CYP interactions

• Label Updates:
  FDA has updated safety labeling to include warnings about serious infections and DKA risk, though less so than other SGLT2 inhibitors.
• Clinical Guidelines:
  ADA and EASD include Ertugliflozin among recommended agents in patients with T2DM who also have cardiovascular risk factors, though others like empagliflozin or dapagliflozin have stronger CV outcome data.
• Renal Guidelines:
  Recent guidance emphasizes limited efficacy in patients with eGFR <60 mL/min/1.73 m².

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C (59°F–86°F).
• Humidity & Light: Store in a dry place away from direct light.
• Handling: Protect from excessive moisture.
• Reconstitution: Not applicable (oral tablets, not for injection or suspension).
• Container: Keep in original packaging until time of use.