Steglatro (Ertugliflozin) is an oral medicine belonging to the SGLT2 inhibitor class of medicine that has been developed by Merck and Pfizer. It is a highly selective SGLT2 inhibitor. It has 2000 times more selectivity for the SGLT2 receptors than the SGLT1 receptors and is used in the management of patients with Diabetes Mellitus Type 2 as monotherapy or in combination with other drugs. Steglatro (Ertugliflozin) has been studied in patients with diabetes and hypertension. A significant reduction in blood pressure was noted compared to the placebo. Compared to the blood pressure at night, day time reduction in the blood pressure was more significant without alteration in the plasma renin and aldosterone levels [Ref].

Steglatro and Januvia:

Ertugliflozin is also available in a fixed combination with sitagliptin by the name of Segluromet. The VERTIS-SITA trial demonstrated significant improvement in glycemic control with ertugliflozin and sitagliptin combination at 26 weeks [Ref]. In the VERTIS-SITA trial, an improvement in the pancreatic function as measured by the HOMA-β was also noted.

Steglatro and metformin plus sitagliptin:

Ertugliflozin was studied in the VERTIS SITA2 trial. In this study, ertugliflozin was added to background metformin and sitagliptin. After 52 weeks, a significant reduction in the HbA1C was noted compared to the placebo. At week 26, significant improvement was noted in the fasting blood glucose, systolic blood pressure, and weight compared to the placebo. These effects were sustained after 52 weeks [Ref]. Significant improvement in pancreatic Beta-cell function was also noted as measured by HOMA-β. This could be a result of an indirect effect of reduced glucotoxicity.

Steglatro (Ertugliflozin) vs Glimepiride (Amaryl) in patients with Diabetes:

The VERTIS SU trial compared the efficacy of ertugliflozin and glimepiride in patients on stable doses of metformin. The study concluded that ertugliflozin 15 mg was non-inferior to glimepiride in patients on stable doses of metformin. Patients in the ertugliflozin group had fewer hypoglycemic episodes and an acceptable safety profile. Ertugliflozin 5 mg also reduced the HbA1C but was inferior to glimepiride. Compared to sulfonylurea, there was a significant reduction in weight and blood pressure. The other novel SGLT2 inhibitors include Sergliflozin and remogliflozin.

Ertugliflozin (Steglatro) dose in Adults

Ertugliflozin (Steglatro) dose in Diabetes:

• 5 mg orally once a day initially.
• The dose may be increased to a maximum dose of 15 mg per day if the drug is being tolerated and blood sugars remain out of the target ranges.

Steglatro use in children:

It is not recommended for use in children with diabetes. Dapagliflozin has recently been approved in children with type 1 diabetes mellitus by the European Union.

Pregnancy Risk Category: C

• Animal studies have shown adverse outcomes for fetuses.
• If the drug is given in the second or third trimester, it may cause abnormal renal development.
• Uncontrolled hyperglycemia during pregnancy can be as dangerous as side effects of these medications.
• Pregnancy should not be interrupted by SGLT2 inhibitors.
• Pregnancy is best treated with insulin.

Use while breastfeeding

• Because the drug has not been tested in breastfeeding women, the manufacturer doesn't recommend it.
• It is unknown if the drug will be excreted into breastmilk.

Ertugliflozin dose in kidney disease:

• eGFR ≥60 mL/minute/1.73 m²:

  • Adjustment in the dose is not necessary.

• eGFR 30 to <60 mL/minute/1.73 m²:

  • Patietns who are using it may continue it if worseing in the renal impairment is not seen.
  • However, it should not be initiated in patients with preexisting renal impairment.

• eGFR <30 mL/minute/1.73 m²:

  • Avoid its use.

• ESRD or dialysis:

  • Avoid using it in ESRD and patients on hemodialysis.

Ertugliflozin dose in liver disease:

• Mild or moderate impairment (Child-Pugh class A or B):

  • Adjustment in the dose is not necessary.

• Severe impairment (Child-Pugh class C):

  • Avoid its use in severe hepatic impairment.

Common Side Effects of Ertugliflozin (Steglatro):

• Genitourinary:

  • Genitourinary fungal infection

Side Effects of Steglatro (less common):

• Central nervous system:

  • Headache

• Endocrine & metabolic:

  • Hypovolemia
  • Hypoglycemia
  • Increased thirst
  • Weight loss
  • Severe hypoglycemia

• Genitourinary:

  • Increased urine output
  • Vulvovaginal pruritus

• Neuromuscular & skeletal:

  • Back pain

• Renal:

  • Renal insufficiency

• Respiratory:

  • Nasopharyngitis

Uncommon side effects:

• Endocrine & metabolic:
  • Increased LDL cholesterol
  • Increased serum phosphate

• Genitourinary:

  • Decreased estimated GFR (eGFR)

• Renal:

  • Increased serum creatinine

Ertugliflozin (Steglatro) Contraindication:

• An occurrence of severe allergic reactions to any component of the drug.
• End-stage renal disease or severe kidney disease in patients on dialysis

Warnings and precautions

• Bone fractures

  • An increased number of bone fractures is being attributed to SGLT2 inhibitors. Most often, canagliflozin has been linked to an increased risk for bone fractures.

• Mycotic infections of the genital tract

  • This could increase the likelihood of fungal infections in the genitourinary system.
  • Patients most often develop vulvovaginal candidiasis and vulvovaginal mecotic infections, vulvovaginal vulvovaginitis or balanoposthitis.
  • Patients with genital problems in the past and uncircumscribed men are more at risk for fungal and bacterial infections.

• Hypotension

  • Hypotension may occur, especially for the following patients:
    • Patients with low volume
    • Patients with severe renal impairment
    • Senior citizens
    • Patients taking diuretics, ACE inhibitors or angiotensin receptor blocking medications may also be on antihypertensive medication.
    • Patients with low baseline blood pressure.
  • The patient's volume should be evaluated before starting therapy. Hypotension and hypovolemia should also be addressed.
• Ketoacidosis
  • It has been reported that ketoacidosis can occur with moderately high blood sugars. This is why the term euglycemic Ketoacidosis was used.
  • There are several patients at high risk for developing euglycemic Ketoacidosis.
    • Patients who are insulin insufficient
    • Patients who stop taking insulin
    • Alcohol
    • Strenuous exercise or hard work
    • Recent stroke, myocardial Infarction, Surgery, Severe Infection
    • Caloric restriction
  • The ADA recommends that SGLT2 inhibitors be withheld for 24 hours before events that could lead to ketoacidosis. Experts recommend that SGLT2 inhibitors be withheld for at most 3 - 5 working days.
  • Patients taking ertugliflozin should be evaluated for ketoacidosis if they experience nausea, abdominal pain or malaise. They can also be tested by urine/ serum ketones, and other biochemical tests.

• Lipid abnormality

  • It can cause an increase in LDL-cholesterol (C).
  • It should be monitored and treated accordingly.

• Amputation of the lower limb:

  • SGLT2 inhibitors have been linked to an increased risk for toe amputations.
  • Clinical trials showed that less than 0.5% of patients underwent non-traumatic lower-limb amputations.
  • To identify foot risk signs, patients should be evaluated.
    • Prior to amputation
    • Peripheral vascular disease
    • Neuropathy is a form of and
    • Diabetic foot ulcers.
  • It is important to counsel about the importance and benefits of preventative foot care.
  • If the patient experiences signs of infection, pain tenderness, ulcers or other symptoms, it is best to discontinue treatment.

• Necrotizing fasciitis

  • SGLT2 inhibitors have been linked to an increase in necrotizing fasciitis (Fournier gangrene)
  • This is a potentially life-threatening infection that has been reported in patients who have received SGLT2 inhibitors.
  • Fournier's Gangrene should be treated immediately if patients develop fever, redness and swelling in the perineum.
  • It should be stopped immediately and the appropriate treatment started.

• Effects on the renal system:

  • Acute kidney injury is possible in patients.
  • Hypovolemia, chronic renal failure, heart disease, and use of nephrotoxic drugs or agents that can cause dehydration are all risk factors for acute kidney damage.
  • Patients with low volume should temporarily stop taking the drug.
  • It is important to monitor the function of the renal system regularly.
• Infection of the urinary tract:
  • It has been associated with serious urinary infections, including urosepsis and pyelonephritis. These may need hospitalization.
  • If UTI symptoms develop, patients should be immediately assessed and treated.

• Hepatic impairment

  • It should not be used in severe hepatic impairment patients and should be avoided by advanced liver disease patients.

• Renal impairment

  • Examining the renal functioning is crucial before utilising them.
  • The glycemic efficacy of patients with compromised renal function may be decreased.
  • Patients with eGFR below 60 ml/min should not use it. It should also be avoided in patients with severe renal disease, ESRD and patients on dialysis.

Ertugliflozin: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitor:

• Blood glucose
• HbA1C is taken every 3 months in patients with uncontrolled diabetes, and once a year in patients with stable glucose control.
• Tests of renal function at baseline and as often as necessary.
• Volume status
• Blood pressure
• Hematocrit
• Electrolytes
• Phosphate
• LDL-C
• Genital infections (bacterial and fungal) and urinary tract infections
• Allergy reactions
• Examination of the lower limbs and feet for sores and ulcers.
• Ketoacidosis can be characterized by abdominal pain, nausea & poisoning, malaise and shortness in breath.
• Patients with ketoacidosis-related clinical features have high blood ketone, arterial pH, serum bicarbonate, or urinary ketone levels

How to administer Ertugliflozin?

It should be administered without regard to meals in the morning.

Mechanism of action of Ertugliflozin (Steglatro):

It prevents glucose reabsorption back into blood by blocking sodium-glucose transporter 2 (SGLT2) from the proximal renal tubes. More than 80% is absorbed in the proximal tubes. The excretion via urine of filtered glucose is increased by inhibition of SGLT2. Osmotic diuresis results in more glucose and less water. 93.6 % is the drug

Protein-bound It isMetabolized pIt is rimarily affected by UGT1A9-mediated O-glucuronidation of inactive metabolites. It exhibits a minimal CYP-mediated metabolism. It has been abioavailabilityAbout 100% Eliminating half-lifeThe average time of taking the drug is 16.6 hours When to reach plasma peak concentrationIt takes one hour to administer the drug in a fasting state, and two hours if it is administered with a high fat, high-calorie meal. 41% of the drug is excreted into the urine, while 50% is excreted through the feces (as an unchanged drug).

Ertugliflozin brand name (International):

• Steglatro