Ertugliflozin
SGLT 2 inhibitor for type 2 diabetes
Ertugliflozin is an oral selective inhibitor of the sodium glucose cotransporter 2 (SGLT 2) developed by MSD and Pfizer. The EMA granted marketing authorisation in 2018 under the brand name Steglatro. Combination products are Segluromet (plus metformin) and Steglujan (plus sitagliptin). The substance is approved for treatment of type 2 diabetes in adults when diet and exercise together with other oral antidiabetics or insulin do not achieve adequate control.
Ertugliflozin belongs to the gliflozin class, which also includes empagliflozin, dapagliflozin and canagliflozin. The substance lowers blood glucose through an insulin independent mechanism in the kidney and additionally has mild blood pressure and weight lowering effects. The VERTIS CV cardiovascular outcome trial showed non inferiority to placebo for cardiovascular events, but no significant reduction of cardiovascular mortality as seen with empagliflozin or dapagliflozin. For these indications other gliflozins are preferred.
Mechanism of Action
In the proximal tubule of the kidney, most glomerularly filtered glucose is reabsorbed via the SGLT 2 cotransporter. In healthy adults this is about 180 grams per day. The SGLT 2 transporter is almost exclusively located in this region and works coupled to sodium. Ertugliflozin binds highly selectively and competitively to SGLT 2 and blocks glucose reabsorption.
The result is increased renal excretion of glucose. In trials, 50 to 70 grams of glucose per day are excreted, equating to 200 to 280 kcal. In parallel, sodium reabsorption is slightly reduced, producing an osmotic diuresis. This explains the blood pressure lowering effect of 3 to 5 mmHg systolic and the transient weight loss during the first weeks.
The mechanism is insulin independent, so hypoglycaemia is unlikely in monotherapy and loss of effect through β cell exhaustion does not occur. HbA1c reduction is 0.5 to 1 percentage point depending on dose and baseline. Effect diminishes in advancing renal impairment because less glucose is filtered.
Indications
- Type 2 diabetes in adults to improve glycaemic control
- Monotherapy in patients with metformin intolerance
- Combination with metformin as a dual combination
- Triple therapy with metformin plus DPP 4 inhibitor, sulfonylurea or insulin
- Combination with insulin to spare insulin and improve control
In patients with established cardiovascular disease, heart failure (HFrEF and HFpEF) or chronic kidney disease, other gliflozins such as empagliflozin or dapagliflozin are preferred over ertugliflozin because of documented endpoint reductions. Current guidelines of the European Society of Cardiology and the American Diabetes Association reflect this ranking.
Dosage and Administration
Standard dose: 5 mg once daily in the morning. If glycaemic control is inadequate after at least 3 months, increase to 15 mg once daily. Take with or without food, preferably at the same time of day. Swallow tablet whole.
Renal impairment: use is possible at eGFR 45 to 60 ml/min/1.73m². Initiation is not recommended when eGFR is below 45 ml/min. During ongoing therapy, if eGFR falls below 45 ml/min the glucose lowering effect decreases; continuation or discontinuation is decided individually.
Hepatic impairment: no dose adjustment in mild to moderate impairment; use in severe hepatic impairment is not recommended (limited data). Older patients: more frequent monitoring of volume status and renal function because of increased hypovolaemia risk.
Side Effects
Very common: genital mycoses in women and men, urinary tract infections.
Common: increased urinary frequency, volume depletion (in older patients or under diuretics), dyslipidaemia with slight LDL rise, pruritus, candidal balanitis, back pain, elevated haematocrit.
Uncommon to rare: diabetic ketoacidosis even at normal blood glucose values (euglycaemic DKA), acute kidney injury from hypovolaemia, Fournier gangrene (a rare but potentially life threatening necrotising fasciitis of the perineum), amputations (documented for canagliflozin; in VERTIS CV no significant signal for ertugliflozin).
Important: at signs of ketoacidosis (nausea, vomiting, abdominal pain, dyspnoea, hyperventilation, fatigue) seek immediate medical help and measure ketones in urine or capillary blood. Risk rises with reduced calorie intake, acute illness, surgery, excessive physical exertion and insulin dose reductions.
Interactions
- Diuretics (thiazides, loop diuretics): additive volume depletion, dose adjustment or monitoring
- Insulin and sulfonylureas: increased risk of hypoglycaemia, reduce insulin dose if necessary
- ACE inhibitors, angiotensin II receptor blockers, NSAIDs: additive risk of acute renal dysfunction during volume depletion
- UGT inducers (rifampicin, carbamazepine, phenytoin): reduced plasma levels and efficacy of ertugliflozin
- Oral contraceptives, digitalis glycosides, warfarin: no relevant interactions documented
Special Notes
Volume status: patients should ensure adequate fluid intake. In fever, diarrhoea, vomiting, heat or other states of high fluid loss, temporary interruption (sick day rule) is advised. This applies especially to older people, patients on diuretics and those with impaired renal function.
Perioperatively: pause 3 to 4 days before planned surgery to reduce the risk of euglycaemic ketoacidosis. Restart after surgery only once nutrition and hydration are stable.
Genital hygiene: counsel patients about increased risk of genital mycoses and advise early topical antifungal treatment at the onset of symptoms. In repeated infections a therapy change may be sensible.
Pregnancy: ertugliflozin is contraindicated. When pregnancy is planned, switch to safer antidiabetics such as insulin in good time. Breastfeeding: not recommended, data on passage into breast milk are lacking. Children and adolescents: no authorisation under the age of 18.
Monitoring: HbA1c every 3 months until the target is reached, then every 6 months. Renal function, volume status, blood pressure and LDL regularly. Patient education on ketoacidosis warning signs and the sick day rule.
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Frequently Asked Questions
Why is sugar simply excreted via urine?
Ertugliflozin blocks the SGLT 2 transporter in the kidney, which normally pumps glucose from urine back into blood. Without this transport, glucose remains in the urine and is excreted. Roughly 50 to 70 grams of sugar are lost via urine each day, contributing to lower blood glucose and reduced calorie intake.
Why do I get more fungal infections?
Increased glucose in urine promotes the growth of Candida and bacteria in the genital and urinary tract. Women are more often affected than men. Good hygiene, cotton underwear and early antifungal treatment keep the problem in check in most cases. Recurrent severe infections argue for a change of therapy.
What is euglycaemic ketoacidosis?
It is a metabolic derangement with acidic blood and ketone bodies that can occur under SGLT 2 inhibitors even at near normal glucose values. Typical triggers are fasting, alcohol, severe illness or insulin dose reductions. Warning signs are nausea, abdominal pain, rapid breathing and fatigue. Seek medical help immediately.
Should I stop the tablet before surgery?
Yes. Current recommendations are to pause SGLT 2 inhibitors 3 to 4 days before planned surgery to reduce the risk of euglycaemic ketoacidosis in the perioperative period. Resume once nutrition is stable and hydration is adequate, in consultation with your doctor.
Sources
- EMA, Steglatro (Ertugliflozin) EPAR
- AWMF, National Care Guideline Type 2 Diabetes
- Gelbe Liste, Ertugliflozin active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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