Ertugliflozin

Ertugliflozin is a potent, selective and reversible inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the main transporter that returns glucose from the filtered fluid in the kidney to the circulation. Blocking it makes the kidney pass more glucose in the urine, which lowers blood glucose in type 2 diabetes.

Mechanism of Action

• SGLT2 inhibition: SGLT2 in the proximal tubule of the nephron reabsorbs most of the filtered glucose (80–90% according to DrugBank). Ertugliflozin blocks it, which lowers the renal threshold for glucose and increases urinary glucose excretion.
• Dose-dependent effect: urinary glucose excretion and urine volume rise with the dose. In patients with type 2 diabetes, 5 mg and 15 mg produce 87% and 96% of the maximal inhibition of urinary glucose excretion.
• Osmotic diuresis: the glucose in the urine carries water with it, which can reduce intravascular volume and cause a small early rise in serum creatinine with a fall in eGFR.
• Dependence on kidney function: the glucose-lowering effect is reduced in moderate renal impairment and likely absent in severe renal impairment.
• Urine glucose tests: patients test positive for glucose in the urine while taking ertugliflozin.

Pharmacokinetics

• Absorption: the median time to peak plasma concentration is about 1 hour when fasted, and absolute oral bioavailability is about 100% (15 mg dose). Cmax and AUC rise in proportion to the dose. A high-fat, high-calorie meal lowers Cmax by 29% and delays the peak by 1 hour without changing AUC, so the tablet can be taken with or without food. Steady state is reached after 4 to 6 days of once-daily dosing, with 10–40% accumulation. Ertugliflozin is a substrate of P-glycoprotein and breast cancer resistance protein.
• Distribution: the mean steady-state volume of distribution is about 86 L after an intravenous dose. About 93.6% is bound to plasma proteins, independent of concentration and not meaningfully changed by renal or hepatic impairment. The blood-to-plasma concentration ratio is 0.66.
• Metabolism: the main route is O-glucuronidation by UGT1A9 and UGT2B7 to two glucuronides that are pharmacologically inactive at clinically relevant concentrations. A smaller share (about 12% according to DrugBank) is oxidised by CYP enzymes.
• Elimination: the mean elimination half-life is about 16.6 hours in patients with type 2 diabetes and normal kidney function (population estimate). After a radiolabelled dose about 50% of the radioactivity was recovered in urine and about 41% in faeces; only 1.5% of the dose was excreted unchanged in urine.
• Special populations: dose recommendations for kidney and liver impairment and for older patients are given under Administration and Dosage; see the SmPC for the pharmacokinetic data in these groups.

Ertugliflozin is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus, as an adjunct to diet and exercise:

• As monotherapy when metformin is considered inappropriate because of intolerance or contraindications.
• In addition to other medicinal products for the treatment of diabetes.

Ertugliflozin is also an ingredient of two fixed-dose combinations, with metformin (Segluromet) and with sitagliptin (Steglujan), which are covered on their own product pages.

• Hypersensitivity to ertugliflozin or to any of the excipients (listed under Composition).

The safety of ertugliflozin was assessed in 7 placebo- or active comparator-controlled studies with 3,409 patients treated with 5 mg or 15 mg, and in the VERTIS CV cardiovascular outcomes study (5,493 patients treated, mean exposure 2.9 years). The most commonly reported side effects were urinary tract infections and vulvovaginal and other female genital mycotic infections. Serious diabetic ketoacidosis occurred rarely.

Very common (≥1/10): urinary tract infections; vulvovaginal mycotic infection and other female genital mycotic infections.

Common (≥1/100 to <1/10): balanitis candida and other male genital mycotic infections; hypoglycaemia; volume depletion; increased urination (frequent or urgent urination, polyuria, increased urine output, nocturia); vulvovaginal pruritus; thirst (including polydipsia); altered serum lipids; increased haemoglobin; increased blood urea nitrogen.

Uncommon (≥1/1,000 to <1/100): dysuria; increased blood creatinine or decreased glomerular filtration rate.

Rare (≥1/10,000 to <1/1,000): diabetic ketoacidosis.

Not known: necrotising fasciitis of the perineum (Fournier’s gangrene) and rash, both identified after marketing.

Details from the SmPC:

• Genital mycotic infections: in the pooled placebo-controlled trials they occurred in 9.1% (5 mg) and 12% (15 mg) of women versus 3% on placebo, and in 3.7% and 4.2% of men versus 0.4%, more often in uncircumcised men.
• Urinary tract infections: in VERTIS CV, 12.2% (5 mg), 12% (15 mg) and 10.2% (placebo) of patients; serious infections were 0.9%, 0.4% and 0.8%.
• Hypoglycaemia: documented hypoglycaemia occurred in 5% (5 mg) and 4.5% (15 mg) versus 2.9% on placebo in the placebo-controlled pool. It matters mainly when ertugliflozin is added to insulin or a sulfonylurea.
• Volume depletion: below 2% and not notably different from placebo in the placebo-controlled pool, but more frequent in patients with an eGFR below 60 mL/min/1.73 m², patients aged 65 or over and patients taking diuretics.
• Diabetic ketoacidosis: identified in 0.3% of ertugliflozin-treated patients versus 0.1% on placebo in VERTIS CV.
• Kidney function: serum creatinine rises and eGFR falls early in treatment, usually transiently; the changes are larger in moderate renal impairment and reverse after treatment stops.

Serious reactions to watch for are diabetic ketoacidosis (which can occur with only moderately raised blood glucose), necrotising fasciitis of the perineum, volume depletion with low blood pressure, and urinary tract infections, during which treatment may need to be interrupted if pyelonephritis or urosepsis develops (see Special Instructions).

• Diuretics: ertugliflozin may add to their diuretic effect and increase the risk of dehydration and hypotension.
• Insulin and insulin secretagogues: insulin and secretagogues such as sulfonylureas cause hypoglycaemia, and ertugliflozin may increase that risk. A lower dose of the insulin or secretagogue may be required.
• Rifampicin and other enzyme inducers: multiple doses of rifampicin (an inducer of UGT and CYP enzymes) lowered ertugliflozin AUC by 39% and Cmax by 15%. This is not considered clinically relevant and no dose adjustment is recommended. A clinically relevant effect of other inducers (carbamazepine, phenytoin, phenobarbital) is not expected.
• UGT inhibitors: not studied clinically; a possible rise in ertugliflozin exposure is not considered clinically relevant.
• Other glucose-lowering medicines and simvastatin: single-dose studies in healthy volunteers suggest that sitagliptin, metformin, glimepiride and simvastatin do not alter ertugliflozin pharmacokinetics, and that ertugliflozin has no clinically relevant effect on sitagliptin, metformin or glimepiride. Ertugliflozin raised simvastatin AUC by 24% and simvastatin acid AUC by 30%, which is not considered clinically meaningful.
• Alcohol: excessive or chronic alcohol use may increase the risk of ketoacidosis.
• Food: the tablet can be taken with or without food.

Before starting, the prescriber assesses kidney function and volume status and corrects any volume depletion. The tablet is taken by mouth once daily in the morning, with or without food. If swallowing is difficult, the tablet may be broken or crushed because it is an immediate-release form.

Recommended Dose

• Starting dose: 5 mg once daily.
• Increase: in patients who tolerate 5 mg, the dose can be raised to 15 mg once daily if additional glycaemic control is needed.
• With insulin or an insulin secretagogue: a lower dose of the insulin or secretagogue may be required to reduce the risk of hypoglycaemia.

Renal Impairment

• Kidney function is assessed before starting and periodically thereafter.
• Treatment should not be started if eGFR is below 45 mL/min/1.73 m² or creatinine clearance is below 45 mL/min.
• With an eGFR of 45 to below 60 mL/min/1.73 m², start at 5 mg and increase to 15 mg as needed for glycaemic control.
• The glucose-lowering effect is reduced in moderate renal impairment and likely absent in severe impairment, so other glucose-lowering medicines should be considered if more control is needed.
• Stop treatment when eGFR is persistently below 30 mL/min/1.73 m² or creatinine clearance is persistently below 30 mL/min.
• Do not use in severe renal impairment, end-stage renal disease or dialysis, as there are no clinical data supporting effectiveness.

Other Special Populations

• Hepatic impairment: no dose adjustment in mild or moderate impairment. Not studied and not recommended in severe impairment.
• Elderly: no dose adjustment based on age; kidney function and the risk of volume depletion should be taken into account.
• Children and adolescents: safety and efficacy under 18 years have not been established; no data are available.

Missed Dose

Take it as soon as it is remembered. Never take two doses on the same day.

Type 1 Diabetes and Diabetic Ketoacidosis

Ertugliflozin must not be used in type 1 diabetes, where it may increase the risk of diabetic ketoacidosis (DKA).

• Rare cases of DKA, including life-threatening and fatal ones, have been reported with SGLT2 inhibitors. Some presented atypically, with blood glucose only moderately raised (below 14 mmol/L, 250 mg/dL).
• Consider DKA with non-specific symptoms such as nausea, vomiting, loss of appetite, abdominal pain, excessive thirst, difficulty breathing, confusion, or unusual tiredness or sleepiness, and assess for ketoacidosis at once whatever the blood glucose. If DKA is suspected or diagnosed, stop ertugliflozin immediately.
• Interrupt treatment in patients hospitalised for major surgery or acute serious illness and monitor ketones (blood ketones are preferred). Restart when ketone values are normal and the patient has stabilised.
• Higher-risk patients include those with low beta-cell reserve (low C-peptide, latent autoimmune diabetes in adults or a history of pancreatitis), restricted food intake or severe dehydration, reduced insulin doses, or increased insulin needs from acute illness, surgery or alcohol abuse. SGLT2 inhibitors should be used with caution in them.
• Restarting an SGLT2 inhibitor after DKA on an SGLT2 inhibitor is not recommended unless another clear precipitating factor has been identified and resolved.

Volume Depletion and Low Blood Pressure

Ertugliflozin causes an osmotic diuresis, so symptomatic hypotension may occur after starting, particularly in patients with an eGFR below 60 mL/min/1.73 m², patients aged 65 or over, patients on diuretics and patients on antihypertensive therapy with a history of hypotension. Assess and correct volume status before starting and monitor afterwards. In illness that causes fluid loss (for example gastrointestinal illness), monitor volume status and electrolytes and consider a temporary interruption until the fluid loss is corrected.

Kidney Function

Monitor kidney function before starting and periodically afterwards, and more often if eGFR is below 60 mL/min/1.73 m² or creatinine clearance is below 60 mL/min. Ertugliflozin raises serum creatinine and lowers eGFR, more so in moderate renal impairment.

Genital and Urinary Tract Infections

• Genital mycotic infections: patients with a history of such infections and uncircumcised men were more likely to develop them. Monitor and treat appropriately.
• Urinary tract infections: urinary glucose excretion may increase the risk. Consider a temporary interruption of ertugliflozin while pyelonephritis or urosepsis is treated.

Necrotising Fasciitis of the Perineum (Fournier’s Gangrene)

Rare but serious and potentially life-threatening cases have been reported after marketing in women and men taking SGLT2 inhibitors; urgent surgery and antibiotics are needed. Patients should seek medical attention for pain, tenderness, redness or swelling in the genital or perineal area together with fever or malaise. A urogenital infection or perineal abscess may come first. If Fournier’s gangrene is suspected, stop ertugliflozin and start prompt treatment, including antibiotics and surgical debridement.

Lower Limb Amputations

In VERTIS CV, non-traumatic lower limb amputations, mainly of the toe, occurred in 2% (5 mg), 2.1% (15 mg) and 1.6% (placebo) of patients. More cases have been seen in long-term studies of SGLT2 inhibitors, and it is not known whether this is a class effect. Patients with diabetes should be counselled on routine preventive foot care.

Elderly Patients

Patients aged 65 or over are at higher risk of volume depletion and renal impairment and had more volume-depletion reactions. In VERTIS CV safety and efficacy were similar in patients aged 65 or over and in younger ones.

Heart Failure, Urine Tests and Laboratory Monitoring

• There is no clinical study experience with ertugliflozin in New York Heart Association class IV heart failure.
• Urine glucose tests are positive during treatment, so other methods should be used to monitor glycaemic control.
• The 1,5-anhydroglucitol assay is unreliable for assessing glycaemic control in patients taking SGLT2 inhibitors and is not recommended.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: data are limited. Animal studies show that ertugliflozin may affect renal development and maturation, so it should not be used during pregnancy.
• Breastfeeding: nothing is known about excretion in human milk. Ertugliflozin is present in rat milk and affected the offspring. Human kidney maturation occurs in utero and during the first 2 years of life, so a risk to newborns and infants cannot be excluded. It should not be used during breastfeeding.
• Fertility: the effect on human fertility has not been studied. No effects on fertility were seen in animals.

Lactose and Sodium

The tablets contain lactose monohydrate (28 mg in the 5 mg tablet, 85 mg in the 15 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Ertugliflozin has no or negligible influence on the ability to drive and use machines. Patients should be alerted to the risk of hypoglycaemia when it is combined with insulin or an insulin secretagogue, and to volume-depletion effects such as dizziness on standing.

Steglatro needs no special storage conditions. The tablets are supplied in aluminium/PVC/PA/aluminium blisters (packs of 14, 28, 30, 84, 90 or 98 tablets, or 30 x 1 in perforated unit-dose blisters; not all pack sizes may be marketed). Keep out of the sight and reach of children.

2 years. Do not use after the expiry date on the packaging.

Prescription only (Rx): a medicinal product subject to medical prescription. Ertugliflozin is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.