Dapagliflozin

Dapagliflozin is a highly potent, selective and reversible inhibitor of the sodium-glucose co-transporter 2 (SGLT2), the transporter in the proximal tubule of the kidney that takes back most of the glucose filtered by the glomeruli. Blocking it makes the kidneys excrete glucose and sodium, which lowers blood glucose and also reduces the fluid and pressure load on the heart and kidneys. Its cardiac and renal effects are not limited to people with diabetes.

Mechanism of Action

• SGLT2 inhibition: dapagliflozin blocks SGLT2 (Ki 0.55 nM), which normally handles about 90% of renal glucose reabsorption. Less glucose and sodium are taken back from the glomerular filtrate, so glucose is lost in the urine and an osmotic diuresis follows.
• Glucose lowering: urinary glucose loss starts after the first dose, continues across the 24-hour dosing interval and is maintained for the duration of treatment. Fasting and post-prandial glucose both fall. The amount of glucose removed depends on the blood glucose level and on the glomerular filtration rate (GFR). In people with type 2 diabetes taking 5 or 10 mg daily for 12 weeks, about 70 g of glucose was lost in the urine per day, and the effect was close to maximal at 20 mg.
• Independent of insulin: dapagliflozin acts regardless of insulin secretion or insulin action. When blood glucose is normal it has a low tendency to cause hypoglycaemia, and it does not impair the body’s own glucose production in response to hypoglycaemia.
• Haemodynamic effects: reduced sodium reabsorption delivers more sodium to the distal tubule, which increases tubuloglomerular feedback and lowers the pressure inside the glomeruli. Together with the osmotic diuresis this reduces volume overload, blood pressure, preload and afterload. These changes may benefit cardiac remodelling and diastolic function and help preserve kidney function.
• Heart failure and kidney disease: the cardiac and renal benefits are not solely due to glucose lowering and are not restricted to patients with diabetes, as shown in the DAPA-HF, DELIVER and DAPA-CKD studies.
• Other effects: haematocrit rises and body weight falls. After treatment stops, urinary glucose excretion returns towards baseline in about 3 days on average (10 mg dose).
• Cardiac electrophysiology: no clinically meaningful QTc prolongation was seen in healthy volunteers at daily doses up to 150 mg or single doses up to 500 mg.

Pharmacokinetics

• Absorption: rapid and good; peak plasma concentration is usually reached within 2 hours when fasting. At steady state on 10 mg once daily, the geometric mean Cmax is 158 ng/mL and the AUC over the dosing interval is 628 ng·h/mL. Absolute oral bioavailability of a 10 mg dose is 78%. A high-fat meal lowers Cmax by up to 50% and delays Tmax by about 1 hour without changing AUC, which is not clinically meaningful, so the tablets can be taken with or without food.
• Distribution: about 91% bound to plasma proteins, unchanged in renal or hepatic impairment. Steady-state volume of distribution is 118 L.
• Metabolism: extensive, mainly to dapagliflozin 3-O-glucuronide, an inactive metabolite that does not contribute to glucose lowering. It is formed by UGT1A9 in the liver and kidney; CYP-mediated metabolism is a minor pathway.
• Elimination: mean terminal half-life 12.9 hours after a single 10 mg dose; mean total systemic clearance after an intravenous dose 207 mL/min. After a 50 mg radiolabelled dose, 96% was recovered: 75% in urine and 21% in faeces. Less than 2% of the dose is excreted unchanged in urine, and about 15% appears as unchanged drug in faeces.
• Linearity: exposure rises in proportion to dose from 0.1 to 500 mg, and the pharmacokinetics did not change over up to 24 weeks of daily dosing.
• Special populations: exposure is increased in severe hepatic impairment, which is why the starting dose is lower there. The glucose-lowering effect declines as GFR falls (see Administration and Dosage).

Dapagliflozin is authorised in the EU under the names Forxiga and Edistride, which carry the same indications and doses.

• Type 2 diabetes mellitus: adults and children aged 10 years and above with insufficiently controlled type 2 diabetes, as an adjunct to diet and exercise, either as monotherapy when metformin is considered inappropriate because of intolerance, or in addition to other medicinal products for type 2 diabetes.
• Heart failure: adults with symptomatic chronic heart failure.
• Chronic kidney disease: adults with chronic kidney disease.
• Fixed-dose combinations: dapagliflozin is also an ingredient of combination products with metformin (Xigduo, Ebymect) and with saxagliptin (Qtern). Their indications and doses are set out in their own SmPCs and are not covered on this page.

• Hypersensitivity to dapagliflozin or to any of the excipients.

Dapagliflozin must not be used to treat type 1 diabetes (see Special Instructions).

The most frequently reported reactions across the clinical studies were genital infections. More than 15,000 patients with type 2 diabetes have been treated, including 8,574 in a long-term cardiovascular outcomes study. The safety profile in heart failure (DAPA-HF, DELIVER) and in chronic kidney disease (DAPA-CKD) was consistent with this known profile, and none of the reactions was dose-related.

Very common (≥1/10): hypoglycaemia when used with a sulphonylurea or insulin.

Common (≥1/100 to <1/10): vulvovaginitis, balanitis and related genital infections, urinary tract infection, dizziness, rash, back pain, dysuria, polyuria (including frequent urination and increased urine output), increased haematocrit, decreased renal creatinine clearance during initial treatment, dyslipidaemia.

Uncommon (≥1/1,000 to <1/100): fungal infection, volume depletion (dehydration, hypovolaemia, hypotension), thirst, constipation, dry mouth, nocturia, vulvovaginal pruritus, genital pruritus, increased blood creatinine during initial treatment, increased blood urea, weight decrease.

Rare (≥1/10,000 to <1/1,000): diabetic ketoacidosis (when used in type 2 diabetes).

Very rare (<1/10,000): necrotising fasciitis of the perineum (Fournier’s gangrene), angioedema, tubulointerstitial nephritis.

Haematocrit values above 55% were recorded in 1.3% of patients on dapagliflozin 10 mg and 0.4% on placebo. Serious reactions to watch for are diabetic ketoacidosis, Fournier’s gangrene, severe urinary tract infection and volume depletion (see Special Instructions).

Dapagliflozin is cleared mainly by glucuronidation (UGT1A9) rather than by cytochrome P450 enzymes, so few pharmacokinetic interactions are expected. In vitro it did not inhibit or induce the main CYP enzymes tested.

• Diuretics (thiazide and loop diuretics): dapagliflozin may add to the diuretic effect and increase the risk of dehydration and low blood pressure.
• Insulin and insulin secretagogues (such as sulphonylureas): these cause hypoglycaemia, so a lower dose of insulin or of the secretagogue may be required when dapagliflozin is added in type 2 diabetes.
• Lithium: dapagliflozin may increase the renal excretion of lithium and lower blood lithium levels. Serum lithium should be monitored more often after dapagliflozin is started and after dose changes, and the patient should be referred to the doctor who prescribes the lithium.
• UGT1A9 inhibitors and inducers: mefenamic acid (a UGT1A9 inhibitor) raised dapagliflozin exposure by 55% and rifampicin lowered it by 22%, in neither case with a clinically meaningful change in 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect of other inducers (carbamazepine, phenytoin, phenobarbital) is not expected.
• Other medicines: metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan and simvastatin did not alter dapagliflozin exposure. Dapagliflozin did not change the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin or warfarin (nor the effect of warfarin on INR). With simvastatin, exposure rose by 19% (simvastatin) and 31% (simvastatin acid), which is not clinically relevant.
• 1,5-anhydroglucitol assay: results are unreliable in people taking SGLT2 inhibitors; other methods should be used to monitor glycaemic control.
• Alcohol: excessive or chronic alcohol intake and binge drinking should be avoided because they can predispose to ketoacidosis.
• Food: the tablets may be taken with or without food.
• Children: interaction studies have been done only in adults.

Dapagliflozin is taken by mouth once daily, at any time of day, with or without food. The tablets are swallowed whole. The dose is the same for type 2 diabetes, heart failure and chronic kidney disease.

Recommended Dose

• 10 mg once daily for type 2 diabetes mellitus, for heart failure and for chronic kidney disease.
• With insulin or an insulin secretagogue (such as a sulphonylurea): a lower dose of insulin or of the secretagogue may be considered to reduce the risk of hypoglycaemia.

Special Populations

• Renal impairment: no dose adjustment based on renal function. Starting treatment is not recommended when GFR is below 25 mL/min because of limited experience. In type 2 diabetes the glucose-lowering effect is reduced when GFR is below 45 mL/min and is likely absent in severe renal impairment, so additional glucose-lowering treatment should be considered if further control is needed.
• Hepatic impairment: no adjustment in mild or moderate impairment. In severe impairment, start with 5 mg; if well tolerated, the dose may be increased to 10 mg.
• Elderly (65 years and over): no dose adjustment based on age.
• Children: in type 2 diabetes no dose adjustment is needed from 10 years of age; there are no data below 10 years. Safety and efficacy in heart failure and chronic kidney disease below 18 years have not been established.

Missed Dose

A missed dose should be taken as soon as the patient remembers, provided this is within 12 hours of the missed dose. Otherwise the dose is skipped and the next one taken at the usual time. A double dose must not be taken on the same day.

Type 1 Diabetes and Diabetic Ketoacidosis

Dapagliflozin must not be used to treat type 1 diabetes; in type 1 diabetes studies, diabetic ketoacidosis (DKA) was reported commonly. Rare cases of DKA, some life-threatening or fatal, have been reported with SGLT2 inhibitors including dapagliflozin, and in a number of cases blood glucose was only moderately raised (below 14 mmol/L, or 250 mg/dL).

• Warning symptoms: nausea, vomiting, loss of appetite, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue or sleepiness call for immediate assessment for ketoacidosis, whatever the blood glucose. If DKA is suspected or diagnosed, dapagliflozin is stopped immediately.
• Surgery and acute illness: treatment is interrupted in patients hospitalised for major surgery or acute serious illness. Ketones are monitored, preferably in blood rather than urine, and treatment may restart when ketone values are normal and the patient is stable.
• Higher-risk patients: low beta-cell reserve (for example type 2 diabetes with low C-peptide, latent autoimmune diabetes in adults or a history of pancreatitis), restricted food intake or severe dehydration, reduced insulin doses, and increased insulin needs from acute illness, surgery or alcohol abuse. SGLT2 inhibitors are used with caution in these patients.
• Duration and restarting: ketoacidosis and glucosuria may last longer after stopping than the half-life suggests. Restarting after a DKA episode on an SGLT2 inhibitor is not recommended unless another clear precipitating factor is found and resolved.

Volume Depletion and Low Blood Pressure

The diuretic action can lower blood pressure modestly, more so when blood glucose is very high. Caution is needed in patients for whom a fall in blood pressure would be a risk, such as those on antihypertensive treatment with a history of hypotension, and in the elderly. During illness that may cause volume depletion (for example gastrointestinal illness), volume status is monitored by examination, blood pressure and laboratory tests including haematocrit and electrolytes, and dapagliflozin is interrupted until the depletion is corrected.

Kidney Function

Treatment is not started when GFR is below 25 mL/min. In one study in type 2 diabetes with moderate renal impairment (GFR below 60 mL/min), more patients on dapagliflozin than on placebo had increases in creatinine, phosphorus and parathyroid hormone, and hypotension.

Fournier’s Gangrene and Urinary Tract Infections

Cases of necrotising fasciitis of the perineum (Fournier’s gangrene) have been reported after marketing in women and men taking SGLT2 inhibitors. It is a serious, potentially life-threatening event that needs urgent surgery and antibiotics. 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 it is suspected, dapagliflozin is stopped and treatment started promptly. Urinary glucose excretion may increase the risk of urinary tract infection, so temporary interruption should be considered during treatment of pyelonephritis or urosepsis.

Hepatic Impairment and the Elderly

Experience in hepatic impairment is limited and exposure is higher in severe impairment. Elderly patients are at greater risk of volume depletion, are more often treated with diuretics, and more often have impaired kidney function or take ACE inhibitors or angiotensin II receptor blockers; the same renal recommendations apply as for all patients.

Heart Failure and Chronic Kidney Disease

Experience in NYHA class IV heart failure is limited, and patients with infiltrative cardiomyopathy have not been studied. There is no experience in chronic kidney disease in patients without diabetes who have no albuminuria; patients with albuminuria may benefit more from treatment.

Haematocrit, Foot Care and Urine Tests

• Increased haematocrit: patients with pronounced elevations should be monitored and investigated for underlying haematological disease.
• Lower limb amputations: more amputations (mainly of the toe) were seen in long-term studies of SGLT2 inhibitors in type 2 diabetes; it is unknown whether this is a class effect. Patients with diabetes should be counselled on routine preventive foot care.
• Urine tests: patients taking dapagliflozin will test positive for glucose in urine.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women. Studies in rats showed toxicity to the developing kidney during a period corresponding to the second and third trimesters, so use is not recommended in the second and third trimesters. When pregnancy is detected, dapagliflozin is discontinued.
• Breastfeeding: it is unknown whether dapagliflozin passes into human milk; animal data show excretion in milk and effects in nursing offspring. A risk to the newborn or infant cannot be excluded, so it should not be used while breastfeeding.
• Fertility: the effect on human fertility has not been studied. In male and female rats there was no effect on fertility at any dose tested.

Lactose

The tablets contain lactose (25 mg in the 5 mg tablet, 50 mg in the 10 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. A nationally authorised generic in Spain (Daforbis) contains 23.75 mg and 47.5 mg of lactose respectively.

Effect on Driving

Dapagliflozin 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 a sulphonylurea or insulin, and to dizziness as a possible reaction.

Edistride tablets, which are identical in strength and appearance to Forxiga tablets, need no special storage conditions. They are supplied in aluminium blisters (14, 28 and 98 tablets in calendar blisters; 30 x 1 and 90 x 1 in perforated unit-dose blisters; not all pack sizes may be marketed). Keep out of the sight and reach of children.

3 years. A nationally authorised generic in Spain (Daforbis) has a shelf life of 4 years and also needs no special storage conditions. Do not use after the expiry date on the pack.

Prescription only (Rx). Dapagliflozin is taken as tablets at home, so it is supplied to the patient or to the treating clinic on prescription.