Dapagliflozin

The sodium glucose co-transporter (SGLT) is an active transport system for glucose resorption in the proximal convoluted tubule (PCT) of the nephrons within the kidney. SGLT2 is a high capacity, low affinity transporter located proximally in the PCT responsible for reabsorbing 90% of the glucose filtered into the urine while SGLT1, a high affinity, low capacity transporter positioned more distally in the PCT, reabsorbs the remaining 10% of glucose. SGLT inhibition offers a means of treating hyperglycaemia in diabetes. However, SGLT1 plays a key role in glucose absorption from the gut and thus SGLT1 inhibition could predispose to hypoglycaemia and osmotically induced diarrhoea. Thus the target became a selective SGLT2 inhibitor. Dapagliflozin became the first SGLT2 inhibitor licensed for use for type 2 diabetes (T2DM) in the UK in November 2012, followed by canagliflozin, empagliflozin and ertugliflozin. Subsequently, SGLT2 inhibitors have become firmly established as a central component of pharmacological management of T2DM and now cardio-renal disease. Dapagliflozin is approximately 1400 times more selective for SGLT2 than SGLT1. At a dose of 10mg once-daily dapagliflozin facilitates a loss of around 70g of glucose in the urine daily in people with T2DM (equivalent of 280kcal/day). The precise amount of glucose excreted from the kidney will vary depending on plasma glucose concentration and estimated glomerular filtration rate (eGFR). Dapagliflozin has an oral bioavailability approaching 80% of which approximately 90% is protein bound in the circulation. The principal route of metabolism is enzymatic conversion to the (inactive) glucuronide in the liver which is subsequently excreted in the urine. (Figure 1.) In healthy subjects dapagliflozin has an elimination half-life of 12.9 hours enabling once-daily dosing. A small amount of unchanged dapagliflozin (<2%) is excreted into the urine and it is this fraction that is responsible for binding to the SGLT2 site in the PCT and reducing glucose reabsorption. Dapagliflozin is effective in improving glycaemic control in T2DM either as monotherapy or in combination with other antidiabetic agents, generating HbA1c reductions of around 6–11mmol/mol (0.5–1.0%) with greater improvements seen in individuals with higher baseline HbA1c values. Use of dapagliflozin is associated with weight loss (variable, but typically around 2–3kg) and a small reduction in blood pressure (around 4/2mmHg). The dapagliflozin cardiovascular outcome trial in people with T2DM (DECLARE-TIMI 58) recruited a population in which two-thirds did not suffer from established cardiovascular disease (CVD), i.e. was predominantly a primary prevention cohort.1 The dual primary outcomes for this trial were major adverse cardiovascular events (MACE – a composite of CV death, non-fatal myocardial infarction and non-fatal stroke) and the composite outcome of CV death and hospitalisation for heart failure (HHF). While the trend towards a reduction in MACE did not reach significance versus placebo (hazard ratio [HR] 0.93, 95% CI 0.84–1.03; p=0.17), there was a significant reduction in the composite outcome of CV death and HHF (HR 0.83, 95% CI 0.73–0.95; p=0.005). The latter was largely driven by a 27% relative risk reduction (RRR) in HHF versus placebo. DAPA-HF was a double-blind randomised controlled trial in a population with heart failure with reduced ejection fraction (HFrEF) in individuals with (45%) or without (55%) T2DM.2 Compared to placebo, dapagliflozin demonstrated a significant reduction in the primary composite outcome of CV death and worsening heart failure (HR 0.74, 95% CI 0.65–0.85; p<0.001). These benefits occurred irrespective of diabetes status and baseline GFR. Crucially, participants were already receiving largely optimised treatment for heart failure – ACE-inhibitors or angiotensin receptor blockers, beta-blockers, mineralocorticoid receptor antagonists and diuretics. The DELIVER trial complemented DAPA-HF by finding that dapagliflozin achieved the same primary outcome versus placebo in a population with heart failure with moderately reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF), i.e. a population with left ventricular ejection fraction >40% (HRR 0.82, 95% CI 0.73–0.92; p<0.001).3 Again, improved outcomes occurred whether T2DM was present or not. DAPA-CKD was a double-blind randomised controlled trial comparing dapagliflozin 10mg once-daily against placebo with a composite primary renal outcome of a decline in eGFR of at least 50%, end-stage renal disease, and death from a renal or CV cause in individuals with albuminuria and a range of renal function down to an eGFR of 25ml/min/1.73m2.4 An impressive significant reduction in the primary outcome was found in favour of dapagliflozin (HR 0.61, 95% CI 0.51–0.72; p<0.001). These benefits were similar whether or not individuals had T2DM and whatever their baseline renal function. The glycosuria consequent upon use of dapagliflozin predisposes to genital fungal infection and to a lesser extent urinary tract infection. Increased frequency of micturition carries a risk of volume depletion and associated postural hypotension, notably in the elderly. In the situation of hypovolaemia arising from acute illness, dapagliflozin should be temporarily discontinued to reduce the risk of acute kidney injury and diabetic ketoacidosis (DKA). Systematic reviews confirm an increased risk of euglycaemic DKA with SGLT2 inhibitors with an absolute rate around three events per 1000 person-years. To minimise this risk dapagliflozin should be avoided or used with caution in situations of low endogenous insulin – type 1 diabetes, latent autoimmune diabetes of adults (LADA), and pancreatogenic diabetes. To mitigate the risk of lower limb amputation, avoid initiating dapagliflozin if there is active foot ulceration and consider stopping it if foot ulceration, osteomyelitis or gangrene arises. There is an association of SGLT2 inhibitors with Fournier's gangrene – a rare but potentially life threatening necrotising soft-tissue infection of the perineum. Dapagliflozin is a first-line option to add to metformin to improve glycaemic control in T2DM, especially if weight loss and avoidance of hypoglycaemia are priorities. Importantly, dapagliflozin is licensed to be used for all its indications down to an eGFR of 15ml/min/1.73m2, although its glucose-lowering potential falls off significantly below an eGFR of 45ml/min/1.73m2. National Institute for Health and Care Excellence (NICE) guidelines recommend that dapagliflozin can be offered to people with T2DM who have atherosclerotic heart disease (secondary prevention) or who are at high risk of developing this (primary prevention) – as defined by a QRISK CV score of >10% for the next 10 years. Based on the evidence of recent trials, dapagliflozin 10mg once-daily (or empagliflozin 10mg once-daily) is advised for all people with symptomatic chronic heart failure (with reduced or preserved ejection fraction) whether or not they have T2DM, as an add-on to standard care. Dapagliflozin is licensed for use in chronic kidney disease in people with T2DM alongside other therapies, such as ACE-inhibitors or angiotensin receptor blockers. NICE recommends offering dapagliflozin to people with albuminuria with and without T2DM.