Spironolactone is a mineralocorticoid receptor antagonist (MRA) and potassium-sparing diuretic used in the management of hypertension, primary hyperaldosteronism, heart failure and ascites. It has anti-androgenic properties and is used off label for acne vulgaris, hirsutism and female pattern hair loss. Figure 1 outlines the pharmacological actions of spironolactone. It is a non- selective antagonist at mineralocorticoid nuclear receptors in the cells of the distal tubule of the nephron. This reduces the production of aldosterone-induced proteins that through several mechanisms, including blocking potassium exchange transporters, promotes excretion of sodium and water with potassium retention. Spironolactone also has a weak antagonist effect at androgen and progesterone receptors, with unwanted side effects of gynaecomastia and sexual dysfunction limiting its use. Spironolactone has good bioavailability reaching peak plasma concentration at 2–3 hours. It is rapidly metabolised in the liver and its metabolites are excreted in urine and bile. Hyperkalaemia is a common and important adverse effect requiring careful monitoring of potassium, particularly in elderly patients and those with renal impairment. The RALES trial (Randomized Aldactone Evaluation Study) was a double-blind, placebo-controlled, randomised trial in 1663 patients with moderate to severe heart failure with reduced ejection fraction (HFrEF) terminated early at 24 months. Compared to placebo, treatment with 25mg spironolactone was associated with a 35% reduction in the risk of hospitalisation (relative risk [RR] 0.65; 95% CI 0.54–0.77; p<0.001) and 30% reduction in risk of death from cardiac causes, a combination of heart failure and sudden cardiac death (RR 0.70; 95% CI 0.60–0.82; p<0.001).1 There was a low incidence of serious hyperkalaemia (2% in the spironolactone group compared to 1% in the placebo group). Ten percent of participants reported gynaecomastia and breast pain. Its effects are thought to be mediated by a reduction in fibrosis and improvement in left ventricular function. The TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) was a randomised, double-blind trial comparing 15–45mg spironolactone with placebo in 3445 patients with heart failure with preserved ejection fraction (HFpEF).2 With a mean follow up of 3.3 years, there was no difference in the primary outcome, a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalisation for the management of heart failure (hazard ratio [HR] 0.89; 95% CI 0.77–1.04; p=0.14). Hospitalisation for heart failure was less in the treatment group (206 patients [12.0%] vs 245 patients [14.2%]; HR 0.83; 95% CI 0.69–0.99; p=0.04). Subsequent analysis of the TOPCAT data has been done to try and identify patients within a heterogenous group who may respond.3 The PATHWAY-2 study (Prevention And Treatment of Hypertension With Algorithm-based therapy) was a double-blind, crossover, placebo-controlled trial which compared the effectiveness of spironolactone in resistant hypertension testing the hypothesis that it is often caused by excessive sodium retention.4 Patients rotated through 12 weeks of once-daily treatment with each of spironolactone (25–50mg), bisoprolol (5–10mg), doxazosin modified release (4–8mg), and placebo, in addition to their baseline blood pressure drugs. Spironolactone was better at lowering blood pressure compared to doxazosin (-4.03mmHg [-5.04 to -3.02]; p<0.0001) and bisoprolol (-4.48mmHg [-5.50 to -3.46]; p<0.0001). These positive results support previous non-placebo-controlled evidence in the ASCOT-BPLA study where spironolactone was added as a fourth-line agent.5 In PATHWAY-2 spironolactone was well tolerated and only 2% of patients experienced hyperkalaemia. There was no significant renal impairment or gynaecomastia when compared to placebo. For the studies with positive primary outcomes, people with diabetes were included (25% of RALES study population and 14% in PATHWAY-2) and the use of spironolactone in HFrEF and resistant hypertension should be considered. Patients with hypertension and diabetes have higher aldosterone concentrations than those with hypertension alone, and the deleterious effect of aldosterone on the vascular endothelium and cardiac function suggests a role for spironolactone in the management of hypertension in this group. This is being investigated in the ESCAM trial (Effect of spironolactone on cardiovascular morbidity and mortality in patients with hypertension and glucose metabolism disorders).6 At the time of writing, this large trial is due to finish at the end of 2023. There has also been interest in the use of spironolactone in diabetic kidney disease (DKD). A meta-analysis of 16 studies in patients with DKD found that the addition of spironolactone resulted in significant reductions in urinary albumin excretion.7 However, the emergence of finerenone, a more selective MRA, may limit the use of spironolactone for this indication. Spironolactone has proven efficacy in reducing morbidity and mortality in moderate to severe heart failure with reduced ejection fraction, including people with diabetes. Its role in patients with HFpEF with or without diabetes is less clear. It should be considered for the management of anyone with resistant hypertension. While an ongoing study is investigating whether spironolactone has cardiovascular benefit in those with diabetes and hypertension, it is unlikely to be used widely in slowing the progression of DKD given the emergence of the more selective and novel MRA finerenone, which has recently been approved for this indication and has fewer side effects.
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.
