Metolazone

Heart failure is a leading cause of morbidity and mortality in people with diabetes and is now one of the most common presentations of cardiovascular disease in people with diabetes. In the past 10 years there have been major advances in the management of heart failure, from evidence supporting new medications like sacubitril/valsartan to evidence supporting interventions ranging from device implantation, ablation for atrial fibrillation to revascularisation surgery. These advances in treatment have resulted in a positive shift and improvement in both life expectancy and quality of life, including a reduction in the burden of symptoms. With all these advances, diuretics remain a major cornerstone in treatment of heart failure. Some diuretics provide symptomatic relief, others can provide both symptomatic and prognostic benefit. Resistant oedema can be challenging to treat, especially in the context of advanced heart failure coexisting with other comorbidities like kidney disease and diabetes mellitus. Metolazone, alone or combined with loop diuretics, can provide a powerful diuretic effect for the reduction of heart failure symptoms but close monitoring of renal function and potassium level is required. Metolazone is a diuretic acting on the distal renal tubule. It is chemically distinct from thiazide diuretics but has a similar mode of action. Metolazone is less potent than loop diuretics when used alone, but combining loop diuretics with metolazone has a synergistic effect although at the expense of possible reductions in renal function. Loop diuretics deliver a greater fraction of filtered load of sodium to the distal convoluted tubule, the site of action of metolazone, thus potentiating its action. Metolazone is a long-acting quinazoline based thiazide-like diuretic. Metolazone acts on the distal convoluted tubule by inhibiting the sodium-chloride symporter, inhibiting the reabsorption of both sodium and chloride resulting in equivalent exertion of both which in turn enhance water excretion (Figure 1). An antihypertensive effect of metolazone is related to the excretion of salt and water. Increased sodium delivery to the distal tubule results in increased potassium excretion resulting in possible hypokalaemia, so close monitoring of renal function and serum potassium is important when using metolazone. Combining metolazone with frusemide can induce a profound diuresis which can result in volume and potassium depletion. Overall, metolazone probably causes a greater degree of potassium depletion than thiazide diuretics. Smaller doses of metolazone, e.g. 2.5–5mg, can be used in the treatment of hypertension while in congestive cardiac failure higher doses of up to 20mg can be used. For the safe introduction and use of metolazone in heart failure it is preferable to start patients on a low dose, preferably in a hospital setting, paired with close monitoring of renal function and electrolytes balance. The duration of effect of metolazone is 24 hours. In the United Kingdom, metolazone is now available in an unlicensed preparation after Sanofi-Aventis ceased to manufacture and distribute metolazone. Published clinical trials supporting the use of metolazone in heart failure are scarce. In an early small study, 17 patients with resistant congestive cardiac failure already treated with frusemide, captopril and digoxin were given metolazone with a dose varying from 1.25 up to 10mg daily. All responded with a brisk diuresis within 48–72 hours. In 1994, a randomised controlled trial examined the use of bendrofluazide and metolazone in combination with loop diuretics in the treatment of resistant heart failure.1 This study recruited 33 patients (40 episodes) admitted with congestive cardiac failure NYHA class III and IV resistant to intravenous loop diuretics after 48 hours. The outcome measures included daily weight, electrolytes changes and clinical heart failure improvement. Overall, both metolazone and bendrofluazide were equally effective in patients with resistant heart failure providing similar diuresis and weight loss effect. Moreover, a fixed three-day course of either combination was as equally effective as longer courses. A recent larger retrospective study examined 242 patient hospitalised with acute heart failure treated with diuretics.2 Three regimens were compared: continuous frusemide infusion, continuous bumetanide infusion and combination for frusemide and metolazone. All regimens increased urine output. The incidence of renal dysfunction was not different among the regimens; however, blood urea was higher in the frusemide/metolazone and bumetanide groups compared to frusemide. One of the advantages of metolazone is its efficacy as a diuretic even in subjects with reduced renal function; however, there are no robust clinical trials comparing metolazone with thiazide diuretics in subjects with renal impairment. There are no clinical trials of the efficacy of metolazone in people with diabetes. In 1974, the effect of metolazone on glycaemic control was examined in 20 patients using monitoring of blood glucose, and it was concluded that there was worsening of glycaemic control with metolazone.3 Advanced heart failure with resistant oedema can be challenging to treat. Diuretics are a major cornerstone in treating acute heart failure and having multiple treatment options tailored to different patients is valuable. Loop diuretics are the usual first-choice treatment in the acute phase. Mineralocorticoid receptor inhibitors like spironolactone and eplerenone provide both symptomatic and prognostic benefit. The addition of thiazide diuretics or metolazone can be useful in patients with resistant oedema not responding to standard treatment. When combined with loop diuretics, metolazone can induce a powerful diuresis and is efficacious even in the context of renal impairment. Initiation at a low dose with gradual up titration and close monitoring of renal function and serum potassium is essential due to the risk of renal impairment and hypokalaemia. There are no conflicts of interest declared.