Switching hydrochlorothiazide to furosemide is the most appropriate next step in this patient. Uncontrolled hypertension in a patient who is already on three drugs, one of which is a diuretic, is defined as resistant hypertension. The approach to patients with resistant hypertension centers around lifestyle changes (particularly salt reduction and optimizing medication adherence) and choosing appropriate drug combinations. In patients with diabetic nephropathy and chronic kidney disease (CKD), ACE inhibitors or angiotensin receptor blockers should be used as an initial therapy given the established benefit of these agents in patients with diabetes mellitus and proteinuria. Most patients will require a second medication, and diuretic therapy is typically used in patients with CKD because persistent volume expansion contributes significantly to hypertension. Although thiazide diuretics are frequently used as initial therapy, they are generally less effective when the glomerular filtration rate drops below 30 mL/min/1.73 m². When this occurs, loop diuretics tend to be more effective and should be used instead of (or added to) thiazide diuretics. The dosage of loop diuretics depends on the sodium intake and the severity of CKD. Generally, furosemide doses of 40 to 80 mg once or twice daily is initiated with a salt-restricted diet and adjusted according to the response.

Adding a second inhibitor of the renin-angiotensin system such as aliskiren increases the risk of acute kidney injury and hyperkalemia without any benefit on renal and cardiovascular end points; therefore, combination therapy with renin-angiotensin inhibitors should not be used.

The centrally acting agent clonidine and the vasodilator minoxidil are potent antihypertensives sometimes used in cases of resistant hypertension if maximal doses of more conventional agents are unsuccessful. However, this patient is not currently on optimal triple therapy, and both agents also increase the risk of orthostatic hypotension in those with autonomic neuropathy, such as this patient. Moreover, the use of minoxidil without adequate diuresis will worsen salt and water retention and should be avoided.