PATHWAY-3: Comparison of single and combination diuretics in low-renin hypertension

Although thiazide diuretics are widely used for treatment of hypertension, and their efficacy well documented, hypokalaemia and impaired glucose tolerance are well recognised complications. Although the exact mechanism underlying the increase in blood glucose in patients receiving thiazides is uncertain, low potassium is felt to be a likely culprit.

pathway 3 hypothesis

The above figure is from a systematic review, and shows that the decrease in potassium due to treatment with thiazides, is associated with an increase in blood glucose. PATHWAY-3 is designed to determine whether a K+-sparing diuretic improves glucose tolerance in patients with hypertension, and to ascertain whether combining diuretics is associated with improved efficacy and tolerability, compared to one class of diuretic alone.

pathway 3 protocol

The protocol for PATHWAY-3 is shown above. Patients will be recruited if they have:

  • blood pressure over target
  • an indication for a diuretic
    • untreated (age>55, black ethnicity, low renin)
    • monotherapy with ACE inhibitor or angiotensin receptor blocker (ARB)
    • monotherpay with a calcium channel blocker (CCB)
    • dual therapy with ACEi/ARB + CCB
  • an additional component of metabolic syndrome (i.e. in addition to hypertension):
    • Central obesity
    • Fasting glucose >5.6mmol/L
    • Fasting triglycerides >1.7mmol/L
    • Low HDL

Patients will be randomised to three arms: a thiazide diuretic (hydrochlorothiazide), a potassium sparing diuretic (amiloride), or a combination of the two. The dose will be increased after 3 months, and BP and biochemical measures (including an oral glucose tolerance test) will be carried out at the start and end of the 6 month treatment period.

British Heart Foundation British Hypertension Society