The purpose of this study is to determine whether the routine combination of optimal thiazide and K+-sparing diuretic will both increase efficacy of BP reduction and reduce risk of glucose intolerance; and whether K+-sparing diuretics alone may have a neutral or even beneficial effect upon glucose tolerance.

A major attraction of K+-sparing diuretics may be the absence of risk of new-onset diabetes (DM). Since they have not been compared in hypertension outcome trials, and DM has not been an endpoint in heart failure studies of spironolactone or eplerenone, we do not know for certain whether they are clean in this respect. Short-term studies suggest they are.49 Interestingly in INSIGHT there was no excess of DM in patients receiving HCTZ 25mg, which was combined with amiloride 2.5mg, but increased by 30% in patients on HCTZ/amiloride 50/5mg.44 In the proposed study we shall use the oral glucose tolerance test (OGTT) to provide an endpoint for each subject. This strategy has recently been employed to demonstrate a difference after just 12 weeks of dosing with a thiazide diuretic50. Hyperkalaemia has been the traditional concern about K+-sparing diuretics. We expect to demonstrate that in patients with eGFR ≥45, the risk of hyperkalaemia is nullified by combination with a thiazide. Instead then of amiloride being used mainly in trace doses to balance the hypokalaemia of thiazides, practice might reverse to thinking of thaizides as the "partner" used to negate risk of hyperkalaemia.

The challenge to designing this study is to compare several options among the diuretics while achieving clear cut answers to:

1. the comparison of combination with single diuretics and
2. the comparison of K+-sparing diuretics with thiazide.

A study of sufficient duration to establish efficacy and tolerability (especially upon glucose tolerance) cannot be crossover in design and therefore requires a large number of subjects to compare the options. In order to maximize recruitment whilst also maximizing sensitivity to detect changes in OGTT, we will open the trial to most of those patients with hypertension in whom diuretic is a reasonable next option, providing they have one feature of the metabolic syndrome - additional to hypertension.

Inclusion Criteria;

Patients can proceed to placebo run-in if biochemical data available from previous 6 months, but cannot proceed to randomised treatment if eligibility not confirmed by baseline sample:

1. Age 18-80

2. Diagnosis of hypertension according to BHS criteria

3. Systolic BP on permitted background treatment ≥ 140 mmHg and home BP ≥ 130mmHg. Patients may be included if the PI anticipates BP criteria for inclusion will be met at randomisation

4. Indication for diuretic treatment:

   • Untreated + (age>55 AND/OR Black AND/OR renin<12mU/L)
   • receiving one or any permutation of the following: *ACEi, ARB, β-blocker, CCB, direct renin inhibitor

5. At least one other component (i.e. additional to hypertension) of the metabolic syndrome (reduced HDL, raised triglycerides, glucose, waist circumference)* * Definition of Metabolic Syndrome according to the International Diabetes Federation, 2006: Central obesity (waist circumference > 94cm male (>90 if Asian), > 80 female plus two of:

   • SBP ≥ 130 or DBP ≥ 85 mmHg
   • Fasting glucose >5.6mmol/l
   • Fasting Triglycerides > 1.7 mmol/l (or on rx)
   • HDL < 1.03 mmol/l males, < 1.29 mmol/l females (or on rx)

Exclusion Criteria:

1. Diabetes (types 1 or 2)

2. Secondary hypertension

3. eGFR < 45 mls/min

4. Plasma K+ outside normal range on two successive measurements during screening

5. Clinic SBP >200 mmHg or DBP >120mmHg, with PI discretion to override if home BP's lower

6. Requirement for diuretic therapy (other than for hypertension)

7. Absolute contra-indications to any of the study drugs

8. Current therapy for cancer

9. Anticipation of change in medical status planned surgical intervention requiring >2 weeks convalescence, actual or planned pregnancy)

10. Inability to give informed consent

11. Not on stable doses of all hypertensive medications to be continued throughout the study for a minimum of 4 weeks prior to randomisation, or not normally less than 2 weeks if early randomisation is required at the discretion of the PI.

12. Participation in a clinical study involving an investigational drug/device within 4 weeks of screening.

13. Any concomitant condition that may adversely affect the safety and/or efficacy of the study drug or severely limit the subject's lifespan or ability to complete the study

14. Treatment with any of the following prohibited medications:

    • Oral corticosteroids within 3 months of Screening and prohibited during study participation.
    • Chronic stable or unstable use of non-steroidal anti-inflammatory drugs other than acetylsalicylic acid is prohibited. Chronic use is defined as >3 consecutive or nonconsecutive days of treatment per week. intermittent use of NSAIDs is strongly discouraged throughout the duration of this study. If intermittent treatment is required, NSAIDs must not be used for more than a total of 2 days. For all subjects requiring analgesic or anti-pyretic agents, the use of paracetamol is recommended during study participation.
    • The use of short-acting oral nitrates (eg, sublingual nitroglycerin) is permitted; however, subjects should not take short-acting oral nitrates within 4 hours of Screening or any subsequent study visit.
    • The use of long-acting oral nitrates is permitted; however, the dose must be stable for at least 2 weeks prior to screening/ randomisation.
    • Use of sympathomimetic decongestants is permitted; but, not within 1 week prior to screening or randomisation. or within 1 day prior to study visits;
    • The use of theophylline is permitted; however, the dose must be stable for at least 4 weeks prior to Screening and throughout study participation.
    • The use of phosphodiesterase (PDE) type V inhibitors is permitted; however, subjects must refrain from taking these medications within 1 day of Screening or any subsequent study visit.