Trial sparks debate over treatment of diabetic hypertensives

A major new international study published in the Journal of Hypertension has challenged traditional thinking by revealing that the thiazide-like diuretic indapamide SR (Natrilix SR) has equivalent efficacy to enalapril in reducing microalbuminuria (MA) in patients with type 2 diabetes.

The NESTOR (Natrilix SR versus Enalapril Study in Type 2 diabetic hypertensives with micrOalbuminuRia) study is the first randomised study over one year in duration to prove the efficacy of a diuretic on MA, and establishes indapamide SR as the first diuretic to show efficacy in MA reduction.

The implications of NESTOR for UK practice are potentially very significant. MA is an established risk factor in diabetic patients, but its importance, according to leading diabetologist Professor Anthony Barnett, Professor of Medicine at the University of Birmingham, may be underrated.

‘There is increasing evidence to show that microalbuminuria is a sensitive marker of organ damage, and its importance as a renal and cardiovascular risk factor is often under-recognised,’ he commented.

Current guidelines recommend first-line use of an ACE inhibitor or, if contraindicated, an angiotensin II receptor blocker (ARB) in patients with type 2 diabetes and MA. The NESTOR authors, however, believe that their findings are ‘consistent with the use of indapamide SR as first-line therapy in hypertensive type 2 diabetic patients.’

NESTOR is a multinational randomised trial involving 570 patients with essential hypertension, type 2 diabetes and MA, who were randomised to receive either enalapril 10mg or indapamide SR 1.5mg once daily. After one year, there was a significant and equivalent reduction in MA in both the indapamide SR (35%) and enalapril (39%) groups. However, SBP reduction in the indapamide group (-23.8 mmHg) was significantly greater than in the enalapril group (-21.0 mmHg). No significant difference occurred in DBP reduction (-13.0 vs -12.1 mmHg). 24-Hour ambulatory blood pressure measurement (24-h ABPM) in a subgroup of 99 patients showed a non-significant mean arterial pressure (MAP) difference of only -0.63 mmHg between treatments over the 24-hour period.

Both regimens were also very well tolerated throughout the 1-year follow-up, with 98% of study participants complying with treatment.

Commenting on NESTOR, Professor Barnett said: ‘These findings add further weight to the evidence behind indapamide SR. While there is a good body of evidence to support the use of ACEIs or ARBs for diabetic patients with hypertension and microalbuminuria, indapamide SR has emerged as another agent that may be suitable first-line in relevant individuals within this patient group, such as older or Afro-Caribbean patients.’

NESTOR is the latest trial in a growing evidence base for indapamide SR. The recent European Society of Hypertension meeting unveiled the findings of X-CELLENT, which showed indapamide SR to be as effective as the angiotensin II receptor blocker (ARB) candesartan and the calcium channel blocker (CCB) amlodipine in reducing blood pressure, more effective than amlodipine in reducing systolic blood pressure (SBP) when measured over 24-hours, and superior to either comparator in controlling pulse pressure in patients with isolated systolic hypertension (ISH).

NESTOR has also added considerable weight to the distinction between thiazide and thiazide-like diuretics, since an earlier study comparing an ACE inhibitor and a conventional thiazide diuretic (hydrochlorothiazide), which is pharmacologically different from indapamide, positioned the diuretic as an inferior treatment.

Dr Douglas Robertson, Consultant in Endocrinology, Sandwell General Hospital, West Bromwich commented:

‘The NESTOR findings provide further evidence to differentiate indapamide SR from ordinary thiazides. The interesting thing would be how much additive effect there is between an ACEI and indapamide on MA, but the assumption of this effect supports the use of the two drugs in combination for this group of patients.’