The clinical benefit of blood pressure-lowering treatment has been proven for decades, best confirmed for thiazide diuretics and the thiazide-like chlortalidone (HYGROTON) in low dosage (a-t 2003; 34: 1-2). Nevertheless, there is no end to the series of new placebo-controlled long-term studies in which hypertensive patients are taking part (see also page 85). In these studies blood pressure in the placebo groups is regularly inadequately and more poorly controlled than with the study drug, even when additional antihypertensives are used (cf. a-t 2000; 31: 21-2; 2001: 32: 97-8) (1-3), with deplorable consequences. But ethics committees throughout the world approve this design again and again.

A most recent example is the ADVANCE* study, in which the combination of 4 mg daily of the ACE inhibitor perindopril plus 1.25 mg of the thiazide-like indapamide (BIPRETERAX, COVERSUM COMBI) is compared with placebo in 11,140 high-risk-patients with type 2 diabetes, the majority of whom are known to have hypertension (4). Patients with type 2 diabetes and hypertension have a particularly high risk of suffering or dying from cardiovascular disease such as heart attack or stroke. The absolute benefit of antihypertensive therapy is correspondingly greater in these patients: chlortalidone prevents consequences of high blood pressure twice as often in diabetic patients as in persons without diabetes (a-t 1997; Nr. 2: 22-3) (5). In the ADVANCE study, the patients in the control group were not only at disadvantage because of the placebo treatment. They were also deprived of the antihypertensive class with the best documentation of benefit: thiazides and thiazide-like diuretics were not allowed. With the exception of a maximum daily dose of 4 mg perindopril, which might be taken additionally in both groups, this also applied for ACE inhibitors. 15% of the participants had to discontinue the thiazide they had been taking hitherto at the start and an open-label thiazide was prescribed for only 5% of the control group during the study. In contrast, crossover was high with the ACE inhibitor component: 55% in the placebo group were given the permitted perindopril, usually from the start, 5% were subsequently given an other ACE inhibitor openly and 13% were given an angiotensin-II blocker (4).

The average blood pressure at the start of the study was 145/81 mmHg. 60% of the participants had inadequately controlled hypertension (BP at least 140/90 mmHg). Although a greater proportion of the patients in the placebo group were given open-label additional therapy with antihypertensive drugs (83% vs. 74%), the average blood pressure fell by 5.6/2.2 mmHg with perindopril plus indapamide compared to placebo over the study period of 4.3 years. In contrast, there were no differences in blood sugar and lipid levels between the two groups. A combined end point of macro- and microvascular complications was reduced from 16.8% with placebo to 15.5% with the trial drugs (Number needed to treat [NNT] = 77). Fewer patients died in the drug group (7.3% vs. 8.5%; NNT = 84), mainly because of a reduction in cardiovascular deaths (3.8% vs. 4.6%; NNT = 125). The incidence of coronary complications was also reduced (8.4% vs. 9.6%; NNT = 84), but not the cerebrovascular incidence. Of the microvascular secondary end points, only microalbuminuria was influenced significantly (19.6% vs. 23.6%; NNT = 25) (4).

Allegedly, a new strategy for hypertension treatment was investigated with the ADVANCE study: the "simple" addition of the fixed combination of perindopril plus indapamide to the existing medication independent of the initial blood pressure, instead of the traditional strategy of starting treatment above a certain blood pressure level with the aim of reaching a certain blood pressure target level (4). However, the traditional strategy was also not pursued at all in the control group. Not only were stipulations about the target blood pressure levels lacking, but the "strategy" in the control group was also robbed of one of its best supports, namely, the thiazide diuretics. The study design therefore amounts to a comparison in which one group was given a treatment of proven efficacy in addition to the inadequate baseline medication, while this was denied to the other group, thus constituting a comparison with deliberate under-treatment. When the authors in conclusion recommend routine prescription of the fixed combination in type 2 diabetes, casting their eyes at half of the world's diabetic patients, the actual purpose of the study promoted with financing from the manufacturer becomes obvious: opening up a gigantic sales market for an obscure me-too product.

The results of the ADVANCE study confirm, however, that non-prescription of thiazide diuretics worsens blood pressure control in diabetic patients with hypertension and increases their mortality and morbidity. The patients do not have better blood sugar and lipid levels without thiazides. The contribution of the perindopril component to the observed effects remains unclear because of the high crossover. The benefit of this ACE inhibitor, which did not show any clinical effect in the PROGRESS** study despite a reduction in blood pressure, is doubtful (a-t 2001; 32: 98-9) (6). The subsequently defined subgroup analyses of the ADVANCE study cannot confirm whether diabetic patients with or without well controlled hypertension benefit from (further) antihypertensive therapy.

	The ADVANCE study, in which over 11,000 high-risk patients with type 2 diabetes, the majority with known hypertension, took part, is an ethically dubious marketing study, which is intended to promote the sales of a fixed combination of the ACE inhibitor perindopril plus the thiazide-like indapamide (BIPRETERAX, COVERSUM COMBI).
	The fixed combination was compared with placebo in the ADVANCE study, when added to other antihypertensives. Although the clinical benefit of thiazides and thiazide-like diuretics has long been proven for diabetic patients with hypertension, they were not allowed to be prescribed in the control group, according to the study protocol.
	The study confirms that non-prescription of thiazides and thiazide-like diuretics worsens blood pressure control in diabetic patients with hypertension and increases their morbidity and mortality.
	In contrast, better blood sugar and lipid control was not found in patients who were denied a thiazide.
	The proportion of the ACE inhibitor in the observed effect remains uncertain, partly because of the high crossover.
	The study cannot confirm that diabetic patients without or with well-controlled hypertension benefit from (further) antihypertensive therapy.
	Low-dose thiazides or thiazide-like diuretics are the agent of first choice in the treatment of high blood pressure in diabetes mellitus. Because the data are better overall, we recommend the standard preparations hydrochlorothiazide (ESIDRIX etc.) or chlortalidone (HYGROTON).

(R = randomised study)

1

The Heart Outcomes Prevention Evaluation Study Investigators: N. Engl. J. Med. 2000; 342: 145-53

2

BRENNER, B.M. et al.: N. Engl. J. Med. 2001; 345: 861-9

3

LEWIS, E.J. et al.: N. Engl. J. Med. 2001; 345: 851-60

4

ADVANCE Collaborative Group: Lancet 2007; 370: 829-40

5

CURB, J.D. et al.: JAMA 1996; 276: 1886-92

6

PROGRESS Collaborative Group: Lancet 2001; 358: 1033-41

*

ADVANCE = Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation

**

PROGRESS = Perindopril Protection against Recurrent Stroke Study