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The ADVANCE Trial : results, clinical implications and perspectives

An article from the e-journal of the ESC Council for Cardiology Practice

The fixed combination of an ACE-inhibitor (perindopril, 2mg) and a diuretic agent (indapamide, 0.625mg) on top of standard treatment in more than 11.000 diabetic in 20 countries of the blood pressure lowering arm of ADVANCE, has had since 2001, a favourable impact on their elevated cardiovascular risk profile. According to the trial's author’s opinion, this treatment should be made mandatory in diabetic patients because it is practical and affordable safe, well tolerated and requires little monitoring and is effective in the majority of patients. We believe it may become the routine therapeutic approach in the future for patients with diabetes mellitus even when blood pressure is not elevated. New ESC-ESH guidelines speak in favour of initiating antihypertensive treatment in diabetic patients even when blood pressure is still in the high-normal ranges.  

Cardiovascular Pharmacology and Pharmacotherapy


  • I - ADVANCE - the blood pressure lowering arm

ADVANCE (Action in Diabetes and Vascular Disease-PreterAx and DiamicroN Controlled Evaluation) is an ongoing large-scale prospective randomised clinical trial aimed at investigating the effects of blood pressure lowering and intensive blood glucose control in high risk diabetic patients on major macrovascular and microvascular events. Results of the blood pressure lowering treatment study have been published in the LANCET in June (1), while the glucose lowering arm is just coming to a conclusion and data will be presented at the American Diabetes Association Conference in San Francisco at the beginning of June.

1) Hypertension has a prognostic adverse impact on diabetic patients

 A large number of epidemiological and clinical studies have shown that in patients with diabetes mellitus, hypertension is an important risk factor for cardiovascular and renal disease, including macro- and microvascular complications such as nephropathy. This has been shown for example in the:

  • Irbesartan Diabetic Nephropathy Trial (IDNT), performed in about 1600 patients with diabetes and hypertension, in which a systolic blood pressure above 149 mmHg is associated in the four year and half of the follow-up period to a double in baseline serum creatinine and end-stage renal disease (2).
  • United Kingdom Prospective Diabetes Studies (UKPDS), in which an incidence of microvascular complications (represented by proliferative retinopathy, microalbuminuria, renal insufficiency and failure) was directly and continuously related to the systolic blood pressure increase and diabetes-related mortality was strongly associated with blood pressure values.

Altogether these findings strongly support the notion that the presence of hypertension has a prognostic adverse impact on diabetic patients.  

2) The risk associated with high blood pressure in diabetic patients can be reduced with a diuretic alone or in combination with a beta-blocker

 Evidence from several studies has shown that the risk associated with high blood pressure in diabetic patient can be reduced with appropriate therapeutic strategies. This has been shown in the :

  • Systolic Hypertension in the Elderly Program (SHEP). As far as antihypertensive drug treatment is concerned, data from the Systolic Hypertension in the Elderly Program (SHEP) has clearly documented that in patients whith diabetes, a diuretic treatment (alone or combined whith a beta-blocker) is capable of reducing by 34% the risk of major cardiovascular events (4). The protection is even greater when antihypertensive drug treatment allows to achieve a blood pressure level below 130/80 mmHg.
  • Hypertensive Optimal Treatment (HOT) study. In the a subanalysis of the data collected in about 1500 diabetic patients has allowed to show a 51% reduction in the risk of cardiovascular events when target diastolic pressure was 80 mmHg rather than 90 mmHg. This has been the case also in the previously mentioned IDNT trial (3), in which an aggressive blood pressure reduction was associated with a greater nephroprotection than that seen in treated patients with blood pressure levels around 140 mmHg.

3) However optimal blood pressure control is still poor, particularly in subjects in whom high blood pressure is associated with diabetes

Despite these encouraging data, information collected in clinical practice have shown that blood pressure control is poor in uncomplicated hypertensive patients and that this is particularly the case in subjects in whom high blood pressure is associated with diabetes (5). This implies that one of the future therapeutic challenges in the field of antihypertensive treatment will be the achievement of an optimal blood pressure control.  

4) ADVANCE studied the fixed combination of an ACE-inhibitor and a diuretic agent on macrovascular and microvascular complications and deaths

The ADVANCE Trial is the largest-ever study aimed at investigating the effects of a treatment based on the fixed combination of an ACE-inhibitor (perindopril, 2mg) and  a diuretic agent (indapamide, 0.625mg) on macrovascular and microvascular complications and deaths. The main features of ADVANCE can be summarised as follows.

  • First, it randomised to active treatment or placebo 11.140 diabetic patients, of whom about 35% and 10% had pre-existing macrovascular and microvascular complications, respectively.
  • Second, it recruited patients who had a history of major cardiovascular disease or at least one other cardiovascular risk factor.
  • Third, more than 70% of the enrolled patients were hypertensives and already under antihypertensive drug treatment with their mean entry blood pressure values amounting to 145/81 mmHg.

The results can be summarised as follows.

  • Blood Pressure : Compared with patients who were assigned to placebo, those assigned to active therapy had a mean reduction in systolic blood pressure of 5.6 mmHg and a reduction in diastolic blood pressure of 2.2 mmHg (Figure 1), even with the fact that physicians were allowed to adjust antihypertensive therapy according to clinical needs.
  • Events : The relative risk of a major macrovascular and microvascular event (primary endpoint) was reduced by 9% (p = 0.041) in the active group (Figure 1, left panel). The separate reductions in macrovascular and microvascular events were similar but were not independently statistically significant. The relative risk of death was significantly reduced - by 14% (p = 0.025) (Figure 1, right panel), essentially due to a lower death rate from cardiovascular diseases (-18%; p = 0.027) (Figure 2). The incidence of any coronary event was also significantly reduced (-14 %; p = 0.020), while only a trend was observed for all cerebrovascular events. Finally, renal events were significantly less frequent (-21%; p < 0.0001) (Figure 2) whereas all “eye” events were only slightly reduced (-5%; NS) in the active group as compared to the placebo group (Figure 2).

5) Used on top of all other drugs, the combination treatment had a favourable impact on elevated cardiovascular risk profile of the diabetic patient

Thus, the fixed combination treatment used in the ADVANCE trial and administered on top of all other drugs (antihypertensive drugs, statins, aspirin and blood glucose lowering agents) had a favourable impact on the elevated cardiovascular risk profile of the diabetic patient. This makes this therapeutic strategy mandatory in diabetic patients because, according to the ADVANCE Author’s opinion (1), is

  • practical and affordable in clinical practice around the world,
  • safe, well tolerated and requires little monitoring and
  • effective in the majority of patients, independently of age, gender, baseline blood pressure and level of cardiovascular risk.

In commenting the ADVANCE Trial results, an obvious question should be addressed, namely whether the study data imply that a fixed combination of perindopril / indapamide should became a routine therapeutic approach for patients with diabetes mellitus, even when blood pressure is not elevated. An analysis of the ADVANCE data suggest that this is the case, also considering that the recent Guidelines for the Management of Hypertension, jointly issued by the European Society of Hypertension / European Society of Cardiology, speak in favour of initiating antihypertensive treatment in diabetic patients even when blood pressure is still in the high-normal range (7).  

II - ADVANCE blood glucose lowering arm - results in June

Along with the blood pressure lowering arm completed in June 2007 with results published in The Lancet (1), ADVANCE also includes the blood glucose lowering arm which is still an ongoing investigation.

An effective glycaemic control is of great relevance in clinical practice.

  • In the UKPDS study hypertensive patients with type 2 diabetes showed marked benefits from intensive blood glucose control particularly when microvascular complications were considered (8). In other studies this has been shown to be the case also for macrovascular complications as well (9-10).
  • The issue is currently examined by the ADVANCE Trial (12). and another ongoing large scale randomized trials, the Action to Control CardiOvascular Risk in Diabetes (ACCORD), (11). Recently, information was released that the ACCORD study was prematurely stopped because of a higher number of deaths in patients allocated to intensive glucose lowering rather than standard treatment (13). This data, however, appear not confirmed by the ACCORD results, because in a recent press release the Chairman of the ADVANCE Management Committee, Prof John Chalmers, George Institute, Sidney, Australia and the principal Investigators, Prof. Stephen MacMahon, George Institute, Sidney Australia, have informed that “the preliminary findings from the ADVANCE Trial provide no evidence that intensive treatment to lower blood glucose in type 2 diabetes increases mortality risk”. The two studies, ACCORD and ADVANCE, will be presented at the American Diabetes Association Conference in San Francisco at the beginning of June. 

 Figure 1. Combined primary outcome and mortality curves in patients of the ADVANCE Trial randomised to placebo or Perindopril/Indapamide combination treatment. Figure modified from Ref 1.

Figure 2. Percent reduction in micro and macrovasular events, coronary heart disease (CHD), stroke, renal disease and new microalbuminuria (MA) in the ADVANCE Trial. Data from Ref. 1

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

References


1. Patel A, ADVANCE Collaborative Group, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.

2. Pohl MA, Blumenthal S, Cordonnier DJ, De Alvaro F, Deferrari G, Eisner G, Esmatjes E, Gilbert RE, Hunsicker LG, de Faria JB, Mangili R, Moore J Jr, Reisin E, Ritz E, Schernthaner G, Spitalewitz S, Tindall H, Rodby RA, Lewis EJ. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial: clinical implications and limitations. J Am Soc Nephrol. 2005;16:3027-3037.

3. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. British Med Journal. 2000;321:412-419.

4. Mancia G, Omboni S, Parati G, Clement DL, Haley WE, Rahman SN, Hoogma RP. Twenty-four hour ambulatory blood pressure in the Hypertension Optimal Treatment (HOT) study. J Hypertens 2001;19:1755-1763.

5. Mancia G, Grassi G. Systolic and diastolic blood pressure control in antihypertensive drug trials. J Hypertens. 2002;20:1461-464.

6. Chalmers J, Joshi R, Patel A. Advances in reducing the burden of vascular disease in type 2 diabetes. Clin Exp Pharmacol Physiol. 2008;35:434-437.

7. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.


8. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.


9. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-494.

10. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383-393.

11. Goff DC Jr, Gerstein HC, Ginsberg HN, Cushman WC, Margolis KL, Byington RP, Buse JB, Genuth S, Probstfield JL, Simons-Morton DG; ACCORD Study Group. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007;99(12A):4i-20i.

12. Rationale and design of the ADVANCE study: a randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with type 2 diabetes mellitus. Action in Diabetes and Vascular Disease: PreterAx and DiamicroN Modified-Release Controlled Evaluation. J Hypertens Suppl. 2001;19:S21-28.

13. ACCORD news conference.

14. Press release: ADVANCE does not confirm ACCORD results.

VolumeNumber:

Vol6 N°28

Notes to editor


*Prof. G. Grassi and **Prof G. Mancia
Milan , Italy
*Past-Chairman ESC Working Group Hypertension and the Heart, **Past-President European Society of Hypertension (ESH), Past-President International Society of Hypertension, Chairman of the ESH/ESC Task Force for the management of hypertension.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.