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The ADVANCE trial - new findings and updated results

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

Since the first publication of the ADVANCE Trial, further findings have been published. New data regard the blood pressure and the glucose lowering arms, atrial fibrillation and renal outcome. Authors further report on the benefit of the perindopril/indapamide combination as well as on the best predictors of coronary and cardiovascular events in the diabetic population.

Cardiovascular Pharmacology and Pharmacotherapy


Since the first publication of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Trial (1), further findings have been published. New data regard the blood pressure and the glucose lowering arms, atrial fibrillation and renal outcome.

1. Blood pressure lowering arm

Initial results from the blood pressure lowering arm published in 2007 had demonstrated that the perindopril/indapamide fixed combination, in addition to background treatment exerts beneficial effects on blood pressure values (1). A reduction in systo-diastolic values amounting to 9/8 mmHg, with a significant decrease in all-cause mortality (-14%), cardiovascular mortality (-18%) and major cardiovascular events (-9%) were observed (Figure 1).

Further recent anayses report that the perindopril/indapamide combination:

  1. Has detectable beneficial effects in a wide range of patient subgroups according to a) blood pressure values at study entry < or > 140/90 mmHg, b) presence or absence of other blood pressure lowering treatments, or c) concomitant administration of statins and/or antiplatelet agents.
  2. Has similar efficacy and safety, as well as a similar risk reduction for primary and secondary endpoints in patients aged below 65 years and in those aged 75 years or more (2).
  3. Has blood pressure lowering effects that are not affected by a given patient's cognitive dysfunction even though cognitive dysfunction will increase the risk of cardiovascular outcomes (3).
  4. Intervenes effectively on the cardiovascular risk profile diabetic patients.
  5. Holds significantly greater benefit in terms of risk reduction in high risk patients.

Additional analysis reports on the relative importance of various blood pressure values as determinants of cardiovascular risk in a diabetic population (5). Results indicate that systolic blood pressure and pulse pressure are the two most effective predictors of coronary and cardiovascular events in the diabetic population, while mean arterial pressure and diastolic blood pressure fail to show such predictive value.

2. Glucose lowering arm

The glucose arm had addressed a question with important clinical implications, i.e. whether intensive glucose control (glycated hemoglobin = 6.5%) exerts cardioprotective and nephroprotective effects greater than those achieved by standard glucose control (glycated hemoglobin 7-7.5%) (6). To this aim more than 11000 diabetic patients were treated with glicazide modified release (30-120 mg) added to other treatments or with standard drugs for a mean follow-up of 5 years.

Results showed the benefit of a more intensive glucose control, with a 10% relative reduction in the combined outcome of major macrovascular and microvascular events (the primary study end-point), and a 21% decrease in the occurrence of renal insufficiency and failure. The trial also provided information on another issue of clinical relevance, i.e. the safety profile of the two interventions (6). Severe hypoglycaemia was indeed rare however it was more common in the intensively-treated than in standard-treated control group. (2.7% vs 1.5%, p <0.001). This was not an unexpected finding nevertheless it calls for close following of diabetic patients undergoing strict glucose control.

More recent study of the combined effects of routine blood pressure lowering and intensive glucose control on cardiovascular and renal outcomes (7), reported the benefits of the pharmaceutical intervention on renal events (including microalbuminuria) and death for any cause (Figure 2).

3. Atrial fibrillation

A further set of data reports on the occurrence of atrial fibrillation in diabetic patients and the impact of the perindopril/indapamide fixed combination on it(8). Results can be summarised as follows:

  1. Atrial fibrillation is common in diabetic patients (incidence close to 8%) and is associated with an increased risk of all cause mortality (+61%), cardiovascular events (+77%), cerebrovascular events (+68%) and heart failure (+68%).
  2. Risk of atrial fibrillation is higher in diabetic than in non-diabetic diabetic normotensives.
  3. Treatment reduces cardiovascular risk in patients with atrial fibrillation to an extent significantly greater than in controls.
  4. Protection offered by the the combination treatment is particularly evident in terms of incidence of cerebrovascular events or major coronary events.

4. Renal outcomes

Treatment with perindopril/indapamide fixed combination had been reported to provide significant renal benefits (1). Renal outcomes were improved with combination treatment, which was associated with clearcut reductions in the risk of developing microalbuminuria, in the risk of developing overt nephropathy or worsening renal function (overall risk reduction -21%, P< 0.0001) (9).

Recent publications have reported that the combination treatment in renal failure patients also has favourable effects on cardiovascular death (-20%) and major coronary events (-13%), particularly in patients with more advance kidney disease (10).

Figure 1. Effects of blood pressure lowering on death and macrovascular and microvascular disease (coronary and renal) in the ADVANCE Trial. Figure modified from Ref 1.


Figure 2. Effects of blood pressure lowering and intensive glucose control intervention on renal events in the ADVANCE Study. Figure modified from Ref 7.

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. Ninomiya T, Zoungas S, Neal B, Woodward M, Patel A, Perkovic V, Cass A, Cooper M, Grobbee D, Hamet P, Harrap S, Liu L, Mancia G, Mogensen CE, Poulter N, Rodgers A, Williams B, MacMahon S, Chalmers J; ADVANCE Collaborative Group. Efficacy and safety of routine blood pressure lowering in older patients with diabetes: results from the ADVANCE trial. J Hypertens. 2010;28:1141-1149.
3. de Galan BE, Zoungas S, Chalmers J, Anderson C, Dufouil C, Pillai A, Cooper M, Grobbee DE, Hackett M, Hamet P, Heller SR, Lisheng L, Macmahon S, Mancia G, Neal B, Pan CY, Patel A, Poulter N, Travert F, Woodward M; ADVANCE Collaborative Group. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Diabetologia. 2009;52:2328-2336.
4. Zoungas S, Ninomiya T, Patel A et al. The effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes mellitus according to baseline cardiovascular risck in the ADVANCE trial (abstract). J hypertens, 2009; 27: S314. 5. Kengne AP, Czernichow S, Huxley R, Grobbee D, Woodward M, Neal B, Zoungas S, Cooper M, Glasziou P, Hamet P, Harrap SB, Mancia G, Poulter N, Williams B, Chalmers J; ADVANCE Collaborative Group. Blood pressure variables and cardiovascular risk: new findings from ADVANCE. Hypertension. 2009;54:399-404.
6. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-2572.
7. Zoungas S, de Galan BE, Ninomiya T, Grobbee D, Hamet P, Heller S, MacMahon S, Marre M, Neal B, Patel A, Woodward M, Chalmers J; ADVANCE Collaborative Group, Cass A, Glasziou P, Harrap S, Lisheng L, Mancia G, Pillai A, Poulter N, Perkovic V, Travert F. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: New results from the ADVANCE trial. Diabetes Care. 2009;32:2068-2074.
8. Du X, Ninomiya T, de Galan B, Abadir E, Chalmers J, Pillai A, Woodward M, Cooper M, Harrap S, Hamet P, Poulter N, Lip GY, Patel A; ADVANCE Collaborative Group. Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Eur Heart J. 2009;30:1128-1135.
9. de Galan BE, Perkovic V, Ninomiya T, Pillai A, Patel A, Cass A, Neal B, Poulter N, Harrap S, Mogensen CE, Cooper M, Marre M, Williams B, Hamet P, Mancia G, Woodward M, Glasziou P, Grobbee DE, MacMahon S, Chalmers J; ADVANCE Collaborative Group. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol. 2009;20:883-892.
10. Heerspink HJ, Ninomiya T, Perkovic V, Woodward M, Zoungas S, Cass A, Cooper M, Grobbee DE, Mancia G, Mogensen CE, Neal B, Chalmers J; ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide in patients with type 2 diabetes and chronic kidney disease. Eur Heart J. 2010;31:2888-2896.

VolumeNumber:

Vol9 N°29

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.

Address for correspondence:
Prof. Guido Grassi
Clinica Medica, Ospedale San Gerardo,
Università Milano-Bicocca
Via Pergolesi 33, 20052 Monza (Milan), Italy
Phone: +39 039 233 2327
FAX: +39 039 322274
e-mail: guido.grassi@unimib.

The authors have no conflicts of interest to declare.

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.