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Macro- and Microvascular Residual Risk Studies

8 February 2010
The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial
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;370:829-40.
Patel A; ADVANCE Collaborative Group.
Objective: To assess the effects of an angiotensin-converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of baseline blood pressure levels or use of other blood pressure lowering drugs.

11,140 with type 2 diabetes aged ≥55 years, with a history of major cardiovascular disease event or at least one other risk factor for cardiovascular disease.

Exclusion criteria:
  • Indication for, or contraindication to study treatments
  • Contraindications to target HbA1c (≤6.5%; since the study also assessed the effects of intensive glycemic control)
  • Insulin treatment at study entry
  • Patients randomized to treatment with a fixed combination of perindopril (2 mg) and indapamide (0.625 mg) or matched placebo; both doses doubled (4 mg/1.25 mg) after 3 months
  • Use of concomitant treatments except thiazide diuretics allowed during follow-up, with open-label perindopril up to 4 mg as sole ACE-inhibitor allowed.
Primary outcomes:
  • Composite of major macrovascular and microvascular outcomes
  • Composite of major macrovascular outcomes (death from CVD, non-fatal stroke, and non-fatal myocardial infarction)
  • Composite of major microvascular outcomes (new or worsening nephropathy or diabetic eye disease)
Scondary outcomes: A number of secondary outcomes, including all-cause mortality; cardiovascular death; major and total coronary events; major and total cerebrovascular events; heart failure; peripheral vascular disease; new or worsening nephropathy; new or worsening retinopathy; new or worsening neuropathy.
Study design: The ADVANCE trial was a randomized multicentre study with a factorial design assessing the effects of a fixed combination of perindopril and indapamide (blood pressure lowering-arm) and that of intensive glycemic control (using a gliclazide MR-based regimen) in the same population. Follow-up of the blood pressure-lowering arm completed by June, 2007. 
Main results:
  • Mean follow-up: 4.3 years.
  • Relative risk of combined major macrovascular or microvascular events reduced by 9% (hazard ratio 0·91, 95% CI 0.83–1.00, p=0.04).
  • No significant reduction in macrovascular events considered separately (0.92; 0.81–1.04, p=0.16)
  • No significant reduction in microvascular events considered separately (0.91; 0.80–1.04, p=0.16).
  • Significant 18% reduction in relative risk of death from CVD (0.82, 0.68–0.98, p=0.03)
  • Significant 14% reduction in relative risk of death from any cause (0.86, 0.75–0.98, p=0·03).
  • No significant reduction in new or worsening nephropathy (p=0.055)
  • No significant reduction in new or worsening retinopathy (p=0.23)
Author's conclusion: A fixed combination of perindopril and indapamide reduced the risk of major vascular events, including death..


The ADVANCE study confirmed that blood pressure control is associated with significant vascular benefits in patients with diabetes. The average blood pressure at baseline was 145/81 mmHg. At the end of the 4.3-year follow-up, blood pressure was 135/75 mmHg in the active treatment group versus 140/77 mmHg in the placebo group. Because of the significant reductions of all-cause death and death from CVD, plus the global reduction of  micro- and macrovascular events observed in the active treatment group, ADVANCE was considered by many as a justification of the blood pressure level (<130/80 mmHg) recommended for patients with diabetes.

There was, however, some heterogeneity in the results. The composite endpoint of microvascular and macrovascular events was significantly reduced, but this was not the case for the combined microvascular events and the combined macrovascular events considered separately. The authors provided no explanation for this discrepancy. With regard to components of the combined macrovascular endpoint, cardiovascular death and coronary events were significantly reduced, but an unexpected finding was the absence of significant reduction in risk of cerebrovascular events, usually observed in recent blood pressure reduction trials, both in nondiabetic and diabetic populations.

The analysis of changes in individual microvascular events produced mixed results. While the active treatment reduced microalbuminuria, there was no significant effect on new or worsening nephropathy, new or worsening retinopathy, and neuropathy, which casts further doubt on the validity of microalbuminuria to predict hard clinical renal outcomes in type 2 diabetes, contrary to type 1 diabetes. Peripheral vascular disease was also not reduced.

The authors report that the beneficial effects of the fixed combination of perindopril and indapamide were independent of concomitant treatments at baseline. However, by the end of the trial, more of the participants assigned to placebo were taking an angiotensin receptor blocker or a beta-blocker, calcium channel blocker, thiazide or other diuretic, or other blood pressure-lowering drug(s) than patients in the active treatment group. The fact that 55% of the patients assigned to placebo were also taking perindopril at the end of follow-up, which was, rather oddly, allowed by the protocol, may have also affected the results.

If one concentrates on the main endpoint of ADVANCE, 91% of the relative risk of micro- and macrovascular complications were not reduced by the active treatment. However, ADVANCE was not a study assessing the effect of blood pressure control on residual vascular risk persisting in patients otherwise receiving standards of care. In particular, statins were used by only 29% of ADVANCE patients. Rather, the study confirms that antihypertensive treatments targeting the blood pressure level recommended for diabetic patients (130/80 mmHg) may produce significant morbidity and mortality benefits. Whether the results obtained with the specific antihypertensive treatment used in ADVANCE could have been obtained with any antihypertensive treatment is subject to debate.(1)


1. Kaplan NM. Vascular outcome in type 2 diabetes: an ADVANCE? Lancet. 2007;370:804-805

Key words Type 2 Diabetes – Micro- and Macrovascular Residual Risk – Blood Pressure Control – Perindopril – Indapamide.