ADVANCE study (combination of an angiotensin converting enzyme inhibitor (ACEI) and a diuretic on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus)

• ADVANCE study examined the effect of a fixed dose combination of an angiotensin converting enzyme inhibitor (ACEI) and a diuretic on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus
  • in the ADVANCE study the combination showed some benefits over placebo
  • RCT of 11,140 patients aged 55 years and older with type 2 diabetes
    • patients also had either a history of CV disease (including stroke and MI) or at least one other CV risk factor (e.g. age >= 65 years, smoking, history of major microvascular disease)
    • active treatment with a combination of perindopril and indapamide (initially 2mg/0.625mg, doubled to 4mg/1.25mg after 3 months) was compared with placebo
    • while taking the combination during the run-in phase, 1,737 other recruited patients withdrew, at least 29% of these due to adverse effects
    • primary endpoints were composites of major macrovascular events (death from CV disease, non-fatal stroke or non-fatal MI) and major microvascular events (new or worsening renal disease or new or worsening diabetic eye disease)
      • after 4.3 years, the combined endpoint of major macrovascular and microvascular events was reduced by 1.3% (number needed to treat [NNT]=77; relative risk reduction [RRR] 9%, 95%CI 0% to 17%; P=0.04)
      • death from CV disease was significantly reduced by 0.8% (NNT=125 over 4.3 years; RRR 18%, 95%CI 2% to 32%; P=0.03) and death from any cause was reduced by 1.2% (NNT= 83; RRR 14, 95%CI 2% to 25%; P=0.03)
  • significance of study
    • authors of the paper conclude that, “routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death”
    • however:
      • mean blood pressure in patients in the active arm was 5.6/2.2mmHg lower than that in patients in the placebo arm and this was highly statistically significant (p<0.0001)
        • therefore possible that the differences observed were an effect of lower blood pressure rather than any drug specific action
  • study adds to the body of evidence that lowering blood pressure in patients with type 2 diabetes reduces CV complications and deaths
  • also "..based on their safety, efficacy, tolerability and cost, thiazide diuretics are a good first choice agent for most people, including those with type 2 diabetes.." (2)

Reference:

• (1) ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial). Lancet 2007;370:829-40.
• (2) MeReC Extra (November 2007); 30.