Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 DiabetesN Eng J Med 358;24 2560 - 2572

ADVANCE Collaborative Group

Taz Babiker

Population

Patients with type 2 diabetes aged ≥ 30 years at diagnosis

Aged ≥ 55

History of major macrovascular disease, OR

At least one other risk factor for vascular disease

Excluded if: Definite indication for any of the study treatments

Contraindication to any of the study treatments

Definite indication for long-term insulin

Median duration of follow up 5.0 years

Intervention

6 week run in period Fixed combination of perindopril and indapamide

Random assignment to either perindopril or indapamide or placebo

Random assignment to intensive (HbA1c < 6.5%) vs standard glucose control

Gliclazide MR ± metformin, thiazolidinediones, acarbose or insulin

Regular follow up

Comparison

If standard glucose control, discontinued gliclazide and switched to different SU if required

Outcome

Primary outcomes – composite of macrovascular and microvascular events Death from cardiovascular causes

Nonfatal MI

Nonfatal stroke

New or worsening nephropathy

Doubling of serum creatinine

Renal replacement therapy

Death due to renal disease

Retinopathy

Outcome

HbA1c 6.5% vs 7.3% ?significant

Systolic BP 135.5 vs 137.9 mmHg (p<0.001)

Weight 0.7 kg greater in intensive group (p<0.001)

Major macro/microvascular event: 18.1 vs 20.0% (hazard ratio 0.90, p=0.01)

In a 5 yr period, an event would be averted in 1 in 52 participants

Sig reduction in major microvascular but not major macrovascular events

No evidence of interaction between BP and glucose intervention

Outcome

Death: 8.9% vs 9.6% (p=0.28)

Reduction in renal events

new/worsening nephropathy (HR 0.79, p=0.006)

New-onset microalbuminuria (HR 0.91, p=0.02)

Macroalbuminuria 2.9% vs 4.1% (HR 0.70, p<0.001)

Reduced RRT or death from renal causes – 0.4% vs 0.6%, HR 0.64, p=0.09)

Increased severe hypoglycaemia (BM < 2.8) and minor hypos in intensive group

Discussion

ACCORD – excess mortality in intensive arm led to premature termination

ADVANCE – no sig difference in mortality from any cause/CV causes

Not enough statistical power to achieve expected improvement in CV risk with intensive group

Lower BP explains some but no more than 25-33% of the relative risk reduction