ADVANCE

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Patel A, et al. "Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes". The New England Journal of Medicine. 2008. 358(24):2560-2572.
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Clinical Question

In patients with T2DM, what are the vascular effects of intensive glycemic therapy targeting a HbA1c ≤6.5%?

Bottom Line

Intensive glycemic control targeting HbA1c ≤6.5% improves microvascular outcomes but has no impact on macrovascular outcomes in patients with T2DM.

Major Points

In the 2008 ADVANCE trial, sulfonylurea-based intensive glycemic therapy targeting a HbA1c ≤6.5%, was associated with a 10% reduction in combined micro- and macrovascular events compared with standard therapy. This was largely driven by a 23% reduction in the risk of microvascular events, principally nephropathy. There was no reduction in the risk of macrovascular events.

In addition, intensive glycemic control was associated with an increased risk of severe hypoglycemia and an increased rate of hospitalization. Of note, unlike the findings in the concurrently published ACCORD trial, ADVANCE did not demonstrate an increased risk of mortality with intensive therapy.

A 2014 publication[1] by the ADVANCE group presented an additional 5.4 years of follow-up data. The group assigned to intensive glucose control still did not have any macrovascular or mortality benefits over the standard therapy group.

Guidelines

ADA Medical Care in DM (2013)[2]

  • Goal A1C <7% in non-pregnant adults to reduce microvascular and macrovascular disease complications (level B)
  • Goal A1C <6.5% for selected patients, provided no hypoglycemia or other adverse events (level C)
  • Goal A1C <8% for those with previous severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, comorbidities, and long-standing difficult-to-control DM despite appropriate education and multiple agents including insulin (level B)

Design

  • Multicenter, factorial, randomized, controlled trial
  • N=11,140
    • Intensive glucose control (n=5571)
    • Standard glucose control (n=5569)
  • Setting: 215 collaborating centers in 20 countries from Asia, Australasia, Europe, and North America
  • Median follow-up: 5 years

Population

Inclusion Criteria

  • Age ≥55 years
  • T2DM diagnosed at ≥30 years of age
  • History of major macrovascular or microvascular disease or at least one other risk factor for vascular disease

Exclusion Criteria

  • Definite indication for, or contraindication to, any of study treatments
  • Definite indication for long-term insulin therapy at time of study entry

Baseline Characteristics

  • Median age: 66 years
  • Female: 42.5%
  • Age when diabetes first diagnosed: 58 years
  • Duration of diabetes: 8.0 years
  • Region: Australia and New Zealand (13%), Asia (37%), Europe (46%), North America (4%)
  • History of major macrovascular disease (MI, stroke): 32%
  • History of major microvascular disease (macroalbuminuria, retinopathy): 10%
  • History of microalbuminuria: 27%
  • HbA1c: 7.5%
  • Fasting blood glucose level: 153 mg/dl
  • Blood pressure: 145/81
  • LDL: 121 mg/dl
  • Creatinine: 0.97 mg/dl
  • Weight: 78 kg
  • BMI: 28
  • Current smoking: 14%

Baseline Medications

  • Any oral hypoglycemic agents: 91%
    • Gliclazide: 7.8%
    • Other sulfonylurea: 64%
    • Metformin: 61%
    • Thiazolidinedione: 3.6%
    • Acarbose: 9%
    • Glinide: 1.7%
  • Insulin: 1.5%
  • None: 9%
  • Other drugs:
    • Aspirin: 44%
    • Other antiplatelet: 4.6%
    • Statins: 28.3%
    • Other lipid-modifying drug: 8.4%
    • Any blood pressure-lowering drug: 75%

Interventions

  • 6-week run-in period: continued usual glucose control strategy plus fixed combination of perindopril and indapamide
  • Those compliant with treatment during run-in period were randomly assigned to:
    • Intensive glycemic strategy, using sulfonylurea gliclazide 30-120 mg daily, targeting HbA1c ≤6.5%; follow-up at week 2; then at months 1, 2, 3, 4, and 6; and every 3 months thereafter
    • Standard glycemic strategy targeting HbA1c defined by local guidelines; follow-up at 3, 4, and 6 months after randomization and every 6 months thereafter

Outcomes

Comparisons are intensive vs. conventional therapy.

Primary Outcomes

Combined macrovascular and microvascular events
18.1% vs. 20.0% (HR 0.90; 95% CI 0.82-0.98; P=0.01)
Major macrovascular events (nonfatal MI, nonfatal stroke, death from CV causes)
10.0% vs. 10.6% (HR 0.94; 95% CI 0.84-1.06; P=0.32)
Major microvascular events (new or worsening nephropathy or retinopathy)
9.4% vs. 10.9% (HR 0.86; 95% CI 0.77-0.97; P=0.01)
New or worsening nephropathy
4.1% vs. 5.2% (HR 0.79; 95% CI 0.66-0.93; P=0.006)

Secondary Outcomes

Death from any cause
8.9% vs. 9.6% (P=0.28)
Major coronary events (death due to CAD or nonfatal MI)
5.6% vs. 6.1% (P=NS)
All coronary events (major coronary events, silent MI, coronary revascularization, hospital admission for UA)
10.1% vs. 10.3% (P=NS)
Major cerebrovascular events (nonfatal stroke, death due to cerebrovascular disease)
4.3% vs. 4.4% (P=NS)
Total cerebrovascular events (major cerebrovascular events, TIA, SAH)
6.3% vs. 6.9% (P=NS)
Heart failure
3.9% vs. 4.1% (P=NS)
Peripheral vascular events
6.2% vs. 6.6% (P=NS)
All CV events
22.1% vs. 22.4% (P=NS)
New-onset macroalbuminuria
2.9% vs. 4.1% (HR 0.70; 95% CI 0.57-0.85; P<0.001)
New-onset microalbuminuria
23.7% vs. 25.7% (HR 0.91; 95% CI 0.95-0.98; P=0.02)
New or worsening neuropathy
42.2% vs. 41.5% (P=NS)
Hospitalization
44.9% vs. 42.8% (HR 1.07; 95% CI 1.01 to 1.13; P=0.03)

Other Outcomes

  • HbA1c: 6.5% vs. 7.3%
  • Fasting glucose: 118 mg/dL vs. 139 mg/dL
  • Systolic BP: 135.5 vs. 137.9 mmHg (P<0.001)
  • Weight (kg): 78.1 vs 77.0 (P<0.001)
  • Any oral hypoglycemic agents: 93.7% vs. 84.4%
    • Gliclazide (modified release): 90.5% vs. 1.6%
    • Other sulfonylurea: 1.9% vs. 57.1%
    • Metformin: 73.8% vs. 67%
    • Thiazolidinedione: 16.8% vs. 10.9%
    • Acarbose: 19.1% vs. 12.6%
    • Glinide: 1.2% vs. 2.8%
  • Insulin: 40.5% vs. 24.1%
  • No glucose-lowering agent: 1.5% vs. 6.4%
  • Other drugs:
    • Aspirin: 57% vs. 55% (P=NS)
    • Other antiplatelet: 7.1% vs. 6.2% (P=NS)
    • Statins: 45.6% vs. 47.7% (P=NS)
    • Other lipid-modifying drug: 7% (P=NS)
    • Any blood pressure-lowering drug: 88.4% vs. 88.4% (P=NS)

Subgroup Analysis

Effects of intensive control on major macrovascular and microvascular events were consistent across subgroups (P for heterogeneity ≥0.10 for all comparisons), including age, sex, SBP, HbA1c, blood glucose, BMI, history of macrovascular disease, history of microvascular disease, treatment with any antihypertensive, treatment with statin, treatment with antiplatelet agent.

Adverse Events

Severe hypoglycemia (blood glucose level ≤50 mg/dl or presence of typical symptoms and signs of hypoglycemia without other apparent cause):

  • 2.7% vs. 1.5% (HR 1.86; 95% CI 1.42-2.40; P<0.001)
  • 0.7 event per 100 patients per year vs. 0.4 event per 100 patients per year

Criticisms

  • The authors do not elaborate on baseline and post-randomization differences between the standard and intensive therapy groups; notably, the intensive therapy group had more volume overload, heart failure, and weight gain. Some of this may have been due to specific drugs administered rather than to the target HbA1c of 6.5%.[3]

Funding

Supported by grants from Servier and National Health and Medical Research Council of Australia. Servier manufactures gliclazide and fixed combination of perindopril and indapamide. Multiple disclosures from authors.

Further Reading

  1. Zoungas S, et al. "Follow-up of blood-pressure lowering and glucose control in type 2 diabetes." The New England Journal of Medicine. 2014; epublished 2014-09-19. Accessed 2014-09-19.
  2. Multiple authors. "Executive summary: Standards of medical care in diabetes--2013" Diabetes Care 2013;36(supp 1):s4-s10.
  3. Various authors. "Intensive Glucose Control in Type 2 Diabetes." N Engl J Med. 2008;359:1519-1521