VADT

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Duckworth W, et al. "Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes". The New England Journal of Medicine. 2009. 360(2):129-39.
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Clinical Question

Among individuals with poorly-controlled T2DM, does intensive glycemic control reduce the risk of macrovascular complications?

Bottom Line

Intensive glycemic control has minimal impact on both macrovascular and microvascular endpoints in T2DM.

Major Points

Some 60% of type 2 diabetics die of cardiovascular (CV) complications; thus many diabetes initiatives seek to investigate the role of glycemic control in reducing the risk of these macrovascular events. Several trials in T2DM have studied the impact of intensive glycemic therapy on macrovascular and microvascular outcomes, often with mixed results. UKPDS 33 (1998), ACCORD (2008), ADVANCE (2008), and the Veterans Affairs Diabetes Trial (VADT; 2009) were among the largest of these trials. UKPDS showed a similar reduction in microvascular complications, and was the first to demonstrate a nonsignificant trend towards reduced CV risks among those treated with intensive glycemic therapy. However, ACCORD failed to demonstrate a reduction in CV events with intensive therapy, and actually suggested that intensive therapy may be associated with increased mortality. Similarly, ADVANCE failed to demonstrate a CV benefit with intensive therapy; however, it did show a modest reduction in albuminuria, a surrogate for microvascular complications.

VADT studied a relatively homogeneous population of older men with poorly controlled T2DM (average hemoglobin A1C of 9.4%) and randomized them to intensive versus standard glucose control. Both groups had aggressive treatment of CVD risk factors with BP control, smoking cessation, aspirin therapy, and statin therapy. At median 5.6 years of follow-up, the intensive therapy group had a lower hemoglobin A1C than the standard therapy group (6.9% vs. 8.4%) but did not have an improvement in the primary outcome of time to first CV event. Furthermore, intensive therapy was associated with only a modest improvement in microvascular outcomes using the familiar surrogate marker, albuminuria. Intensive therapy came at the expense of more hypoglycemic episodes, including coma. However, a post hoc analysis has suggested that those with shorter duration of diabetes (less than 12 years) gained benefit from intensive therapy while those with longstanding disease derived no benefit or were harmed.[1] Additional analyses demonstrated added CVD risk for those with hypoglycemia and benefit for those with low (but not high) coronary calcification scores.[1]

Ten-year follow up of UKPDS[2] and VADT[3] demonstrated a CVD benefit with intensive glycemic therapy.

Guidelines

ADA Medical Care in DM (2013)[4]

  • 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

  • Multi-center, double-blind, parallel-group, randomized, placebo-controlled trial
  • N=673 (at follow-up)
    • Intensive (n=344)
    • Conventional (n=329)
  • Setting: 20 Veterans Affairs centers in the US
  • Enrollment: December 2000 to May 2003
  • Analysis: intention to treat
  • Mean follow-up: 5.6 years

Population

Inclusion Criteria

  • Adults with T2DM
  • Inadequate response to max oral agent or insulin therapy

Exclusion Criteria

  • HbA1c <7.5%
  • CV event within prior 6 months
  • Advanced CHF
  • Severe angina
  • Life expectancy <7 years
  • BMI >40
  • Cr >1.6
  • ALT >3x ULN

Baseline Characteristics

From the intensive therapy group.

  • Demographics: Age 60 years, male 97%, white and non-hispanic 60%, white and hispanic 17%, black 17.0%
  • Time since DM diagnosis: 11.5 years
  • PMH: CV event 39.8%, HTN 72%, current smoker 17%, former smoker 55%
  • Health data: Weight 214 lbs, BMI 31.3 kg/m2, BP 131/76 mmHg
  • Laboratory results: A1C 9.4%, Tchol 182 mg/dL, LDL 107 mg/dL, HDL 36 mg/dL, TG 201 mg/dL, creatinine 1.0 mg/dL

Interventions

  • Randomly assigned to treatment, stratified by study site, prior macrovascular event, current insulin use
  • In each group, treatment given according to BMI:
    • BMI >27: metformin + rosiglitazone
    • BMI <27: glimiperide + rosiglitazone
  • Intensive group:
    • Start on maximum doses
    • If HbA1c >6%, insulin added
    • Goal for HbA1c reduction by 1.5 absolute percentage points
  • Conventional group:
    • Start on half-maximum doses
    • If HbA1c >9%, start insulin
  • Comorbidities treated according to ADA guidelines for HTN, diet, exercise, diabetes education
  • All patients received aspirin and statin unless contraindicated

Outcomes

Comparisons are 6-year event rates in intensive vs. conventional therapy groups.

Primary Outcomes

Time to first CV event

CV event defined as MI, stroke, CV mortality, new or worsening HF, surgery for CV/cerebrovascular/peripheral vascular needs, inoperable CAD, or ischemic gangrene requiring amputation.

No difference (HR for intensive group 0.88; 95% CI 0.74-1.05; P=0.14)
Rate: 29.5% vs. 33.5% (P=NS)

Secondary Outcomes

New or worsening angina
21% vs. 18% (HR 1.20; 95% CI 0.86-1.51; P=0.11)
New TIA
3% vs. 2% (HR 1.48; 95% CI 0.73-2.99; P=0.28)
New claudication
2% in each (HR 0.78; 95% CI 0.38-1.6; P=0.49)
New critical limb ischemia
2% vs. 3% (HR 0.8; 95% CI 0.4-1.56; P=0.51)
All-cause mortality
13% vs. 12% (HR 1.07; 95% CI, 0.81-1.42; P=0.62)
Microvascular complications
No difference in incidence of or progression to severe retinopathy, nephropathy, or neuropathy

Additional Analysis

Hemoglobin A1c
6.9% vs. 8.4%

Adverse Events

Intensive therapy resulted in more frequent hypoglycemia (P<0.001).

Criticisms

  • Cannot easily extrapolate to women given predominantly male VA population studied
  • Underpowered given lower-than-expected event and higher-than-expected dropout rate[5]
  • Use of rosiglitazone, a medication that has been found to exacerbate HF, was used at different doses between the groups and may have confounded the results[5]

Funding

Support provided by SanofiAventis, GlaxoSmithKline, Novo Nordisk, Roche, Kos Pharmaceuticals, and Amylin.

Further Reading