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Macro- and Microvascular Residual Risk Studies

13 September 2008
Micro- and macrovascular residual risk after 7.8 years of intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria: the Steno-2 study
Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med 2003;348:383-93.
Gæde P, Vedel P, Larsen N, Jensen GVH, Parving H-H, and Pedersen O.
Objective To compare the effect of targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular (CV) disease.
Study population
160 patients, mean age 55.1 years with type 2 diabetes and microalbuminuria.
Primary endpoint Composite of death from CV causes, non-fatal myocardial infarction (MI), non-fatal stroke, revascularization and amputation.
Secondary endpoint Development or progression of diabetic retinopathy or neuropathy.
Study design Open, randomized parallel group.
Follow-up for 8 years. Analysis using survival techniques and hazard ratios [HR].
Main results Patients who received intensive therapy had a significantly lower risk of CV disease (HR: 0.47; 95% confidence interval [CI]: 0.24-0.73), nephropathy (HR, 0.39; 95% CI: 0.17-0.87), retinopathy (HR, 0.42; 95% CI: 0.21-0.86), and autonomic neuropathy (HR, 0.37; 95% CI: 0.18-0.79). Authors’ conclusions: Target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of macrovascular and microvascular events by about 50%.


Most studies of intensified intervention have looked at single risk factors, for example tight blood pressure control or aggressive lipid-modifying regimens.1,2,3 In most of these trials approximately 70-80% of CV events were not prevented, thus there still remained a large residual risk.
The American Diabetes Association and other organizations have recommended that an intensified, multifactorial treatment approach could be the way forward to achieve further reduction in the risk of vascular disease. With this in mind, the Steno-2 Study was conducted in Denmark, to compare the effect of targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for CV disease in patients with type 2 diabetes and microalbuminuria. The intensive multifactorial intervention included lifestyle modification and pharmacological therapy for hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of CV disease with aspirin. The control group received conventional treatment in accordance with Danish national guidelines.

Long-term, targeted, intensive intervention reduces vascular risk
The targeted, long-term (mean, 7.8 years), intensified treatment reduced the risk of CV events (Figure 1). The absolute 20% reduction in the risk of CV events was higher than in studies applying single-factor intervention strategies. This improvement showed continued divergence of study endpoint.

Reductions in the risk of microvascular events such as nephropathy, retinopathy, and autonomic neuropathy, were obtained after four years of intensified intervention and were maintained at eight years, again demonstrating the importance of long-term continuous intervention in providing beneficial effects. The study design precluded any conclusions about which treatment component was the most crucial in reducing the incidence of CV- or diabetes- and/or hyperglycemia-related complications.

Elevated micro- and macrovascular residual risk even after intensive multifactorial intervention
The intensive multifactorial intervention assessed in the Steno-2 study was directed toward all vascular risk factors acknowledged in current diabetes recommendations and guidelines. In particular, treatment of dyslipidemia was aimed at lowering elevated LDL cholesterol using a statin. As they represent the closest to optimal real-life target attainment by current standards of care, Steno-2 results make it possible to calculate (from the numbers of patients who experienced events) the micro- and macrovascular residual risk persisting in patients with type 2 diabetes after combined implementation of all standard preventive interventions including lifestyle changes.
Despite the significant improvements in vascular prevention afforded by 7.8 years of such intensive multitherapy, 24% of patients still experienced CVD events. The incidence of microvascular complications remained even higher, with 48% of intensively-treated patients still developing retinopathy, 30% autonomic neuropathy, 50% peripheral neuropathy, and 20% nephropathy (Figure 2).

Thus, Steno-2 demonstrates both the efficacy while highlighting the limits of current preventive strategies to tackle macro- and microvascular risk. The study demonstrates that multifactorial intervention is necessary and beneficial. It also shows that major progress remains to be made to reduce the important vascular residual risk that endures despite current preventive strategies.


Figure 1: Kaplan–Meier estimates of the composite end point of death from cardiovascular causes, non-fatal myocardial infarction,
coronary artery bypass grafting, percutaneous coronary intervention, non-fatal stroke, amputation,
or surgery for peripheral atherosclerotic artery disease


Figure 1: Impact of the treatment on the development and the progression of microvascular complications

  1. UK Prospective Diabetes Study Group. UKPDS 38. BMJ 1998;317:703–13.
  2. LaRosa JC, Grundy SM, Waters DD, et al for the Treating to New Targets (TNT) Investigators. N Engl J Med 2005;352:1425-35.
  3. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;371:117-25.
Key words Diabetes – intensive, multifactorial intervention - macrovascular and microvascular events