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Macro- and Microvascular Residual Risk Studies

21 November 2009
Persistence of vascular residual risk after long-term intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria: Steno-2 extension
Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes. N Engl J Med 2008;358:580-91 ( number, NCT00320008).
Gæde P, Lund-Andersen H, Parving H-H and Pedersen O.
Objective (1) to assess, at the end of a 5.5-year observational follow-up of the original Steno-2 study, the effect of targeted, intensified, multifactorial intervention on rates of death from any cause and from cardiovascular (CV) causes; and (2) to verify whether the risk reductions achieved during the Steno-2 study were maintained during follow-up.
Study population
160 patients, mean age 55.1 years at original study entry with type 2 diabetes and microalbuminuria.
Primary endpoint Time to death from any cause after a total 13.3- year follow-up.
Secondary endpoint Death from CV causes, and composite of death from CV causes, nonfatal stroke, non-fatal myocardial infarction (MI), revascularization, and amputation.
Tertiary endpoints Incident diabeticnephropathy, development or progression of
diabetic retinopathy or neuropathy.
Study design 5.5-year observational follow-up of the original 7.8-year open, randomized parallel group study.
Analysis using survival techniques and hazard ratios [HR].
Main results
  • Absolute reduction of death from any cause was 20% in patients on intensive therapy (HR, 0.54; 95% confidence interval [CI]: 0.32, 0.89; p=0.02).
  • Absolute reduction of death from CV causes was 13% in patients on intensive therapy (HR, 0.43; CI: 0.19, 0.94; p=0.04) and 29% of CV events (HR, 0.41; CI, 0.25, 0.67; p<0.001).
  • Reductions in the risk of microvascular events maintained over the 13.3 year period.


The risk of death from CV disease in people with type 2 diabetes is two to six times that of people without diabetes. Atherogenic dyslipidemia is prevalent in people with diabetes, and they are more likely to develop hypertension and other macrovascular events such as stroke and microvascular complications affecting the retina, kidneys and nerves. Hence a regimen which can target all these conditions is essential if CV and microvascular risk is to be reduced in type 2 diabetes.
The Steno-2 Study, conducted in Denmark, compared the effect of targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for CV and microvascular disease in patients with type 2 diabetes and microalbuminuria.1 The intensive therapy, which included lifestyle modification and multifactorial pharmacological therapy, reduced the risks of both macrovascular and microvascular events by about 50% compared with conventional treatment as control.
The Steno-2 results also highlighted the persistence of an impressive micro- and macrovascular residual risk after intensive multifactorial therapy, although the latter corresponded to the strict application of current guidelines in an ideal setting, unlikely to be achieved and sustained in routine clinical practice.
After completion of the Steno-2 study, all participants in both study groups and their diabetologists were informed of the benefits of multifactorial treatment. Patients were subsequently followed observationally for an additional mean of 5.5 years.
At the end of the follow-up period, analysis of the risk factors for the two therapy groups showed some convergence. This was because all patients were offered intensive treatment at the end of the randomized study period.

Risk of CV death persists after long-term, targeted, intensive intervention

After the total 13.3 year follow-up, the death rate among patients receiving conventional therapy was 50%, compared with 30% on intensive therapy. The absolute residual risk of death from CV cause in the intensive treatment group was 11% (vs. 24% in the conventional treatment group). There was a 29% reduction in absolute risk, and a 59% reduction in relative risk of CV events with intensive therapy (Figure 1).

Microvascular residual risk remains substantial after 13 years of multifactorial therapy
Reductions in the risk of microvascular complications were maintained over the 13.3-year period. This means that the important microvascular residual risk seen in the original randomized study persisted and even increased over time (Table 1).
In fact, this extension of the Steno-2 study is akward to interpret. It might be seen as a comparison of two different durations of multifactorial intervention, but the number of patients either maintained on (or switched to) intensive therapy at the beginning of the observational follow-up is unknown.

With this in mind, results tend to confirm that long-term, targeted, intensive intervention involving multiple risk factors reduces the risk of both macrovascular and microvascular events among patients with type 2 diabetes and microalbuminuria. Persistence of incident important micro- and macrovascular complications despite long-term treatment with currently acknowledged interventions also seems to be confirmed.


Figure 1: Number of events for each component of the composite cardiovascular endpoint

Microvascular complication of diabetes

Intensive multifactorial


Development of diabetic nephropathy



Progression of diabetic retinopathy



Laser therapy for diabetic retinopathy



Blindness in one eye



Autonomic neuropathy



Peripheral neuropathy



Table 1. Microvascular residual risk (percentage of patients affected) in participants of the Steno-2 study initially allocated to intensive multifactorial or conventional treatment after a 13.3 year follow-up (7.8 year randomized study plus 5.5 year observational follow-up)

  1. Gæde P, Vedel P, Larsen N, et al. N Engl J Med 2003;348:383-93.
Key words Diabetes – intensive, multifactorial intervention - macrovascular and microvascular events