Issue 145 Item 10 Aggressive Multifactor Risk-Reduction Treatment Approach Works

Until now efficacy of the multifactorial approach has never been validated in a prospective trial. The Steno-2, from Denmark, makes it abundantly clear that this strategy is clearly superior to the conventional one of targeting individual risks.

The Steno-2 trial involved 160 type 2 diabetic adults with microalbuminuria who were assigned randomly to a conventional or an intensive, multifactorial, goal-targeted strategy for a period of 8 years. The protocol specified 2 analyses — microvascular end points and macrovascular end points — hence, the inclusion criterion of microalbuminuria, which is a predictor of both kinds of complications.

All subjects in both groups received an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB). In the "targeted, intensified, multifactorial intervention group," a stepwise treatment plan was adopted for each of 4 factors, with the goals of reducing HbA1c to < 6.5% (with diet, exercise, metformin, sulfonylurea, and various insulins), blood pressure to < 130/80 mm Hg (with a variety of antihypertensive agents added to the ACE-I or ARB), fasting serum total cholesterol to < 175 mg/dL (with statins), and fasting serum triglycerides to < 150 mg/dL (with fibrates). All patients in the intensive group also received aspirin, regardless of whether there was a history of coronary heart disease or peripheral vascular disease. The primary end point was a macrovascular outcome: a composite of death from cardiovascular causes, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, nonfatal stroke, amputation for ischemia, or vascular surgery for peripheral arterial atherosclerosis.

The secondary end points were microvascular outcomes: the development of diabetic nephropathy (24-h urine albumin > 300 mg) or development or progression of diabetic retinopathy or neuropathy.

The study results were quite spectacular, with an overall reduction in the risk of cardiovascular and microvascular events by about 50% in the intensive, multiple risk factor target group.

Specific group differences in the degree of change in key clinical parameters at the end of the study were (in the intensive group): lower systolic and diastolic blood pressures, increased carbohydrate and decreased fat intake as percentages of total energy, and decreased HbA1c, total cholesterol, LDL-cholesterol, triglycerides, and 24-h urine albumin excretion. These translated to the following significant group differences in key end points: 44% in the conventional group had a cardiovascular event compared with 24% in the intensive group; the curves representing time to first cardiovascular event for the 2 groups continued to diverge throughout the follow-up period; relative risk of developing nephropathy, retinopathy, and autonomic neuropathy all pointed to a significant benefit for the intensively treated group.

For the practicing physician, the chief lesson from the Steno-2 study is that early and continuous use of an intensive, targeted, multifactorial approach produces significant and persistent benefits in diminishing diabetic complications. The lesson by no means confines the practitioner to a specific algorithm. Indeed, it might be possible to achieve even greater benefits by utilizing additional interventions or by broadening the application of existing therapies.

For example, as pointed out by Dr. C.G. Solomon in an accompanying editorial,[1] the Heart Outcomes Prevention Evaluation (HOPE) study demonstrated that ACE-I use decreased the cardiovascular event rate by 25% even in diabetic patients without microalbuminuria, whereas the Steno-2 study was limited to subjects with microalbuminuria. Potentially greater risk reduction might accrue to mutifactorial intervention, including ACE-I treatment, in diabetic patients without any clinical evidence of renal dysfunction.

A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent. N Engl J Med. 2003;348:457-459.