THE STENO DIABETES STUDY
This study was a randomized, open, parallel trial at the Steno Diabetes Center in Denmark and offers us a comparison of the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on risk factors for cardiovascular disease in type 2 diabetes. It was done by Gaude P, et al. The results can be found in the New England Journal of Medicine 348:383-393, 2003. Eighty patients with type 2 diabetes and microalbuminuria were assigned to receive conventional treatment in accordance with national guidelines, and another eighty assigned to receive intensive treatment with stepwise implementation of behavior modification and pharmacological therapy that treated hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with aspirin. The endpoints were death from CVD, nonfatal MI, nonfatal stroke, revascularization, and amputation.
People with diabetes have a two to three times risk of CVD than those without diabetes. Effective treatments are available to treat macro-and microvascular complications of diabetes. In particular, there is evidence of benefit of single-factor interventions: intensive glucose, lipid, and blood pressure control; treatment of microalbuminuria; and the use of regular aspirin. There is, however, scant literature on the effectiveness of multifactorial interventions, as would be applied in clinical practice, on CVD among people with diabetes.
The Steno study attempted to close this gap in evidence by testing an intensive multifactorial intervention against conventional treatment. The intensive intervention consisted of step-wise introduction of lifestyle and pharmacological interventions aimed at keeping glycated hemoglobin <6.5%, blood pressure <130/80mmHg, total cholesterol <175mg/dl, and triglycerides <150mg/dl. The lifestyle component of the intensive intervention included reduction in intake dietary fat, regular exercise, and smoking cessation. Participants receiving intensive intervention were also advised to take aspirin. A dietary supplement consisting of vitamins E and C, folic acid, and chromium picolinate were given as a angiotensin-converting enzyme (ACE) inhibitor, regardless of blood pressure.
After 7.8 years of follow-up, 44% of patients in the conventional arm, but only 24% in the intensive, multifactorial arm, developed CVD, representing a 53% reduction in risk. One CVD event was prevented for every five patients treated for 7.8 years with intensive, multifactorial intervention. The risks for nephropathy, retinopathy, and autonomic neuropathy were also lower in the multifactorial treatment group by 61, 58, and 63% respectively.
Reviewers of the study say that from a study such as this one, it is not possible to tease out the effects of each component of the multifactorial intervention, nor was this the purpose of the study. The authors were justified, based on existing evidence of CVD benefit, in including smoking cessation, physical activity promotion, lipid and blood pressure control, aspirin therapy, and ACE inhibitor therapy. Strong evidence for microvascular benefits from glycemic control exists and, although not unequivocally established, glucose control may also have positive benefits on CVD. On the other hand, CVD benefits from routine vitamin or mineral supplementation have not been established, and their inclusion in a multifactorial intervention to prevent CVD is thought by some reviewers to be premature.
Despite these limitations, the Steno study provides evidence that an aggressive multifactorial intervention which can be delivered in a real-life clinical practice situation can lower the risk of CVD among people with diabetes and microalbuminuria by 50%. The quality of diabetes care remains suboptimal in the United States and elsewhere, despite the availability of effective treatments to prevent CVD. The Steno study shows us the benefits of multifactorial interventions in practice and gives us strong reason to believe that evidence-based guidelines can be translated into clinical practice. The potential benefit to be accrued, in terms of CVD prevention, from systematic application of current knowledge, is enormous.
UK PROSPECTIVE DIABETES STUDY
The UKPDS is the largest and most comprehensive study of type 2 diabetes that has been undertaken. It was undertaken after the results of the DCCTs for type 1 diabetes were recognized. It was set up in 1977, initially as a pilot scheme involving five centers in England, Scotland and Northern Ireland. The study was subsequently extended to 23 centers. In 1987, the study of treatment of hypertension was started. UKPDS recruited 5100 patients who were allocated to various treatment groups. From the point of view of their age and racial mix, these people were representative of the typical British patients with type 2 diabetes. UKPDS closed at the end of 1997 and the results published in 1998.
The initial results indicated that intensive blood glucose control policy decreased the risk of diabetic complication. It also found that tight blood pressure control decreased the risk of diabetic complications.
The 5-year Post Study Monitoring (DSM) program for the UK Prospective Diabetes Study ran from 1997 to 2002. Its main objectives were: 1. to observe the glycemic and blood pressure levels achieved after the trial stopped, 2. to determine the degree to which glycemia and blood pressure related risk reductions obtained during the trial remained evident, 3. to examine the impact on macrovascular outcomes with extended follow up of improved glucose control, and, in overweight patients, of metformin therapy, and 4. to re-evaluate the apparent increased case observed in the sulphonylurea/metformin study. Careful monitoring for the predefined UKPDS clinical outcomes continued with collection of detailed documentation and adjudication by the UKPDS Endpoint Committee, exactly as during the trial. In addition, patients were seen annually in UKPDS clinics where possible to continue standardized collection of clinical and biochemical measurements.
The results:
- Mean HbA1c levels rose in patients randomized previously to an intensive glucose control policy such that by year three, mean HbA1c levels were indistinguishable from those for patients randomized previously to a conventional glucose control policy. After year three, mean HbA1c levels improved in both groups.
- Mean systolic blood pressure rose in patients randomized to a tight blood pressure control policy so that by year two, mean blood pressure levels were indistinguishable from those for patients randomized previously to a less tight blood pressure control policy. After year two, mean systolic and diastolic blood pressure levels improved in both groups.
Given that:
- Patients returned to routine diabetic care
- Mean HbA1c levels converged by three years
- Mean BP levels converged by two years
Initial analyses presented on the Tuesday 27th August 2003 qt the IDF meeting in Paris suggest that the risk reductions seen five years after the end of the study:
- On people previously randomized to more intense glucose control, were similar to those seen during the trial
- In people previously randomized to tight blood pressure control, tended to be less than those seen during the trial
- In overweight people previously randomized to first line therapy with metformin, had diminished, but remained significant for the primary endpoints, mortality and cardiovascular disease.
In addition, the apparently increased case fatality rate, which was observed in the sulphonylurea/metformin sub study, had decreased substantially and was no longer statistically significant.
They concluded that the benefits of improved glucose control obtained during the UKPDS trial appear to persist in the longer term whereas those obtained with improved blood pressure control were maintained to a lesser extent, once the study protocol was discontinued.
BSP
