The United Kingdom Prospective Diabetes Study (UKPDS) was a randomised multi-centre trial which demonstrated that intensive glucose therapy in patients with newly diagnosed type 2 diabetes mellitus resulted in a decreased risk of clinically evident microvascular complications and a non-significant reduction in the relative risk of myocardial infarction (p=0.052). The results of 10 year follow up of the UKPDS survivor cohort have been published ‘on-line early’ in the New England Journal of Medicine’ and examined:
1. was a microvascular benefit from earlier improved glycaemic control sustained?
2. did such therapy have a long term effect on macrovascular outcomes?
3. was a continued benefit of earlier improved blood pressure control evident and if so to what degree did this persist?
Between group differences in glycated haemoglobin levels (HbA1c) were lost after the first year. In the sulphonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes related end-point (9%, p=0.04), microvascular disease (24%, p=0.001), myocardial infarction (15%, p=0.01) and death from any cause (13%, p=0.007). In the metformin group significant reductions persisted for any diabetes related end-point (21%, p=0.01), myocardial infarction (33%, p=0.005) and death from any cause (27%, p=0.002). Differences in blood pressure control between the 2 groups were lost within 2 years of the trial ending. The significant relative risk reductions found during the trial between intensive therapy and a less rigorous regime in any diabetes related end-point, diabetes related death, microvascular disease and
stroke were not sustained during the trial follow-up period. A risk reduction for peripheral vascular disease with tight blood pressure control became significant (p=0.02).
This large post-trial study shows that benefits of an intensive strategy to control blood glucose levels in patients with Type 2 diabetes are sustained for up to 10 years after the cessation of the randomised interventions. Furthermore, the risk reductions for myocardial infarction and death from any cause were observed only with extended post-trial follow-up.
The pathophysiology behind the so called ‘legacy effect’ appears to be uncertain. Possible mechanisms include increased intracellular formation of advanced glycosylation end-products. Long term hyperglycaemia is associated with the gradual onset of microvascular disease which may be mediated by the accumulation of these end-products which are then subsequently slowly degraded by intensive glycaemic control. This might also have a role in cardiovascular disease processes. The sustained post-interventional benefit observed in UKPDS might be explained by a lag phase before a reduction in events could occur because of improved glycaemic control in the conventional therapy arm after the implementation of stricter guidelines on the basis of the initial UKPDS results.
The 10 year follow up from the blood pressure intervention cohort demonstrates that the benefits seen in patients assigned to an intensive regime were not maintained once the difference in blood pressure seen during the trial itself were lost. The lower blood pressure levels attained in the early stages of diabetes do not appear to confer a subsequent ‘legacy effect’ as is seen with glycaemic control. Since UKPDS, other trials have demonstrated the importance of treating hypertension in patients with Type 2 diabetes( e.g. CONSENSUS, MRFIT), however none have reported long-term post trial follow-up data.
- Holman RR, Paul SK, Bethel MA etal. 10-Year Follow-Up of Intensive Glucose Control in Type 2 Diabetes. N. Engl J Med 2008;359: (published online September 10th 2008)
- Holman RR, Paul SK, Bethel MA etal. Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes. N. Engl J Med 2008;359: (published online September 10th 2008)