Macro- and Microvascular Residual Risk Studies

COMMENT

Started in 1977, the United Kingdom Prospective Diabetes Study (UKPDS) was designed to establish whether, in patients with type 2 diabetes, intensive blood glucose control reduced the risk of macrovascular or microvascular complications, and whether any particular therapy was more advantageous.
It was known that improved blood glucose control decreased the progression of diabetic microvascular disease,however the effect on macrovascular complications was unknown.^1,2
In UKPDS 33, conducted between 1977 and 1991, general practitioners were asked to refer all patients newly diagnosed with type 2 diabetes to one of 23 UKPDS hospital clinics. Eligible patients** were first entered in a 3-month dietary run-in followed by random assignment to a conventional dietary regimen or intensive pharmacological treatment with insulin or a sulphonylurea (chlorpropamide, glibenclamide, or glipizide). Because of the possibility of weight gain with insulin or sulphonylureas, overweight patients could take metformin.

Can we rest satisfied with the fact that a statistically significant reduction in risk of microvascular events is achieved after intensive blood glucose control?

The intensive blood glucose control resulted in an 11% reduction in median glycated hemoglobin (HbA1c) over the first 10 years. A 25% reduction in relative risk of microvascular complications, mainly due to fewer patients requiring photocoagulation, was observed (Figure 1). Though statistically significant, this result shows that intensive blood glucose control alone failed to prevent 3 out of 4 microvascular events, thus leaving room for major improvements in risk reduction. No difference was seen between the three intensive treatment arms, showing that improved glycaemic control per se, rather than any one therapy, was the principal controlling factor. The observed disadvantages of intensive treatment were weight gain and risk of hypoglycemia.

Intensive blood glucose control does not prevent macrovascular disease in type 2 diabetic patients

Despite an impressive figure of patients-years of follow-up, inconclusive evidence of a 16% risk reduction (p=0·052) for myocardial infarction (MI), which included non-fatal and fatal MI and sudden death was seen. Furthermore, diabetes-related mortality and all cause mortality did not significantly differ between the intensive and conventional groups. The data did not support the suggestion of adverse cardiovascular effects from sulphonylureas or insulin.

Tight blood glucose control alone leaves a substantial unaddressed residual risk of micro- and macrovascular events

The evidence suggests that intensive blood glucose control alone does not prevent most microvascular complications, and is not effective in reducing the risk of macrovascular events. Other therapeutic approaches may therefore be required to decrease cardiovascular morbidity and mortality. These findings and data from subsequent trials, such as STENO-2,3 support the case for additional strategies to reduce the residual risk of micro- and macrovascular events.

Figure 1: Kaplan-Meier plots of aggregate endpoint microvascular disease (renal failure, death from renal failure,
retinal photocoagulation, or vitreous haemorrhage)