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Macro- and Microvascular Residual Risk Studies

9 March 2009
UKPDS 33: Despite improved blood glucose control, 75% of microvascular complications and 84% of macrovascular events are not prevented in patients with type 2 diabetes
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53
UK Prospective Diabetes Study Group.
Objective To compare the effects of intensive sulphonylurea or insulin therapy with conventional diet on risk of macro- and microvascular disease in type 2 diabetes patients.
Study population
3867 patients with newly diagnosed type 2 diabetes, 48–60 years old, with mean fasting plasma glucose (FPG) 6·1–15·0 mmol/L.
Primary endpoint: FPG <6 mmol/L in the intensive group, and the best achievable FPG in the conventional group.
Secondary endpoint(s): Any diabetes-related endpoint; diabetes-related death; all-cause mortality.
Study design Randomized controlled trial.
Outcomes were analysed over 10 years.
Main results
  • Comparing intensive with conventional therapy:

    • Glycated haemoglobin (HbA1c) was 7·0% vs 7·9%, with more hypoglycaemic episodes.
    • Despite a significant decrease in risk for any diabetes-related endpoint (12%; P = 0·029), non significant decrease in myocardial infarction (16%, p=0·052), any diabetes-related death (10%; P = 0·34) or all-cause mortality (6%; P=0·44).
    • A significant 25% risk reduction (P = 0·0099) in microvascular endpoints.
Author's conclusion Intensive blood glucose control decreases risk of microvascular, but not macrovascular disease.


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)


  1. Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28: 103–17.
  2. University Group Diabetes Program. JAMA 1978; 240: 37–42.
  3. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. N Engl J Med. 2003;348:383-93.
Key words HDL cholesterol – LDL cholesterol –- predictive on major cardiovascular events