Intensive blood glucose control reduced type 2 diabetes mellitus-related end points
ACP J Club. 1999 Jan-Feb;130:2. doi:10.7326/ACPJC-1999-130-1-002
UK Prospective Diabetes Study Group. 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 Sep 12;352:837-53.
In patients with newly diagnosed type 2 diabetes mellitus, what is the effect of intensive plasma glucose control on the risk for macrovascular and microvascular complications?
Randomized controlled trial with median follow-up of 10 years.
23 hospital-based diabetes clinics in the United Kingdom.
3867 patients (mean age 53 y, 61% men, mean body mass index 27.5 kg/m2) with newly diagnosed type 2 diabetes and fasting plasma glucose (FPG) levels between 6.1 mmol/L and 15.0 mmol/L after 3 months of dietary therapy without symptoms of hyperglycemia. Exclusion criteria were ketonuria > 3 mmol/L, serum creatinine level > 175 µmol/L, myocardial infarction (MI) in the previous year, heart failure or angina, major vascular events, retinopathy requiring laser therapy, malignant hypertension, an uncorrected endocrine disorder, an occupation precluding insulin therapy, or severe concurrent illness. Follow-up was 96%.
After stratification for obesity (body weight > 120% of ideal), 2729 patients were allocated to intensive treatment aiming for FPG levels of < 6 mmol/L (by dietary treatment and use of oral medication [chlorpropamide, glibenclamide, glipizide, or metformin] or insulin); and 1138 patients were allocated to conventional dietary treatment aiming for FPG levels < 15 mmol/L without hyperglycemic symptoms.
Main outcome measures
A first diabetes-related predefined clinical end point, death related to diabetes, all-cause mortality, MI, stroke, amputation or death from peripheral vascular disease, and microvascular disease.
Analysis was by intention to treat. Patients allocated to intensive treatment had lower median hemoglobin A1c levels (7.0% vs 7.9%, P < 0.001), reduced diabetes-related clinical end points (40.9 vs 46.0 events/1000 patient-y, P = 0.029) and less microvascular disease (P = 0.01), increased major hypoglycemic episodes (0.7%/y for conventional treatment, 1.0%/y for chlorpropamide, 1.4%/y for glibenclamide, and 1.8%/y for insulin, P < 0.001), and a mean 3.1-kg greater weight gain (P < 0.001) than those allocated to conventional treatment. No difference existed for macrovascular events, diabetes-related deaths, or all-cause mortality.
In patients with type 2 diabetes, intensive blood glucose control reduced diabetes-related end points and microvascular disease, increased major hypoglycemic episodes, and had no effect on macrovascular end points.
Sources of funding: 11 government, university, and charitable organizations and 19 independent drug and related companies.
For correspondence: Professor R. Turner, U.K. Prospective Diabetes Study Group, Diabetes Research Laboratories, Radcliffe Infirmary, Oxford OX2 6HE, England, United Kingdom.
The Diabetes Control and Complications Trial (DCCT) clearly showed that tight glycemic control with intensified insulin therapy dramatically reduces microvascular disease in patients with type 1 diabetes (1). The small number of cardiovascular events in the DCCT precluded detection of any cardioprotective effects, despite a tantalizing trend. Although surrogate primary end points were studied, the effect size and consistency of the effect across different end points in this and other studies led to widespread acceptance of tight glucose control for prevention of microvascular complications in type 1 diabetes. Until now, the DCCT results were generalized to patients with type 2 diabetes, without strong direct evidence in this group.
The United Kingdom Prospective Diabetes Study (UKPDS) now provides direct evidence of a policy of intensive blood glucose control for patients with type 2 diabetes. In contrast to the DCCT, the UKPDS used "hard" clinical primary end points and a variety of interventions.
The UKPDS did not achieve stable glucose levels. The hemoglobin A1c level rose steadily in both groups. Furthermore, the 0.9% separation in median hemoglobin A1c throughout the first 10 years of the UKPDS study was considerably less than the 2% separation shown in the DCCT (1).
Despite achieving only modestly better glucose control, the UKPDS clearly showed that an intensive treatment policy reduced diabetes-related end points and microvascular disease. A strong trend in favor of reduced risk for MI was also shown (relative risk reduction = 16%, P = 0.052).
In patients who were overweight, the UKPDS showed that an intensive therapy policy beginning with metformin reduced diabetes-related end points and microvascular disease plus diabetes-related deaths, MI, and all-cause mortality. This approach was superior to the other intensive therapies. Results for the treatment with metformin need to be interpreted cautiously in light of a subsequent analysis showing that addition of metformin to therapy of both obese and nonobese patients with suboptimal control on sulfonylureas increased diabetes-related death and all-cause mortality.
In light of these results, what can we conclude? First, clear and consistent evidence now exists that hyperglycemia in diabetes is a continuous, modifiable risk factor for clinically important outcomes and that reduction in glucose is the key to improving outcomes. Interventions that maintain optimal glucose levels for long periods are likely to result in even larger clinical benefits. Second, intensive therapy with sulfonylureas and insulin, but not metformin, modestly increases the risk for severe hypoglycemia and weight gain, but these adverse effects are offset by the clinical benefits. The higher rate of these adverse effects with insulin suggests that oral agents should be the initial therapeutic choice. Third, these data support the choice of metformin as a first-line agent for obese patients, unless contraindicated. Fourth, type 2 diabetes is clearly a progressive disease. Increased effort and several types of therapies need to be applied over time for adequate glycemic control. Finally, the UKPDS provides no support for the belief that exogenous insulin causes cardiovascular disease; indeed, there was a strong trend in the opposite direction.
We now have convincing evidence that glucose control is an important goal for type 2 diabetes. Unless patients are seriously ill or have a short life expectancy, the long-term benefits of intensive therapy clearly outweigh the few risks. Merely eliminating symptoms of hyperglycemia is unsatisfactory. Our task is to convince patients of the value of this approach and to work with the health care team to teach patients how to improve glycemia and reduce their risk for the many complications of diabetes.
Hertzel C. Gerstein, MD
McMaster University Health Sciences CentreHamilton, Ontario, Canada
1. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:977-86.