Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Objective: To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Design: Prospective observational study. Setting: 23 hospital based clinics in England, Scotland, and Northern Ireland. Participants: 4585 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. Outcome measures: Primary predefined aggregate clinical outcomes: any end point or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photo-coagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 1% reduction in updated mean HbA 1c adjusted for possible confounders at diagnosis of diabetes. Results: The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA 1c was associated with reductions in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P Conclusions: In patients with type 2 diabetes the risk of diabetic complications was strongly associated with previous hyperglycaemia. Any reduction in HbA 1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA 1c values in the normal range (

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Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

Background In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. Methods In a double-blind trial lasting five years, we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. Results The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 per...

The Effect of Pravastatin on Coronary Events after Myocardial Infarction in Patients with Average Cholesterol Levels

BACKGROUND
Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.


METHODS
3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.


FINDINGS
Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).


INTERPRETATION
Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)

OBJECTIVE To assess predictors of CVD mortality among men with and without diabetes and to assess the independent effect of diabetes on the risk of CVD death. RESEARCH DESIGN AND METHODS Participants in this cohort study were screened from 1973 to 1975; vital status has been ascertained over an average of 12 yr of follow-up (range 11–13 yr). Participants were 347,978 men aged 35–57 yr, screened in 20 centers for MRFIT. The outcome measure was CVD mortality. RESULTS Among 5163 men who reported taking medication for diabetes, 1092 deaths (603 CVD deaths) occurred in an average of 12 yr of follow-up. Among 342,815 men not taking medication for diabetes, 20,867 deaths were identified, 8965 ascribed to CVD. Absolute risk of CVD death was much higher for diabetic than nondiabetic men of every age stratum, ethnic background, and risk factor level—overall three times higher, with adjustment for age, race, income, serum cholesterol level, sBP, and reported number of cigarettes/day ( P CONCLUSIONS These findings emphasize the importance of rigorous sustained intervention in people with diabetes to control blood pressure, lower serum cholesterol, and abolish cigarette smoking, and the importance of considering nutritional-hygienic approaches on a mass scale to prevent diabetes.

https://www.siditalia.it/pdf/Diabete-ed-Arterosclerosi/MRFIT_Diab_care_1993.pdf

Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.

In the Whitehall study of 18 403 male civil servants aged 40-64 years the 10 year mortality rates from coronary heart disease and stroke showed a non-linear relation to two hour blood glucose values, with a significantly increased risk for glucose intolerant subjects with concentrations above the 95th centile point (5.4-11.0 mmol/l; 96-199 mg/100 ml) and for diabetics (blood glucose greater than or equal to 11.1 mmol/l; greater than or equal to 200 mg/100 ml). Multiple logistic analysis showed that between one half and three quarters of the relative risks for deaths from coronary heart disease and stroke were "unexplained" by between group differences in risk factors such as age, blood pressure, obesity, smoking, cholesterol concentration, and electrocardiographic abnormalities. Within the glucose intolerant and diabetic groups the risk factors most strongly related to subsequent death from coronary heart disease were age and blood pressure, with less consistent relations for smoking, cholesterol concentration, and obesity. This study confirms the importance of hypertension as a cardiovascular risk factor in groups with glucose intolerance and diabetes, and this may have important preventive implications.

https://www.bmj.com/content/bmj/287/6396/867.full.pdf

Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.

To study the possible role of an "increased thrombotic tendency" in the vascular complications of diabetes several tests of haemostatic function were carried out on 91 men and 63 women with diabetes aged 35-54 years and the results compared with findings in 686 men and 393 women of the same age in the Northwick Park Heart Study. Mean values for factors VII and X, fibrinogen, and platelet adhesiveness were higher in the diabetics, but mean fibrinolytic activity and whole blood platelet counts were lower. Antithrombin III values were also higher in the diabetics, which may have constituted a protective response to other changes favouring the onset of vascular disease. Diabetics with retinopathy had higher factor VII and antithrombin III values, and those with proteinuria had higher values for factor VII, fibrinogen, and platelet adhesiveness than those without these complications. These findings suggest a potentially important association between a thrombogenic tendency and vascular disease in diabetes. Nevertheless, prospective data are needed to clarify whether the haemostatic abnormalities precede the onset of clinically manifest vascular complications or are a consequence of them.

https://www.bmj.com/content/bmj/2/6196/964.full.pdf

Haemostatic variables associated with diabetes and its complications.

Myocardial ischæmia, risk factors and death from coronary heart-disease

To study the role of nutritional factors in the genesis of diabetes, estimations of blood sugar concentration, food intake, and adiposity (as body mass index; BMI) were carried out on three normal population samples--namely, 961 employees of Beecham Ltd, 1005 employees of the Greater London Council, and 1488 middle-aged male civil servants (Whitehall study). Blood sugar concentrations and indices of glucose tolerance correlated positively with the degree of adiposity but tended to be negatively correlated with total food energy intake and its component nutrients (total carbohydrate, sucrose, and fat). This inverse trend was largely accounted for by highly significant inverse correlations between food energy intake and adiposity, a relation found in both sexes and in all three population samples and which extended across the whole range of nutrient intake and BMI. These findings suggest that greater degrees of adiposity are associated with lower than average food energy intakes and hence lower total energy expenditures. The association of increased adiposity with low food energy consumption may indicate an underlying "low energy throughput" state, and it may be the mechanisms of this, as well as the obesity, that are responsible for disease.

H Keen

Papers

Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.

Haemostatic variables associated with diabetes and its complications.

Myocardial ischæmia, risk factors and death from coronary heart-disease

Nutrient intake, adiposity, and diabetes.

Hyperglycaemia and coronary heart disease: the Whitehall study.