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 photocoagulation). 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 < 0.0001), 21% for deaths related to diabetes (15% to 27%, P < 0.0001), 14% for myocardial infarction (8% to 21%, P < 0.0001), and 37% for microvascular complications (33% to 41%, P < 0.0001). No threshold of risk was observed for any end point. 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 ( < 6.0%).

The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.

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Not all patients with type 2 diabetes develop renal dysfunction. Identifying those at risk is problematic because even microalbuminuria, often used clinically as an indicator of future renal dysfunction, does not always precede worsening renal function. We sought to identify clinical risk factors at diagnosis of type 2 diabetes associated with later development of renal dysfunction. Of 5,102 U.K. Prospective Diabetes Study (UKPDS) participants, prospective analyses were undertaken in those without albuminuria (n ‫؍‬ 4,031) or with normal plasma creatinine (n ‫؍‬ 5,032) at diagnosis. Stepwise proportional hazards multivariate regression was used to assess association of putative baseline risk factors with subsequent development of albuminuria (microalbuminuria or macroalbuminuria) or renal impairment (Cockcroft-Gault estimated creatinine clearance <60 ml/min or doubling of plasma creatinine). Over a median of 15 years of follow-up 1,544 (38%) of 4,031 patients developed albuminuria and 1,449 (29%) of 5,032 developed renal impairment. Of 4,006 patients with the requisite data for both outcomes, 1,534 (38%) developed albuminuria and 1,132 (28%) developed renal impairment. Of the latter, 575 (51%) did not have preceding albuminuria. Development of albuminuria or renal impairment was independently associated with increased baseline systolic blood pressure, urinary albumin, plasma creatinine, and Indian-Asian ethnicity. Additional independent risk factors for albuminuria were male sex, increased waist circumference, plasma triglycerides, LDL cholesterol, HbA 1c (A1C), increased white cell count, ever having smoked, and previous retinopathy. Additional independent risk factors for renal impairment were female sex, decreased waist circumference, age, increased insulin sensitivity, and previous sensory neuropathy. Over a median of 15 years from diagnosis of type 2 diabetes, nearly 40% of UKPDS patients developed albuminuria and nearly 30% developed renal impairment. Distinct sets of risk factors are associated with the development of these two outcomes, consistent with the concept that they are not linked inexorably in type 2 diabetes.

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FOR THE U.K. PROSPECTIVE DIABETES STUDY GROUPOBJECTIVE -To evaluate the efficacy of the addition of insulin when maximal sulfonylurea therapy is inadequate in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODS -Glycemic control, hypoglycemia, and body weight were monitored over 6 years in 826 patients with newly diagnosed type 2 diabetes in 8 of 23 U.K. Prospective Diabetes Study (UKPDS) centers that used a modified protocol. Patients were randomly allocated to a conventional glucose control policy, primarily with diet (n ϭ 242) or an intensive policy with insulin alone (n ϭ 245), as in the main study. However, for patients randomized to an intensive policy with sulfonylurea (n ϭ 339), insulin was added automatically if the fasting plasma glucose remained Ͼ108 mg/dl (6.0 mmol/l) despite maximal sulfonylurea doses.RESULTS -Over 6 years, ϳ53% of patients allocated to treatment with sulfonylurea required additional insulin therapy. Median HbA 1c in the sulfonylurea Ϯ insulin group was significantly lower (6.6%, interquartile range [IQR] 6.0 -7.6) than in the group taking insulin alone (7.1%, IQR 6.2-8.0; P ϭ 0.0066), and significantly more patients in the sulfonylurea Ϯ insulin group had an HbA 1c Ͻ7% (47 vs. 35%, respectively; P ϭ 0.011). Weight gain was similar in the intensive therapy groups, but major hypoglycemia occurred less frequently over all in the sulfonylurea (Ϯ insulin) group compared with the insulin alone group (1.6 vs. 3.2% per annum, respectively; P ϭ 0.017).CONCLUSIONS -Early addition of insulin when maximal sulfonylurea therapy is inadequate can significantly improve glycemic control without promoting increased hypoglycemia or weight gain. Diabetes Care 25:330 -336, 2002T he U.K. Prospective Diabetes Study (UKPDS) showed that intensive control of blood glucose with sulfonylurea or insulin, and with metformin in overweight patients, substantially reduced the risk of diabetic complications (1). The intensive glucose control policy used in the first 15 UKPDS centers (Glucose Study 1) required patients to remain on their allocated monotherapy, unless fasting plasma glucose (FPG) levels increased to Ͼ15 mmol/l or hyperglycemic symptoms ensued, to evaluate specific advantages or disadvantages of individual therapies. With the realization that progressive hyperglycemia was occurring in all randomized groups (2-4) and that additional therapy might be desirable at the stage of sulfonylurea inadequacy (5) rather than sulfonylurea failure, a modified protocol (Glucose Study 2) was introduced in the last eight UKPDS centers (6). This protocol, the aim of which was to determine whether a more aggressive glucose control policy could minimize hyperglycemic progression, differed only in that insulin therapy was added immediately in patients allocated to sulfonylurea therapy if maximal doses did not maintain FPG levels Ͻ108 mg/dl (6.0 mmol/l).A meta-analysis of randomized controlled trials (7) has shown that combining sulfonylurea and insulin therapy can improve metabolic control with significantly smal...

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