Aims/hypothesis: We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. Methods: Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. Results: Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA(1)c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome ( as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p< 0.0001). Conclusions/interpretation: Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients.

Objective: To determine the relation between systolic blood pressure 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: 4801 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 complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity 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 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders Results: The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, 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 raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

Objective: To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes.Design: Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of < 150/ < 85 mm Hg.Setting 20 hospital based clinics in England, Scotland, and Northern Ireland.Subjects: 1148 hypertensive patients with type 2 diabetes(mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure.Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography.Results: Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment: at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P < 0.0001). Captopril and atenolol were equally effective in reducing the risk of macrovascular end points. Similar proportions of patients in the true groups showed deterioration in retinopathy by two grades after nine years (31% in the captopril group and 37% in the atenolol group) and developed clinical grade albuminuria greater than or equal to 300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg).Conclusion: Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.Design: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <.180/105 mm Hg.Setting 20 hospital based clinics in England, Scotland, and Northern Ireland.Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years.Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography.Results: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P< 0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P= 0.0046), 32% in deaths related to diabetes (6% to 51%) (P= 0.019), 44% in strokes (11% to 65%) (P= 0.013), and 37% in microvascular end points (11% to 56%) (P= 0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P= 0.0004) and a 47% reduced risk (7% to 70%) (P = 0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures.Conclusion: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.

Objectives: To estimate the economic efficiency of tight blood pressure control, with angiotensin converting enzyme inhibitors or beta blockers, compared with less tight control in hypertensive patients with type 2 diabetes.Design: Cost effectiveness analysis incorporating within trial analysis and estimation of impact on life expectancy through use of the within trial hazards of reaching a defined clinical end point Use of resources driven by trial protocol and use of resources in standard clinical practice were both considered.Setting: 20 hospital based clinics in England, Scotland, and Northern Ireland.Subjects: 1148 hypertensive patients with type 2 diabetes from UK prospective diabetes study randomised to tight control of blood pressure (n = 758) or less tight control (n = 390).Main outcome measure: Cost effectiveness ratios based on (a) use of healthcare resources associated with tight control and less tight control and treatment of complications and (b) within trial time free from diabetes related end points, and life years gained.Results: Based an use of resources driven by trial protocol, the incremental cost effectiveness of tight control compared with less tight control was cost saving. Based on use of resources in standard clinical practice, incremental cost per extra year free from end points amounted to pound 1049 (costs and effects discounted at 6'% per year) and pound 434 (costs discounted at 6%, per year and effects not discounted). The incremental cost per life year gained was pound 720 (costs and effects discounted at 6% per year) and pound 291 (costs discounted at 6% per year and effects not discounted).Conclusions: Tight control of blood pressure in hypertensive patients with type 2 diabetes substantially reduced the cost of complications, increased the interval without complications and survival, and had a cost effectiveness ratio that compares favourably with many accepted healthcare programmes.

OBJECTIVE To assess the efficacy over 3 years of the addition of metformin to maximum sulfonylurea therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS This multicenter randomized open-controlled trial was conducted in outpatient diabetes clinics in 15 U.K. hospitals. A total of 591 subjects who had already been randomly allocated to sulfonylurea therapy were taking maximum doses with suboptimal glycemic control, i.e., raised fasting plasma glucose (FPG) concentrations of 6−15 mmol/l but no significant hyperglycemic symptoms. The main outcome measures included FPG, glycated hemoglobin, protocol-defined marked hyperglycemia, body weight, blood pressure, fasting plasma lipids, compliance, and hypoglycemia and other side effects. RESULTS After the addition of metformin, FPG concentrations decreased by mean (95% CI) −0.47 (−0.82 to −0.13) mmol/l over 3 years compared with an increase of 0.44 (0.07−0.81) mmol/l in subjects on sulfonylurea alone (P < 0.00001). Median FPG concentrations at 3 years were 8.6 vs. 9.9 mmol/l, respectively (P < 0.00001), and HbA1c values were 7.5 and 8.1%, respectively (P = 0.006). Adjustment for baseline BMI or FPG concentration did not affect response to therapy. Only 7% of those allocated to sulfonylurea plus metformin developed protocol-defined marked hyperglycemia compared with 36% of those allocated to sulfonylurea alone (P < 0.0001). Fasting plasma lipids, body weight, and blood pressure did not change significantly. The incidence of hypoglycemic episodes did not differ between groups: 4% on sulfonylurea plus metformin and 2% on sulfonylurea alone (NS). CONCLUSIONS Early addition of metformin improved glycemic control in patients with suboptimal glycemic control while taking maximum sulfonylurea therapy, irrespective of obesity or baseline FPG concentrations.

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 atone; 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 A(1c) (HbA(1c)) 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 HbA(1c) 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 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. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.

Background In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage.Methods Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10.7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L), were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268).Findings Median glycated haemoglobin (HbA(1c)) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011). Among patients allocated intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032). Early addition of metformin in sulphonyl urea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2-275], p=0.039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78).Interpretation Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.

Background: Uncertainty exists about the suitability of oral hypoglycemic drugs and insulin therapy for patients with newly diagnosed type 2 diabetes.Objective: To assess and compare response to sulfonylurea, insulin, or metformin over 6 years in patients with newly diagnosed type 2 diabetes in whom disease could and could not be controlled with diet therapy alone.Design: Multicenter, randomized, controlled trial.Setting: Outpatient diabetes clinics of 15 hospitals in the United Kingdom.Intervention: Sulfonylurea (chlorpropamide or glyburide), insulin, or metformin (if patients were obese).Patients: 458 patients with newly diagnosed type 2 diabetes that could not be controlled with diet and had hyperglycemic symptoms or fasting plasma glucose levels greater than 15 mmol/L during the initial 3 months of diet therapy (primary diet failure group) and 1620 patients in whom disease was controlled by diet therapy and who had fasting plasma glucose levels of 6 to 15 mmol/L and no hyperglycemic symptoms while receiving diet therapy alone.Measurements: Fasting plasma levels of glucose and insulin, hemoglobin A(1c) concentrations, body weight, and therapy required.Results: Compared with the diet-controlled group, the primary diet failure group was younger and less obese and had more retinopathy, lower fasting plasma insulin levels, and reduced beta-cell function. At 6 years, patients allocated to insulin had lower fasting plasma glucose levels than did patients allocated to oral agents, but hemoglobin A(1c) concentrations were similar. Forty-eight percent (95% CI, 37% to 58%) of patients in the primary diet failure group maintained hemoglobin A(1c) concentrations less than 0.08. By 6 years, 51% of patients (CI, 42% to 62%) allocated to ultralente insulin required additional short-acting insulin and 66% of patients (CI, 58% to 73%) allocated to sulfonylurea required additional therapy with metformin or insulin to control symptoms and maintain fasting plasma glucose levels less than 15 mmol/L. Patients allocated to insulin gained more weight and had more hypoglycemic attacks than did patients allocated to sulfonylurea. Obese patients allocated to metformin gained the least weight and had the fewest hypoglycemic attacks. For all therapies, control achieved at 6 years was worse in the primary diet failure group than in the diet-controlled group.Conclusions: Because initial insulin therapy induced more hypoglycemic reactions and weight gain without necessarily providing better control, it may be reasonable to start with oral agents and change to insulin if goals for glycemic levels are not achieved.

Objective: To determine the prevalence of hypertension in newly diagnosed type 2 diabetic patients and its association with risk factors for cardiovascular and diabetic complications.Design: Cross-sectional study.Patients: Newly diagnosed type 2 diabetic patients (n = 3648, mean age 52 years, 59% male) recruited for the UK Prospective Diabetes Study (UKPDS).Measurements: Blood pressure, body mass index, waist:hip ratio, ECG signs of ischaemia and of left ventricular hypertrophy (Minnesota code), fasting plasma glucose, urate, creatinine, insulin, triglycerides, high-density lipoprotein-, low-density lipoprotein- and total cholesterol, urinary albumin: creatinine ratio, retinopathy grading.Results: Thirty-nine per cent of the patients (35% of the males, 46% of the females) were hypertensive (mean blood pressure greater-than-or-equal-to 160 systolic and/or greater-than-or-equal-to 90 mmHg diastolic 2 and 9 months after diagnosis of diabetes, or taking antihypertensive therapy). The hypertensive patients had a greater mean body mass index (30.1 versus 28.0 kg/m2, P < 0.0001) than the normotensive patients. They also had higher fasting plasma triglyceride (1.94 versus 1.69 mmol/l, P < 0.0001) and insulin (15.0 versus 12.8 mU/l, P < 0.0001) levels but these associations disappeared or weakened when obesity was taken into account. Hypertensive compared with normotensive subjects suffered a higher prevalence of cardiovascular events before the diagnosis of diabetes (4.8 versus 2.5%, P < 0.0001), of microalbuminuria (albumin: creatinine ratio > 5.0 g/mol; 24 versus 14%, P < 0.0001), of ECG signs of probable and possible ischaemia (24 versus 14%, P < 0.0001) and of left ventricular hypertrophy (8.5 versus 3.8%; P < 0.0001). The prevalence of retinopathy was similar in the two groups.Conclusions: Hypertension is common in newly diagnosed type 2 diabetes and is associated with obesity. The association between hypertension and higher triglyceride and insulin levels may be secondary to obesity in this population. An association between hypertension and cardiovascular complications is already apparent at diagnosis of diabetes.

Objective: To determine the degree to which hypertension is a risk factor for macrovascular and microvascular complications in type 2 diabetes.Design: Observational prospective study.Subjects: Newly diagnosed Type 2 diabetic patients recruited into the UK Prospective Diabetes Study (n = 3648; mean age 52 years), 40% of whom were hypertensive (blood pressure greater-than-or-equal-to 160 mmHg systolic and/or greater-than-or-equal-to 90 mmHg diastolic or already being treated for hypertension).Measurements. The incidence of fatal and non-fatal major diabetes- and hypertension-related clinical events was determined over a median of 4.6 years' follow-up. The 3-year change in prevalence of subclinical indices of macrovascular and microvascular disease was assessed, including ECG abnormalities (Minnesota coding), left ventricular hypertrophy (ECG and chest x-ray), microalbuminuria (albumin/creatinine ratio) and moderately severe retinopathy (grading of retinal photographs).Results: The hypertensive patients had (1) a greater incidence than normotensive patients of death from diabetes-related, mainly cardiovascular events (age-adjusted odds ratio 1.82) and (2) a greater incidence of diabetes-related death and major morbidity combined, including myocardial infarctions, angina, strokes and amputation (age-adjusted odds ratio 1.56). These associations were still present after allowance for other risk factors present at the time diabetes was diagnosed. The change in the prevalence of microvascular disease over 3 years was similar in both hypertensive and normotensive subjects.Conclusions: Hypertension is a major risk factor for cardiovascular morbidity and mortality in type 2 diabetes. Comparison with other studies suggests that patients with both hypertension and diabetes have approximately four times the cardiovascular risk of non-diabetic non-hypertensive subjects. Antihypertensive therapy may provide greater benefit in this high-risk group than in the general population.