C A Cull

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

Abstract 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 HbA1c 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 HbA1c 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 HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%).

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study

Abstract 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.

Risk Factors for Renal Dysfunction in Type 2 Diabetes U.K. Prospective Diabetes Study 74

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, HbA1c (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.

United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus.

Noninsulin-dependent diabetes mellitus (NIDDM) is a common disease that is associated with high mortality and morbidity from macrovascular and microvascular complications. An approximately threefold increased risk exists for all cardiovascular diseases [1, 2], and life expectancy is substantially reduced at all ages of disease presentation [3, 4]. Persons with diabetes presenting in their fourth or fifth decade of life have a twofold increased mortality compared with a control population [4, 5]. Microvascular diseases associated with diabetes are a major cause of blindness, renal failure, and amputations, all of which require expensive health care resources [6]. The continued high incidence of complications in patients with NIDDM [3, 7] indicates that the current therapeutic approach is inadequate for maintaining good health. At present, patients are often treated to prevent marked hyperglycemia when it induces symptoms such as thirst, whereas moderately raised blood glucose levels are often accepted. Mechanisms by which hyperglycemia might induce tissue damage have now been described, including glycosylation of tissues with formation of advanced glycation end products [8] and increased flux through the sorbitol pathway [9]. Reducing glucose concentrations in patients with NIDDM might be sensible [10]. However, it is uncertain whether hyperglycemia should be treated more intensivelywith diet, oral agents, or insulinto maintain near-normal glucose levels and prevent the onset of complications or whether these therapies have a neutral or even harmful effect [7]. Association of Blood Glucose Control with Diabetic Complications The epidemiologic association of glycemic levels with the risk for microvascular and macrovascular disease suggests that these two types of complications are affected by differing degrees of hyperglycemia. The development of diabetic retinopathy [11, 12] and nephropathy [12] mainly occurs when the fasting plasma glucose level is 7.8 mmol/L or higher. The increased risk for these specific diabetic complications when the glucose concentration rises above 7.8 mmol/L has led to it becoming the accepted defining criterion for diabetes [13]. On the other hand, a higher incidence of cardiovascular disease [14, 15] is associated with blood glucose levels at the upper end of the normal range (approximating a fasting plasma glucose level more than 6 mmol/L). The relevance of these data, however, remains controversial because of discordant results [16] and because other associated risk factors may be involved. For instance, patients with impaired glucose tolerance may have been at risk for heart disease because of associated dyslipidemia, hypertension, and raised insulin levels [17-19]. The prospective data in patients with NIDDM suggest that hyperglycemia is a risk factor for cardiovascular disease [4, 20], but insufficient data exist to determine whether there is a glycemic threshold for macrovascular disease. These data suggest that it may be necessary to obtain stricter control of diabetes to prevent cardiovascular disease than is necessary to prevent microvascular disease, but further studies are required. Previous Prospective Clinical Trials The Diabetes Control and Complications Trial (DCCT) studied 1441 patients with insulin-dependent diabetes mellitus (IDDM) (mean age, 27 years) and showed that intensive therapy, which resulted in a mean hemoglobin A1c level of 7.1%, compared with conventional therapy, which resulted in a level of 9.0%, retards the progress of diabetic microvascular disease [21]. Whether such improved glucose control will be similarly beneficial in patients with NIDDM is unknown. A similar reduction in microvascular disease might be expected, but most of the complications in patients with NIDDM are from premature macrovascular, not microvascular, disease. The University Group Diabetes Program (UGDP) studied 1027 patients with NIDDM (mean age, 53 years) and showed no benefit from improved glucose control induced by insulin, biguanide, or sulfonylurea therapy in preventing diabetic complications over 11 years of follow-up [7]. Potential Sting in the Tail of Pharmacologic Therapies The UGDP reported that a sulfonylurea (tolbutamide) [22] and a biguanide (phenformin) [23] appeared to increase cardiovascular mortality as compared with placebo (see Exogenous Insulin Administration and Cardiovascular Risk in NIDDM and IDDM). The results were statistically significant, but because this finding was unexpected and without a previous hypothesis, the study in effect introduced a new hypothesis rather than giving a confirmatory result. A mechanism by which sulfonylureas might increase the risk for cardiovascular disease is the presence in the myocardium of ATP (adenosine triphosphate)-sensitive potassium channels [24]. In theory, closure of these channels by sulfonylurea might prevent ischemia-induced vasodilatation and thus exacerbate ischemic episodes. In addition, ischemic pain might be lessened so that patients do not rest when ischemia becomes critical [25]. In a study done in rabbits, an interaction of sulfonylureas with ouabain induced cardiac arrhythmia with a first- but not second-generation sulfonylurea [26]. The UGDP results can possibly be explained by the use of the first-generation tolbutamide, and the results might not be applicable to second-generation sulfonylurea. Insulin therapy has been suggested to be potentially harmful, because when given subcutaneously it induces higher peripheral insulin levels than the usual endogenous secretion into the portal vein (see Do NIDDM and Cardiovascular Disease Share Common Antecendents?). This event occurs because the therapy needs to provide sufficiently high insulin levels in the portal vein to reduce excess hepatic glucose output. The high peripheral levels may lead to atherogenesis, as suggested by in vitro studies of the effect of raised insulin levels on the morphologic and biochemical responses of the arterial wall [27]. The epidemiologic associations in the general population of high fasting insulin levels with an increased risk for myocardial infarction [28, 29] are in accord with this theory, although the dyslipidemia and hypertension associated with high insulin levels, rather than high insulin levels per se, may account for the association [30]. The Uncertainty about Therapies The previous studies lend no support for the hypothesis that improved glucose control with currently available pharmaceutical agents helps to prevent the complications of NIDDM. The effect of available therapies on the development of cardiovascular disease is unknown, and the side effects of therapies may outweigh any potential gain from their blood glucose-lowering effect. United Kingdom Prospective Diabetes Study The United Kingdom Prospective Diabetes Study (UKPDS) recruited 5102 patients with newly diagnosed NIDDM in 23 centers between 1977 and 1991 [31]. Of these patients, 4209 have been included in randomized, controlled trials of different therapies to determine whether patients with NIDDM can obtain clinical benefit from intensive glycemic control and whether sulfonylurea, metformin, and insulin therapies have specific advantages or disadvantages. The study will end in 1997 when the median duration from randomization will be 11 years (range, 6 to 20 y), and the results will be published in 1998. In 1991, the study was described [31]; the glucose control achieved by the allocated therapies over 3 and 6 years has also recently been described [32, 33]. This article outlines the studys progress, the efficacy of the different therapies over 9 years in improving glucose control, the side effects of the therapies, the natural history of the disease in terms of increasing glycemia, and the overall development of complications. It also compares the UKPDS with two previously reported studiesthe DCCT [21] and UGDP [7]both of which reported data for 9 years of follow-up. Methods Subjects The UKPDS recruited 5102 subjects who were 25 to 65 years old and who had newly diagnosed diabetes. The median age was 53 years, and the median fasting plasma glucose level was 11.9 mmol/L. Fifty percent of the patients were obese (> 120% of ideal body weight [34]), and 39% were hypertensive [31]. Ten percent were Asian-Indian, and 8% were Afro-Caribbean [35]. Approximately 50% of the patients already had an indication of diabetes-related tissue damage: 8% had an indication of cardiovascular disease [31], 37% had microaneurysm or more severe retinopathy in one eye, 18% had retinopathy in both eyes, and 18% had microalbuminuria (> 50 mg/L) [35]. The patients from different ethnic groups had a similar prevalence of preexisting heart disease, retinopathy, and microalbuminuria [35]. Initial Diet Therapy and Randomization During a 3-month run-in period, patients were given intensive dietary advice at monthly clinic visits and lost an average of 5 kg of body weight. Eighty-six percent became symptom free, but only 17% achieved a fasting plasma glucose level of less than 6.0 mmol/L [36]. In two thirds of these patients, the fasting plasma glucose level increased to more than 6.0 mmol/L within 3 years. Between 1978 and 1994, 4209 asymptomatic patients whose fasting plasma glucose level remained at or rose to between 6 and 15 mmol/L were randomly allocated to different therapies. Of the 4209 patients, 3513 were at the end of the initial 3 months of diet therapy; 696 had a fasting plasma glucose level of less than 6 mmol/L after the initial diet therapy but subsequently became hyperglycemic with a fasting plasma glucose level of more than 6 mmol/L. Once patients were entered in the formal therapeutic study, nonobese patients were randomly allocated to four groupsprimary therapy with diet, chlorpropamide, glibenclamide, or insulin therapy. Obese patients were randomly allocated to five groupsthe same four groups as nonobese patients and primary therapy with metformin. Four quest

Cost effectiveness of an intensive blood glucose control policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (UKPDS 41)

Abstract Objective: To estimate the cost effectiveness of conventional versus intensive blood glucose control in patients with type 2 diabetes. Design: Incremental cost effectiveness analysis alongside randomised controlled trial. Setting: 23 UK hospital clinic based study centres. Participants: 3867 patients with newly diagnosed type 2 diabetes (mean age 53 years). Interventions: Conventional (primarily diet) glucose control policy versus intensive control policy with a sulphonylurea or insulin. Main outcome measures: Incremental cost per event-free year gained within the trial period. Results: Intensive glucose control increased trial treatment costs by £695 (95% confidence interval £555 to £836) per patient but reduced the cost of complications by £957 (£233 to £1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was £478 (-£275 to £1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to 1.61) years. The incremental cost per event-free year gained was £1166 (costs and effects discounted at 6% a year) and £563 (costs discounted at 6% a year and effects not discounted). Conclusions: Intensive blood glucose control in patients with type 2 diabetes significantly increased treatment costs but substantially reduced the cost of complications and increased the time free of complications.

Diabetes education and knowledge in patients with type 2 diabetes from the community: The Fremantle Diabetes Study

BACKGROUND Diabetic patients obtain knowledge of the condition from a variety of sources. These include education programs and encounters with health-care staff such as during instruction on self-monitoring of blood glucose (SMBG). OBJECTIVE To assess whether diabetes knowledge is related to prior attendance at diabetes education programs, visits to dieticians or the current use of SMBG in a community-based cohort of subjects with type 2 diabetes. PATIENTS 1264 type 2 patients from the Fremantle Diabetes Study (FDS) cohort. METHODS Subjects answered 15 standard multiple-choice questions about diabetes and its management. Recall of past diabetes education, dietician consultations, and use of SMBG were recorded. Analysis of variance was used to determine whether these activities or other social and demographic factors predicted diabetes knowledge. RESULTS Attendance at education programs, visits to dieticians, and SMBG were independently associated with greater diabetes knowledge. Subjects who were older, whose schooling was limited, who were not fluent in English and/or who were from Southern European or indigenous Australian ethnic groups had significantly lower knowledge scores. Patients who were older, not fluent in English or from an indigenous Australian background were significantly less likely to have received diabetes education, dietetic advice or to be performing SMBG. CONCLUSIONS Diabetes education programs, diabetes-related visits to dieticians and SMBG are associated with, and may be important sources of, improved diabetes knowledge in patients with type 2 diabetes. Our data provide evidence that barriers to access or utilization of contemporary diabetes education confront older patients, minority groups and those with language difficulties. These groups are likely to benefit from specialized programs.

Impact of the Metabolic Syndrome on Macrovascular and Microvascular Outcomes in Type 2 Diabetes Mellitus United Kingdom Prospective Diabetes Study 78

Background— The metabolic syndrome (MetS) and type 2 diabetes mellitus are both associated with increased cardiovascular disease risk. We examined retrospectively the degree to which the presence of MetS in individuals with type 2 diabetes mellitus increased their risk of diabetic complications using United Kingdom Prospective Diabetes Study data. Methods and Results— Of 5102 United Kingdom Prospective Diabetes Study patients recruited with newly diagnosed type 2 diabetes mellitus and followed up for a median of 10.3 years, 4542 had the requisite data for these analyses. After a 3-month dietary run-in, MetS, diagnosed with National Cholesterol Education Program Adult Treatment Panel III, World Health Organization, International Diabetes Federation, or European Group for the Study of Insulin Resistance criteria, was present in 61%, 38%, 54%, and 24%, respectively. Those with MetS by these criteria had increased cardiovascular disease risks relative to those without MetS of 1.33 (95% confidence interval 1.14 to 1.54), 1.45 (95% confidence interval 1.26 to 1.66), 1.23 (95% confidence interval 1.07 to 1.42), and 1.31 (95% confidence interval 1.10 to 1.57), respectively, but similar risks for microvascular complications. The positive predictive value of MetS for cardiovascular disease events, however, was only 18%, 13%, 18%, and 39%, respectively. Conclusions— MetS, diagnosed by Adult Treatment Panel III, World Health Organization, or International Diabetes Federation criteria, identifies diabetic patients at greater risk of macrovascular but not microvascular complications. Poor discrimination by MetS with respect to cardiovascular disease outcomes means that it is of limited clinical value for cardiovascular disease risk stratification in type 2 diabetes mellitus.

Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with Type II diabetes (UKPDS No. 51)

Aims/hypothesis. To estimate the economic efficiency of intensive blood-glucose control with metformin compared with conventional therapy primarily with diet in overweight patients with Type II (non-insulin-dependent) diabetes mellitus. Methods. Cost-effectiveness analysis based on patient level data from a randomised clinical controlled trial involving 753 overweight ( > 120 % ideal body weight) patients with newly diagnosed Type II diabetes conducted in 15 hospital-based clinics in England, Scotland and Northern Ireland as part of the UK Prospective Diabetes Study. Subjects were allocated at random to an intensive blood-glucose control policy with metformin (n = 342) or a conventional policy primarily with diet (n = 411). The analysis was based on the cost of health care resources associated with metformin and conventional therapy and the estimated effectiveness in terms of life expectancy gained from within-trial effects. Results. Intensive blood-glucose control with metformin produced a net saving of £ 258 per patient (1997 United Kingdom prices) over the trial period (median duration of 10.7 years) due to lower complication costs, and increased life expectancy by 0.4 years (costs and benefits discounted at 6 %). Conclusions/interpretation. As metformin is both cost-saving in the United Kingdom and extends life expectancy when used as first line pharmacological therapy in overweight Type II diabetic patients, its use should be attractive to clinicians and health care managers alike. [Diabetologia (2001) 44: 298–304]

Reporting of diabetes on death certificates using data from the UK Prospective Diabetes Study

Aims  To study the effect of age at death, sex, ethnic group, date of death, underlying cause of death and social class on the frequency of reporting diabetes on death certificates in known cases of diabetes.

Changing aspirin use in patients with Type 2 diabetes in the UKPDS

Aims  To examine the proportion of UK Prospective Diabetes Study (UKPDS) patients with Type 2 diabetes taking aspirin regularly for the primary and secondary prevention of cardiovascular disease (CVD) before and after publication of the 1997 American Diabetes Association (ADA) Clinical Practice Recommendations and the 1998 Joint British Recommendations on the Prevention of Coronary Disease in Clinical Practice.