Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75)

Aims/hypothesis The relative importance of glucose and blood pressure control in type 2 diabetes remains uncertain. We assessed interactive effects of glycaemia and systolic blood pressure (SBP) exposure on the risk of diabetic complications over time.Subjects, materials and methods HbA_1c and SBP, measured annually for a median of 10.4 years in 4,320 newly diagnosed type 2 diabetic patients from the UK Prospective Diabetes Study (UKPDS), were categorised as updated mean values <6.0, 6.0–6.9, 7.0–7.9 or ≥8.0%, and <130, 130–139, 140–149 or ≥150 mmHg, respectively. Clinical outcomes were UKPDS predefined composite endpoints.Results The incidence of the ‘any diabetes-related endpoint’ in the lowest (HbA_1c <6.0%, SBP <130 mmHg) and highest (HbA_1c ≥8%, SBP ≥150 mmHg) category combinations was 15 and 82 per 1,000 person-years, respectively, and 24 and 120 per 1,000 person-years in a Poisson model adjusted to white Caucasian male sex, age 50 to 54 years and diabetes duration of 7.5 to 12.5 years. Updated mean HbA_1c and SBP effects were additive in an adjusted proportional hazards model with risk reductions of 21% per 1% HbA_1c decrement and 11% per 10 mmHg SBP decrement. Endpoint rates obtained in the 887 patients randomised in both the glycaemia and hypertension intervention trial arms were consistent with the observational data. Those allocated to both intensive glucose and tight blood pressure control policies had fewer events than those allocated to either policy alone or to neither (p for trend 0.024).Conclusions/interpretation Risk of complications in type 2 diabetes is associated independently and additively with hyperglycaemia and hypertension. Intensive treatment of both these risk factors is required to minimise the incidence of complications.     

Microalbuminuria in a random cohort of recently diagnosed type 2 (non-insulin-dependent) diabetic patients living in the Greater Munich Area

Summary Still under debate is the prevalence of microalbuminuria in patients with recently diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and its relation to existing macro-vascular disease and the major vascular risk markers. Hence, from a representative sample of 1512 patients with Type 2 diabetes of varied duration (recruited from 22 nonspecialized medical practices of the Greater Munich Area) 68 (26 males, 42 females) of 71 eligible subjects with a known duration of diabetes of up to 17 weeks and not less than 4 weeks were examined in the present study. Median age was 61 (39 to 75) years, prevalence of ischaemic heart disease (case history plus ECG, Minnesota code, Whitehall criteria) 41.2%, and that of peripheral vascular and carotid artery disease (both assessed by ultrasound-Doppler) were 35.3 and 4.4%, respectively. Diabetes was well controlled (HbA_1c: 6.9%, 5.6–8.3; fasting blood glucose: 7.7 mmol/l, 5.4–10.4; median±interquartile range IQ), the cardiovascular risk profile was most prominent in terms of triglycerides (3.1 mmol/l, 2.1–4.6, median±IQ range) and systolic blood pressure (164 mm Hg, 140–186, median±IQ range). 13.2% showed signs of urinary tract infection. Of the remainder, 19.0% exhibited microalbuminuria (RIA, >30–200 mg/l), and 5.2% macroalbuminuria (>200 mg/l). Significant correlations (p<0.05) were found between urinary albumin concentration and β₂-microglobubin in serum, systolic blood pressure, serum triglycerides, serum HDL-cholesterol (inversely), HbA_1c, and peripheral vascular disease. The results suggest a high prevalence of increased urinary albumin excretion in recently diagnosed Type 2 diabetic patients and a close relationship with several hallmarks of the so-called metabolic syndrome, probably operative in the pre-clinical state of Type 2 diabetes. Based on these observations, increased albuminuria could be a marker of early and accelerated atherosclerosis.     

Markers of renal tubular dysfunction measured annually do not predict risk of microalbuminuria in the first few years after diagnosis of Type I diabetes

Aims/hypothesis. Early detection of risk of microalbuminuria could prevent early renal damage. We investigated whether urine retinol binding protein and N-acetyl-glucosaminidase could predict the risk of microalbuminuria in a large cohort of children followed from diagnosis of Type I (insulin-dependent) diabetes mellitus. Methods. Subjects under 16 years of age within a georaphically defined region were recruited at diagnosis of Type I (insulin-dependent) diabetes mellitus. Annually, albumin-, retinol binding protein- and N-acetyl-glucosaminidase- to creatinine ratios were each measured in 3 urine samples. Results. A total of 511 subjects were followed for a median of 6 years (range: 1–14). Microalbuminuria (males: ≥ 3.5 mg/mmol; females: ≥ 4.0 mg/mmol, in 2 out of 3 urines) developed in 78 subjects (36 male). The cumulative probability of microalbuminuria was 40 % after 12 years duration of diabetes. Retinol-binding-proteinuria (men: ≥ 21 μg/mmol; women ≥ 33 μg/mmol) developed in 217 subjects (152 men). The cumulative probability of retinol-binding-proteinuria was 67 % after 12 years duration of diabetes. The cumulative probability of retinol-binding-proteinuria was 40 % before the onset of microalbuminuria and 59 % in subjects who did not subsequently develop microalbuminuria. Retinol-binding-proteinuria developed at a higher rate with increasing HbA_{1 c} than microalbuminuria. N-acetyl-glucosaminidase-uria (males: ≥ 56 μmol-pnp · h^–1· mmol^–1; females: ≥ 46 μmol-pnp · h^–1· mmol^–1) developed in 477 subjects. The cumulative probability of N-acetyl-glucosaminidase-uria was 98 % after 10 years of diabetes duration. The cumulative probability of N-acetyl-glucosaminidase-uria was 73 % in the years before the onset of microalbuminuria and 97 % in subjects without microalbuminuria. The probability of N-acetyl-glucosaminidase-uria was 99 % with an HbA_{1 c} greater than or equal to 14.5 %. Conclusions/interpretation. Raised amounts of urine retinol binding protein and N-acetyl-glycosaminidase are related to HbA_{1 c} and the duration of diabetes. They occur in the majority of subjects and are not early markers for the risk of microalbuminuria. [Diabetologia (2001) 44: 224–229] Received: 25 July 2000 and in revised form: 29 September 2000     

High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study

Aims/hypothesis The risk of dying of cardiovascular disease (CVD) before the age of 40 years is increased nearly 20-fold in patients with type 1 diabetes compared with non-diabetic persons. The aim of this study was to evaluate the prevalence of CVD risk factors in a population-based study of children and adolescents with type 1 diabetes. Methods CVD risk factors were examined according to the American Diabetes Association criteria in 2005. Of 26 paediatric clinics in Norway, 25 participated with 1,658 patients, 85% of those eligible. Mean age was 13.1 years and mean diabetes duration 5.7 years. Results HbA_1c was above the target level in 71.4%. A positive family history of early CVD and/or diabetes was found in 33% of participants. LDL-cholesterol was >2.6 mmol/l in 34.5% and HDL-cholesterol was <1.1 mmol/l in 6.9% of participants. Blood pressure was above the 90th percentile by age, sex and height in 7% and above the 95th percentile in 4% of participants. Four per cent of participants were obese, 3% of those ≥12 years of age reported smoking and 1% of all participants had persistent microalbuminuria. Only 0.2% of the patients were receiving statin and 0.3% anti-hypertensive treatments. Dietary habits and physical activity level were evaluated in some patients. Almost all had higher intake of dietary fat and lower intake of fibre than recommended. A large part was less active and watched more TV than recommended. Conclusions/interpretation Of the participants, 86% had at least one, 45% at least two and 15% at least three CVD risk factors. Few patients were treated with statins and anti-hypertensive drugs.     

Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mellitus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC)

Aims/hypothesis To complete a comparative analysis of studies that have examined the relationship between glycaemia and cardiovascular disease (CVD)/coronary artery disease (CAD) and perform a prospective analysis of the effect of change in glycosylated Hb level on CAD risk in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) of childhood-onset type 1 diabetes mellitus (n = 469) over 16 years of two yearly follow-up. Methods Measured values for HbA₁ and HbA_1c from the EDC were converted to the DCCT-standard HbA_1c for change analyses and the change in HbA_1c was calculated (final HbA_1c minus baseline HbA_1c). CAD was defined as EDC-diagnosed angina, myocardial infarction, ischaemia, revascularisation or fatal CAD after medical record review. Results The comparative analysis suggested that glycaemia may have a stronger effect on CAD in patients without, than in those with, albuminuria. In EDC, the change in HbA_1c differed significantly between CAD cases (+0.62 ± 1.8%) and non-cases (−0.09 ± 1.9%) and was an independent predictor of CAD. Conclusions/interpretation Discrepant study results regarding the relationship of glycaemia with CVD/CAD may, in part, be related to the prevalence of renal disease. Measures of HbA_1c change over time show a stronger association with CAD than baseline values.     

Glycaemic control and cardiovascular risk factors in Type 2 diabetes: a population-based study

The objective of this study was to estimate the prevalence of poor glycaemic control and cardiovascular risk factors in an Italian population-based cohort of subjects with Type 2 diabetes mellitus (DM). Out of a cohort of 1967 subjects (estimated completeness of ascertainment 80 %), 1574 (80 %) were investigated, and adherence to targets for control of the European NIDDM Policy Group assessed. Prevalence of poor glycemic control (HbA_1c > = 8) was 47.7 %. Obesity was present in 23.4 % of the cohort, hypertension in 83.4 %, hypertriglyceridaemia (>2.26 mM) in 19.3 %, hypercholesterolaemia (>6.46 mM) in 25.5 %, and low HDL-cholesterol (<0.90 mM in men and <1.03 mM in women) in 13.7 %. Only 153 (9.7 %) subjects were free from other disorders. Subjects were treated as follows: 26.2 % exclusively by general practitioners; 13.3 %, 69.9 %, 10.9 %, and 5.9 % with diet, oral hypoglycaemic drugs, insulin, and both, respectively. Multiple linear regression analysis showed associations between HbA_1c and fibrinogen (p < 0.001), total cholesterol (p = 0.006), and triglycerides (p = 0.04), independent of age, sex, duration of diabetes, and antidiabetic treatment. Neither BMI nor blood pressure were associated with HbA_1c. In conclusion, this Italian population-based cohort of subjects with Type 2 DM showed a high prevalence of poor glycaemic control, high consumption of oral hypoglycaemic drugs, and an independent association between glycaemic control and cardiovascular risk factors (fibrinogen, total cholesterol, and triglycerides). The presence of obesity or hypertension was not significantly associated with glycaemic control. © 1998 John Wiley & Sons, Ltd.     

Carotid intima-media thickness and stiffness in relation to type 2 diabetes in Chinese

We investigated carotid intima-media thickness (IMT) and quantitative carotid stiffness (QCS) index in relation to plasma glycosylated hemoglobin A_1C (HbA_1C) and duration of diabetes mellitus in 337 Chinese diabetic patients. In categorical analyses, carotid IMT was 710 μm in subjects with a duration of diabetes mellitus ≤2 years, 760 μm in subjects with a duration of diabetes mellitus more than two years and with plasma HbA_1C < 6.5% (P < 0.05), and 790 μm in subjects with a duration of diabetes mellitus more than two years but with plasma HbA_1C ≥ 6.5% (P < 0.01). The corresponding values for QCS values were 4.5, 4.6 and 5.1 (P < 0.05), respectively. In multiple stepwise regression analyses carotid IMT was significantly associated with the duration of diabetes mellitus, systolic blood pressure and serum concentration of total cholesterol, whereas QCS was significantly associated with age, HbA_1C, systolic and diastolic blood pressure (P < 0.05). In conclusion, carotid IMT as a structural measure of arterial wall is increased in patients with a longer history of diabetes mellitus, whereas QCS as functional index is mainly influenced by the quality of blood glucose control.     

HbA<Subscript>1c</Subscript> as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study

Aims/hypothesis  Heart failure (HF) incidence in diabetes in both the presence and absence of CHD is rising. Prospective population-based studies can help describe the relationship between HbA_1c, a measure of glycaemia control, and HF risk. Methods  We studied the incidence of HF hospitalisation or death among 1,827 participants in the Atherosclerosis Risk in Communities (ARIC) study with diabetes and no evidence of HF at baseline. Cox proportional hazard models included age, sex, race, education, health insurance status, alcohol consumption, BMI and WHR, and major CHD risk factors (BP level and medications, LDL- and HDL-cholesterol levels, and smoking). Results  In this population of persons with diabetes, crude HF incidence rates per 1,000 person-years were lower in the absence of CHD (incidence rate 15.5 for CHD-negative vs 56.4 for CHD-positive, p<0.001). The adjusted HR of HF for each 1% higher HbA_1c was 1.17 (95% CI 1.11–1.25) for the non-CHD group and 1.20 (95% CI 1.04–1.40) for the CHD group. When the analysis was limited to HF cases which occurred in the absence of prevalent or incident CHD (during follow-up) the adjusted HR remained 1.20 (95% CI 1.11–1.29). Conclusions/interpretations  These data suggest HbA_1c is an independent risk factor for incident HF in persons with diabetes with and without CHD. Long-term clinical trials of tight glycaemic control should quantify the impact of different treatment regimens on HF risk reduction.     

Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study

Aims/hypothesis  Hyperglycaemia is a risk factor for cardiovascular disease (CVD) and all-cause mortality in individuals without diabetes. We investigated: (1) whether the risk of all-cause and CVD mortality extended continuously throughout the range of fasting plasma glucose (FPG), 2 h plasma glucose (2hPG) and HbA_1c values; and (2) the ability of these measures to improve risk prediction for mortality. Methods  Data on 10,026 people aged ≥25 years without diagnosed diabetes were obtained from the population-based Australian Diabetes, Obesity and Lifestyle study. Between 1999 and 2000, FPG, 2hPG and HbA_1c were assessed and all-cause (332 deaths) and CVD (88 deaths) mortality were obtained after 7 years. Results  Both 2hPG and HbA_1c exhibited linear relationships with all-cause and CVD mortality, whereas FPG showed J-shaped relationships. The adjusted HR (95% CI) for all-cause mortality per SD increase was 1.2 (1.1–1.3) for 2hPG and 1.1 (1.0–1.2) for HbA_1c. The HR for FPG <5.1 mmol/l (per SD decrease) was 2.0 (1.3–3.0); for FPG ≥5.1 mmol/l (per SD increase) the HR was 1.1 (1.0–1.2). Corresponding HRs for CVD mortality were 1.2 (1.0–1.4), 1.2 (1.0–1.3), 4.0 (2.1–7.6) and 1.3 (1.1–1.4). The discriminative ability of each measure was similar; no measure substantially improved individual risk identification over traditional risk factors. Conclusions/interpretation  In individuals without diagnosed diabetes, 2hPG and FPG, but not HbA_1c were significant predictors of all-cause mortality, whereas all measures were significant predictors of CVD mortality. However, these glucose measures did not substantially improve individual risk identification.     

HbA1c measured in stored erythrocytes and mortality rate among middle-aged and older women

Aims/hypothesis Diabetes is known to increase mortality rate, but the degree to which mild hyperglycaemia may be associated with the risk of death is uncertain. We examined the association between HbA_1c measured in stored erythrocytes and mortality rate in women with and without diabetes. Methods We conducted a cohort study of 27,210 women ≥ 45 years old with no history of cardiovascular disease or cancer who participated in the Women’s Health Study, a randomised trial of vitamin E and aspirin. Results Over a median of 10 years of follow-up, 706 women died. Proportional hazards models adjusted for age, smoking, hypertension, blood lipids, exercise, postmenopausal hormone use, multivitamin use and C-reactive protein were used to estimate the relative risk of mortality. Among women without a diagnosis of diabetes and HbA_1c <5.60%, those in the top quintile (HbA_1c 5.19–5.59%) had a relative risk of mortality of 1.28 (95% CI 0.98–1.69, p value for linear trend = 0.14) compared with those with HbA_1c 2.27–4.79%. Women with HbA_1c 5.60–5.99% and no diagnosis of diabetes had a 54% increased risk of mortality (95% CI 1–136%) compared with those with HbA_1c 2.27–4.79%. HbA_1c was significantly associated with mortality across the range 4.50–7.00% (p value for linear trend = 0.02); a test of deviation from linearity was not statistically significant (p = 0.67). Diabetic women had more than twice the mortality risk of non-diabetic women. Conclusions/interpretation This study provides further evidence that chronic mild hyperglycaemia, even in the absence of diagnosed diabetes, is associated with increased risk of mortality. ClinicalTrials.gov ID no.: NCT00000479     

Short-term impact of HbA1c on morbidity and all-cause mortality in people with type 2 diabetes: a Danish population-based observational study

Aims/hypothesis  

In a population-based setting, we investigated whether diabetes-related morbidity and all-cause mortality within 2 years of HbA_1c measurement were associated with that HbA_1c level in individuals with type 2 diabetes. The main objective was to compare outcomes in those with HbA_1c ≥ and <7% (53 mmol/mol).     

Glycaemic control and diabetes care utilization in young adults with Type 1 diabetes1

Objectives To explore how glycaemic control in young adults is related to diabetes care utilization during the transition to adult diabetes care and if these variables differ between males and females. Methods This is a retrospective, longitudinal design following patients’ records from age 18–24 years. Adolescents (n = 104) connected to one paediatric outpatient clinic and referred to six different adult clinics were included. Data were collected regarding gender, age at diagnosis and transfer, yearly glycated haemoglobin (HbA_1c) and body mass index, severe hypoglycaemia and diabetic ketoacidosis, retinopathy and diabetes care utilization. Results HbA_1c decreased over time in females (P = 0.004) but not in males. Less than 10% had HbA_1c in the recommended range during the study period. The decrease in severe hypoglycaemia and diabetic ketoacidosis was not significant. The prevalence of background retinopathy increased from 5 to 29% during the study period (P < 0.001). Mean transfer age was 19.8 years. The youths visited the paediatric clinic more often than the adult clinic (P < 0.001) and females visited adult care more often than males (P = 0.04). There was a steady decrease in the number of visits/year over time (P < 0. 001). Poor glycaemic control was associated with more visits for both males and females (P = 0.005) in adult care. Conclusions As there was no gender difference in the relation between HbA_1c and the number of visits in adult diabetes care, the higher frequency of visits in adult care for females cannot be solely explained by their glycaemic control. Gender differences regarding diabetes care utilization should be further explored.     

Diabetes,glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study

Aims/hypothesis There are few data on the target level of glycaemic control among patients with diabetes on haemodialysis. We investigated the impact of glycaemic control on mortality risk among diabetic patients on haemodialysis. Subjects and methods Data were analysed from the Dialysis Outcomes Practice Pattern Study (DOPPS) for randomly selected patients on haemodialysis in Japan. The diagnosis of diabetes at baseline and information on clinical events during follow-up were abstracted from the medical records. A Cox proportional hazards model was used to evaluate the association between presence or absence of diabetes, glycaemic control (HbA_1c quintiles) and mortality risk. Results Data from 1,569 patients with and 3,342 patients without diabetes on haemodialysis were analysed. Among patients on haemodialysis, those with diabetes had a higher mortality risk than those without (multivariable hazard ratio 1.37, 95% CI 1.08–1.74). Compared with those in the bottom quintile of HbA_1c level, the multivariable-adjusted hazard ratio for mortality was not increased in the bottom second to fourth quintiles of HbA_1c (HbA_1c 5.0–5.5% to 6.2–7.2%), but was significantly increased to 2.36 (95% CI 1.02–5.47) in the fifth quintile (HbA_1c ≥ 7.3%). The effect of poor glycaemic control did not statistically correlate with baseline mortality risk (p = 0.27). Conclusions/interpretation Among dialysis patients, poorer glycaemic control in those with diabetes was associated with higher mortality risk. This suggests a strong effect of poor glycaemic control above an HbA_1c level of about 7.3% on mortality risk, and that this effect does not appear to be influenced by baseline comorbidity status.     

Relation of fibre intake to HbA1c and the prevalence of severe ketoacidosis and severe hypoglycaemia

Summary The effect of dietary fibre intake on glycaemic control is still controversial. This study analysed the intake of natural dietary fibre in patients with Type I diabetes mellitus enrolled in the EURODIAB IDDM Complications Study to determine any associations with HbA_1c levels and with the prevalence of severe ketoacidosis or severe hypoglycaemia. Dietary intake was assessed by a 3-day dietary record. The relation between intake of fibre (total, soluble and insoluble) and HbA_1c was examined in 2065 people with Type I diabetes. Associations with severe ketoacidosis (requiring admission to hospital) and severe hypoglycaemia (requiring the help of another person) were analysed in 2687 people with Type I diabetes. Total fibre intake (g/day) was inversely related to HbA_1c (p = 0.02), independently of carbohydrate intake, total energy intake and other factors regarding lifestyle and diabetes management. Severe ketoacidosis risk fell significantly with higher fibre intake (p = 0.002), with an adjusted odds ratio of 0.48 (95 % confidence interval 0.27 to 0.84) in the highest quartile ( ≥ 23.0 g fibre/day) compared with the lowest quartile ( ≤ 13.7 g fibre/day). The occurence of severe hypoglycaemia was not related to fibre intake. Beneficial effects of fibre on HbA_1c and the risk of severe ketoacidosis were particularly pronounced in patients from southern European centres. This study shows that higher fibre intake is independently related to a reduction in HbA_1c levels in European people with Type I diabetes. Furthermore, increased fibre intake may reduce the risk of severe ketoacidosis. These beneficial effects were already observed for fibre intake within the range commonly consumed by people with Type I diabetes. [Diabetologia (1998) 41: 882–890] Received: 31 December 1997 and in revised form: 5 March 1998     

Sustained good glycaemic control in NIDDM patients by implementation of structured care in general practice: 2-year follow-up study

Summary In primary care it is difficult to treat the growing number of non-insulin-dependent diabetic (NIDDM) patients according to (inter)national guidelines. A prospective, controlled cohort study was designed to assess the intermediate term (2 years) effect of structured NIDDM care in general practice with and without ’diabetes service' support on glycaemic control, cardiovascular risk factors, general well-being and treatment satisfaction. The ’diabetes service', supervised by a diabetologist, included a patient registration system, consultation facilities of a dietitian and diabetes nurse educator, and protocolized blood glucose lowering therapy advice which included home blood glucose monitoring and insulin therapy. In the study group (SG; 22 general practices), 350 known NIDDM patients over 40 years of age (206 women; mean age 65.3 ± SD 11.9; diabetes duration 5.9 ± 5.4 years) were followed for 2 years. The control group (CG; 6 general practices) consisted of 68 patients (28 women; age 64.6 ± 10.3; diabetes duration 6.3 ± 6.4 years). Mean HbA_{1 c} (reference 4.3–6.1 %) fell from 7.4 to 7.0 % in SG and rose from 7.4 to 7.6 % in CG during follow-up (p = 0.004). The percentage of patients with poor control (HbA_{1 c} > 8.5 %) shifted from 21.4 to 11.7 % in SG, but from 23.5 to 27.9 % in CG (p = 0.008). Good control (HbA_{1 c} < 7.0 %) was achieved in 54.3 % (SG; at entry 43.4 %) and 44.1 % (CG; at entry 54.4 %) (p = 0.013). Insulin therapy was started in 29.7 % (SG) and 8.8 % (CG) of the patients (p = 0.000) with low risk of severe hypoglycaemia (0.019/patient year). Mean levels of total and HDL-cholesterol (SG), triglycerides (SG) and diastolic blood pressure (SG + CG) and the percentage of smokers (SG) declined significantly, but the prevalence of these risk factors remained high. General well-being (SG) did not change during intensified therapy. Treatment satisfaction (SG) tended to improve. Implementation of structured care, including education and therapeutic advice, results in sustained good glycaemic control in the majority of NIDDM patients in primary care, with low risk of hypoglycaemia. Lowering cardiovascular risk requires more than reporting results and referral to guidelines. [Diabetologia (1997) 40: 1334–1340] Received: 5 February 1997 and in revised form: 22 May 1997     

Occurrence and interrelationships of complications in insulin-dependent diabetes in Finland

The purpose of the study was to examine the prevalence and interrelationships of micro- and macrovascular complications and their risk factors in insulin-dependent (type 1) diabetic patients. The prevalence of nephropathy, retinopathy and cardiovascular disease was examined, and their associations to risk factors (glycemic control, blood pressure, blood lipid concentrations) and neuropathy were estimated in a cross-sectional study. A total of 140 type 1 diabetic patients were examined. They were grouped by gender, age, and duration of diabetes into 14 subgroups of 10 patients each. Nephropathy was observed in 40%, retinopathy in 55%, and signs of cardiovascular disease in less than 5% of patients. Microvascular complications were associated with the duration of diabetes, systolic blood pressure, and serum triglyceride concentration. The glycosylated hemoglobin (HbA_1c) level was significantly associated with the presence of nephropathy, whereas the association with retinopathy was of borderline significance. Statistically speaking, the duration of diabetes, mean systolic blood pressure, HbA_1c, and triglyceride level explained 31% of the variation in log albumin excretion rate (P<0.001). Duration, age, and triglyceride level explained 46% of the variation in the severity of retinopathy (P<0.001) and 31% of the variation in the vibration perception threshold in the ankle (P<0.001). While the well-established risk factors (duration of diabetes, hyperglycemia, and hypertension) are associated with microvascular complications, more than half of the variation in their severity cannot be explained. An additional risk factor may involve triglycerides even at a normal serum concentration. The mechanism could be the incorporation of triglycerides in the cell membrane, leading to variations in membrane fluidity. Received: 30 September 1995 / Accepted in revised form: 19 September 1996     

Glycated haemoglobin and cardiovascular outcomes in people with Type 2 diabetes: a large prospective cohort study

Aims To investigate the association between long‐term glycaemic control, measured by glycated haemoglobin (HbA_1c), and time to first cardiovascular disease (CVD) event for people with Type 2 diabetes in New Zealand. Methods A prospective cohort study including people with Type 2 diabetes but no previous CVD. The primary outcome measure was time to first recorded fatal or non‐fatal CVD event (ischaemic heart disease, cerebrovascular accident, transient ischaemic attack or peripheral vascular disease) as identified from linked primary care, hospital and mortality records between January 2000 and December 2005. A Cox proportional hazards model was used to examine the association between HbA_1c and time to CVD event, adjusting for age at diagnosis, duration of diabetes, gender, ethnicity, socio‐economic status, smoking, blood pressure (BP), serum total cholesterol : high‐density lipoprotein ratio, body mass index (BMI) and urine albumin : creatinine ratio. Results Participants included 48 444 people with Type 2 diabetes. Fifty‐one per cent (n = 24 721) were women, median age 60 years. Median duration of diabetes was 3 years, median BMI 31 kg/m², median HbA_1c 7.1% and mean BP was 138/81 mmHg. During the study period (median follow‐up 2.4 years), there were 5667 first CVD events (11.7% of cohort). Each 1% increase in HbA_1c was associated with an increase in hazard ratio (HR) for CVD of 1.08 (95% confidence interval 1.06–1.10, P < 0.001), myocardial infarction [HR 1.08 (1.04, 1.11)] and stroke [HR 1.09 (1.04, 1.13)]. Conclusion This study has confirmed in a large prospective cohort that increased HbA_1c is an independent risk factor for cardiovascular disease after controlling for traditional risk factors.     

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus

Aims/hypothesis The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA_1c ≥7% and ≤10%) on exercise and diet.Methods A total of 521 patients aged 27–76 years with a mean baseline HbA_1c of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue.Results After 18 weeks, HbA_1c was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA_1c reduction: −0.60% and −0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA_1c (≥9%) experienced greater placebo-subtracted HbA_1c reductions with sitagliptin (−1.20% for 100 mg and −1.04% for 200 mg) than those with HbA_1c <8% (−0.44% and −0.33%, respectively) or ≥8% to 8.9% (−0.61% and −0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight.Conclusions/interpretation Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users.For the Sitagliptin Study 023 Group see electronic supplementary material for list of study investigators.     

Performance of HbA1c for detecting newly diagnosed diabetes and pre‐diabetes in Chinese communities living in Beijing

Aim To determine the performance of glycated haemoglobin (HbA_1c) as a screening tool for detecting newly diagnosed diabetes (NDM) and pre‐diabetes. Methods A diabetes survey was conducted in Beijing among community dwellers who were willing to participate in the survey. Included in the survey were 903 individuals aged 21–79 years without previously diagnosed diabetes and in whom HbA_1c and other required covariates had been measured. NDM and pre‐diabetes (impaired glucose tolerance + impaired fasting glucose) were defined according to the World Health Organization 1999 criteria based on 75‐g oral glucose tolerance test. Receiver operating characteristic curve (ROC) was plotted to determine the performance of HbA_1c. Results The prevalence of NDM and pre‐diabetes was 11.1% and 22.4%, respectively. At an optimal HbA_1c cut‐off point of ≥ 6.0%, the test gave a sensitivity of 80.0% and a specificity of 89.8% for diagnosing NDM; at an optimal cut‐off point of ≥ 5.7%, the sensitivity was 59.4% and specificity 73.9% for diagnosing pre‐diabetes. Individuals with HbA_1c≥ 6.0% tended to be more obese than those with HbA_1c < 6.0%, but blood pressure and lipid profiles did not differ between the two groups. Conclusions HbA_1c as a single screening test is adequate to detect newly diagnosed diabetes but is not able to identify pre‐diabetes in this obese Chinese population.     

Longitudinal screening of serum lipids in children and adolescents with Type 1 diabetes in a UK clinic population

Aims To determine the prevalence of abnormal lipid levels in a large group of children and adolescents with Type 1 diabetes and to examine the changes longitudinally. In addition, to study the relationships of any lipid abnormalities to glycaemic control, age and duration of diabetes. Methods Non‐fasting blood samples were taken annually from all the patients in the Oxford Children's diabetes clinic and total cholesterol (TC), high‐density lipoprotein (HDL) cholesterol, triglycerides (TG) and glycated haemoglobin (HbA_1c) measured over a period of 8 years. Low‐density lipoprotein (LDL) cholesterol and non‐HDL were calculated from these values and compared. Tests performed less than 4 months after diagnosis were excluded. Results A total of 229 children had complete data from more than 1 year and 798 sets of data were examined. TC was lower in males and increased with duration of diabetes and with increasing HbA_1c. HDL cholesterol fell with increasing age, but independently increased with duration, and was not related to HbA_1c. LDL cholesterol and non‐HDL cholesterol were highly correlated (r = 0.9). Both were lower in males and increased with duration of diabetes. Non‐HDL cholesterol increased with HbA_1c. A total of 23.7% had HDL cholesterol < 1.1 mmol/l and 22.5% had TC > 5.2 mmol/l. Thirty‐eight per cent had LDL cholesterol > 2.6 mmol/l and 10.8% > 3.4 mmol/l, the thresholds for lifestyle and drug intervention respectively. Conclusions Abnormalities in plasma lipid levels are common in this age group and the prevalence increases with poor glycaemic control and with duration of diabetes. Around 10% of adolescents would fit criteria for lipid‐lowering medication in adults, but further study is needed to examine the risks and benefits in this age group.