Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Identification of a Common Variant for Coronary Heart Disease at PDE1A Contributes to Individualized Treatment Goals and Risk Stratification of Cardiovascular Complications in Chinese Patients With Type 2 Diabetes.

OBJECTIVE: In this study we aim to unravel genetic determinants of coronary heart disease (CHD) in type 2 diabetes (T2D) and explore their applications. RESEARCH DESIGN AND METHODS: We performed a two-stage genome-wide association study for CHD in Chinese patients with T2D (3,596 case and 8,898 control subjects), followed by replications in European patients with T2D (764 case and 4,276 control subjects) and general populations (n = 51,442-547,261). Each identified variant was examined for its association with a wide range of phenotypes and its interactions with glycemic, blood pressure (BP), and lipid controls in incident cardiovascular diseases. RESULTS: We identified a novel variant (rs10171703) for CHD (odds ratio 1.21 [95% CI 1.13-1.30]; P = 2.4 × 10-8) and BP (ß ± SE 0.130 ± 0.017; P = 4.1 × 10-14) at PDE1A in Chinese T2D patients but found only a modest association with CHD in general populations. This variant modulated the effects of BP goal attainment (130/80 mmHg) on CHD (Pinteraction = 0.0155) and myocardial infarction (MI) (Pinteraction = 5.1 × 10-4). Patients with CC genotype of rs10171703 had >40% reduction in either cardiovascular events in response to BP control (2.9 × 10-8 < P < 3.6 × 10-5), those with CT genotype had no difference (0.0726 < P < 0.2614), and those with TT genotype had a threefold increase in MI risk (P = 6.7 × 10-3). CONCLUSIONS: We discovered a novel CHD- and BP-related variant at PDE1A that interacted with BP goal attainment with divergent effects on CHD risk in Chinese patients with T2D. Incorporating this information may facilitate individualized treatment strategies for precision care in diabetes, only when our findings are validated.

Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians.

BACKGROUND: The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. METHODS: We used data from Biobank Japan (n = 70,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n = 4271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n = 620), carotid intima-media thickness (cIMT) in adult women (n = 781), dyslipidemia (n = 7723), and coronary heart disease (CHD) (n = 2374 cases and 6246 controls) in type 2 diabetes (T2D) patients. RESULTS: Our PRSs aggregating 84-549 genetic variants (0.251 < correlation coefficients (r) < 0.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089 < r < 0.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5 × 10- 103 < P < 1.3 × 10- 75) and 3-year lipid changes (1.4 × 10- 6 < P < 0.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (ß ± SE = 0.052 ± 0.002), 11.7% in TG (ß ± SE = 0.111 ± 0.006), 5.8% in HDL-C (ß ± SE = 0.057 ± 0.003), and 8.4% in LDL-C (ß ± SE = 0.081 ± 0.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183 < r < 0.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5 × 10- 3 < P < 0.0400) and 0.029-0.069 in T2D patients (2.1 × 10- 10 < P < 0.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (ß ± SE = 0.011 ± 0.005, Ptrend = 0.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI) = 1.07 (1.03-1.11)], TG [OR (95% CI) = 1.05 (1.01-1.09)], and LDL-C [OR (95% CI) = 1.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8 × 10- 4 < P < 0.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. CONCLUSIONS: The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.

Declining Trends of Cardiovascular-Renal Complications and Mortality in Type 2 Diabetes: The Hong Kong Diabetes Database.

OBJECTIVE: Nationwide studies on secular trends of diabetes complications are not available in Asia. We examined changes in risk factor control and incidence of complications from diabetes and death in a large longitudinal cohort of Chinese adults with type 2 diabetes in Hong Kong. RESEARCH DESIGN AND METHODS: Between 1 January 2000 and 31 December 2012, 338,908 Chinese adults with type 2 diabetes underwent metabolic and complication assessment in 16 diabetes centers operated by Hong Kong Hospital Authority that provided care to a large majority of diagnosed patients. Patients were followed for incident acute myocardial infarction (AMI), stroke, end-stage renal disease (ESRD), and death until 31 December 2012. Risk factor levels between enrollment periods were compared. Incidence of clinical events, stratified by diabetes duration, was examined over time. RESULTS: Incidence of complications from diabetes and death declined over the observation period in patients at varying disease duration. Among the high-risk group with diabetes for at least 15 years, crude incidence of AMI decreased from 8.7 to 5.8, stroke from 13.5 to 10.1, ESRD from 25.8 to 22.5, and death from 29.0 to 26.6 per 1,000 person-year between the periods 2000 to 2002 and 2010 to 2012. Improvements in levels of metabolic risk factors were detected. Proportion of patients achieving HbA1c <7.0% (53 mmol/mol) was increased from 32.9 to 50.0%, blood pressure ≤130/80 mmHg from 24.7 to 30.7%, and LDL cholesterol <2.6 mmol/L from 25.8 to 38.1%. CONCLUSIONS: From this territory-wide Hong Kong Diabetes Database, we observed decreases in incidence of cardiovascular-renal complications and death and corresponding improvements in risk factor control over a 13-year period.

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus.

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short-acting, prandial, and long-acting GLP-1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short-acting prandial GLP-1RA lixisenatide, with a focus on treatment of Asian patients with T2DM.

Redox-linked effects of green tea on DNA damage and repair, and influence of microsatellite polymorphism in HMOX-1: results of a human intervention trial.

Green tea has many reported health benefits, including genoprotective and antioxidant effects, but green tea has pro-oxidant activity in vitro. A tea-induced pro-oxidant shift that triggers cytoprotective adaptations has been postulated, but human data are lacking. We investigated effects on oxidation-induced DNA damage and redox-linked cytoprotective factors, including 8-oxoguanine glycosylase (hOGG1) and heme oxygenase 1 (HMOX-1) in lymphocytes in a randomised, placebo-controlled, cross-over supplementation trial. hOGG1 catalyses the first step in base excision repair; increased HMOX-1 is a sign of cytoprotective response to pro-oxidant change. The influence of microsatellite polymorphisms in the HMOX-1 promoter region was also explored. Higher numbers of GT repeats [GT(n)] in this region reportedly diminish response to pro-oxidant change. Green tea [2 × 150 ml of 1% w/v tea/day (or water as control)] was taken for 12 weeks by 43 Type 2 diabetes subjects {20 with short [S/S; GT(n) < 25] and 23 with long [L/L; GT(n) ≥ 25]}. Fasting venous blood was collected before and after each treatment. The formamidopyrimidine DNA glycosylase-assisted comet assay was used to measure DNA damage in lymphocytes. For measuring hOGG1 activity, we used photo-damaged HeLa cells incubated with lymphocyte extracts from test subjects, in combination with the comet assay. Lymphocyte HMOX-1 and hOGG1 protein concentrations and expression (mRNA) of redox-sensitive genes, including HMOX-1 and hOGG1, were also investigated. Results showed significantly (P < 0.01) lower (~15%) DNA damage, higher (~50%) hOGG1 activity and higher (~40%) HMOX-1 protein concentration after tea. No changes in mRNA expression were seen. Baseline HMOX-1 protein and hOGG1 activity were higher (P < 0.05) in the S/S group, but tea-associated responses were similar in both GT(n) groups. Green tea is clearly associated with lowered DNA damage, increased hOGG1 activity and higher HMOX-1 protein levels. Further study is needed to confirm a cause and effect relationship and to establish if these effects are mediated by post-translational changes in proteins or by increased gene expression.

Relationships among diabetic retinopathy, antioxidants, and glycemic control.

PURPOSE: Type 2 Diabetes Mellitus (DM) is increasing worldwide and affects ∼11% of the Hong Kong population. Diabetic retinopathy (DR) is a common cause of vision loss in type 2 DM. Risk of DR is increased by poor glycemic control, elevated lipids, and blood pressure, but it is not possible to predict the development or progression of DR at an individual level. Increased oxidative stress is thought to play a role. The use of a wider biomarker profile incorporating biomarkers of antioxidant status and oxidative stress may aid identification of individuals at higher risk or at very early stages of developing DR. METHODS: Four hundred twenty type 2 DM subjects without diabetic complications were investigated. Eyes were examined for DR and anterior and posterior ocular segment pathology. DR was graded according to Early Treatment Diabetic Retinopathy Study criteria. Demographic data were collected. Traditional risk factors plus biomarkers of antioxidant status and oxidative stress in fasting blood and urine were determined. RESULTS: Overall DR prevalence was 89%. No significant differences in any demographic measures or biomarkers were found among those subjects with different DR grades, or in those without DR. Significant correlations (p < 0.0001) between HbA1c and DNA damage, (ρ = 0.32) and fasting plasma glucose and DNA damage (ρ = 0.52) were seen. DNA damage was also significantly and inversely correlated (p < 0.0001) with both plasma ascorbic acid (ρ = -0.41) and plasma total antioxidant level (ρ = -0.21). CONCLUSIONS: DR prevalence was very high in this group, but no biomarker differences were seen in those with DR compared to those free of DR, or in those with different degrees of severity of DR. This group of 420 subjects is being followed up to investigate whether the extended biomarker profile at baseline is related to progression of and/or incident DR.

Phaeochromocytoma in the Hong Kong Chinese population.

OBJECTIVE: To review the clinical manifestations of phaeochromocytoma in a Hong Kong Chinese population. DESIGN: Retrospective review. SETTING. Five public hospitals in Hong Kong. PATIENTS: Seventeen patients with operated phaeochromocytoma between 1994 and 2003 were reviewed retrospectively. RESULTS: Six patients (35%) were men, 11 (65%) were women. The mean age at presentation was 47 (range, 17-72) years. The diagnosis post-presentation was delayed by 1 to 132 months. Over 70% of the patients had hypertension. The most frequent symptoms were headache (53%), palpitations (53%), and sweating (41%); all these symptoms were present in 24% of the patients. Four (24%) had hereditary phaeochromocytoma/paraganglioma syndrome. The sensitivity of 24-hour urinary catecholamine measurements was 82%. Mean urinary adrenaline and noradrenaline concentrations were respectively 7- and 8-fold greater than the upper reference limits. Computed tomography and metaiodobenzylguanidine scintigraphy were the most widely used means for tumour localisation (sensitivity, 100% and 87% respectively). Approximately 65% of the patients had intra-adrenal tumours; 53% were on right side, 18% were bilateral. All the patients were prescribed phenoxybenzamine (dosage range, 20-120 mg/day) preoperatively. Two thirds of the patients had improved blood pressure 1 year after the operation. No malignancy was reported after a mean follow-up period of 7 years. CONCLUSION: Our series of patients with phaeochromocytomas commonly had a high frequency of normotension and extra-adrenal tumours. A high index of clinical suspicion and appropriate biochemical investigations are necessary to make the diagnosis, especially for patients manifesting adrenal incidentaloma and extra-adrenal lesion.

Type 2 diabetes mellitus and its renal complications in relation to apolipoprotein E gene polymorphism.

The apolipoprotein E (APOE) epsilon2 allele is reported to be associated with greater risk of renal impairment in type 2 diabetes. Relationships among APOE polymorphisms, renal impairment, and biochemical parameters were explored. A prospective study of 405 consenting Chinese type 2 diabetic patients [mean age +/- standard deviation (SD): 59.2 +/- 10.3 years] without advanced complications at entry was conducted. APOE genotyping and measurement of plasma biomarkers of oxidative stress and antioxidants were performed at entry. HbA1C, plasma glucose, lipids, creatinine, urine albumin/creatinine, and blood pressure were measured at entry and at up to 4 years of follow-up. APOE allelic frequencies were in Hardy-Weinberg equilibrium. Odds ratios of albuminuria at entry and/or during follow-up for different APOE groups were not significantly different. The non-epsilon2 (epsilon3/3, epsilon3/4, epsilon4/4) group had significantly greater plasma ascorbate (51.6 +/- 20.1 mumol/L) than the epsilon2 (epsilon2/2, epsilon2/3) group (44.5 +/- 16.2 mumol/L, P = 0.021), but higher plasma ascorbate levels did not seem to decrease the risk of renal impairment in the non-epsilon2 group. Baseline plasma lipid-standardized alpha-tocopherol levels were least in epsilon2 subjects with persistent albuminuria (3.6 +/- 1.1 mumol/mmol of total cholesterol plus triglycerides, P = 0.008) compared with epsilon2 subjects who had no albuminuria at entry or during follow-up (4.5 +/- 0.8 mumol/mmol of total cholesterol plus triglycerides). The APOE epsilon2 allele does not seem to be associated with increased risk of renal impairment in Chinese type 2 diabetic patients. Plasma lipid-standardized alpha-tocopherol may play a role in determining risk of renal dysfunction in type 2 diabetes.

Health literacy, complication awareness, and diabetic control in patients with type 2 diabetes mellitus.

AIM: This paper is a report of a study to examine the relationship between health literacy, complication awareness and diabetic control among patients with type 2 diabetes mellitus, and to validate a Chinese version of the Short-form Test of Functional Health Literacy in Adults. BACKGROUND: There is a rapidly increasing trend in the prevalence of diabetes mellitus in Asian countries. Alongside the considerable progress in recent decades of health education in the field of diabetes care, the effects of health literacy and complication awareness have received increasing attention over the past 10 years. METHOD: This study was conducted from September 2005 to February 2006 with 149 Chinese patients (mean = 59.8 years, range: 27-90 years) who were undergoing/had undergone diabetic complication assessment. Survey data were collected using a structured questionnaire incorporating demographics; assessment of complication awareness in two sections: a self-developed 10-item patient awareness score and a modified Chinese version of the Summary of Diabetes Self-Care Activities measure; and health literacy as measured by the Chinese version of the Short Test of Functional Health Literacy in Adults. Diabetic control was assessed by the most recent HbA1c level. FINDINGS: Health literacy (P < 0.001) and patient awareness scores were negatively correlated to diabetic control (P = 0.035), but management of treatment in the Summary of Diabetes Self-Care Activities measure (P = 0.030), gender (P = 0.023) and duration of diabetes (P < 0.001) were positively correlated to HbA1c. CONCLUSION: To develop effective patient education and improve patients' diabetic control and own complications, educational strategies need to consider patients' health literacy levels and self-care skills.

Middle cerebral artery stenosis increased the risk of vascular disease mortality among type 2 diabetic patients.

BACKGROUND: In Chinese populations, middle cerebral artery (MCA) stenosis is the most commonly identified intracranial vascular lesion, and has been shown to be associated with an increased risk of secondary stroke mortality, but has yet to be reported for primary events. We assess whether asymptomatic MCA stenosis is associated with mortality in Chinese type 2 diabetic patients. METHODS: The presence of MCA stenosis was determined by transcranial Doppler and mortality data were collated in the Hong Kong Death Registry. Cox proportional hazards regression was used to determine if the MCA stenosis (n = 272, 53.7% 2-vessel disease) in 2,197 diabetics was associated with all-cause or vascular disease mortality, including after adjustment for conventional vascular risk factors. Anthropometric and fasting biochemical parameters were compared between diabetic patients with MCA stenosis and without evidence of stenosis. RESULTS: A total of 191 deaths were identified (30.9% of vascular disease origin) during a follow-up of 18,279 patient years over 8.32 years. After adjustment for age, gender and diabetes duration, the hazard ratios for vascular mortality for 1- and 2-vessel disease were 2.47 (95% CI = 1.13-5.38) and 4.47 (95% CI = 2.24-8.82), p < 0.001 for trend, for increasing vascular mortality with increasing severity of cerebrovascular involvement, but 0.81 (95% CI = 0.45-1.47) and 2.23 (95% CI = 1.45-1.47), p = 0.001 for trend, for all-cause mortality. For vascular mortality, further adjustments for anthropometric and fasting biochemical parameters, or existing disease and treatment history increased the hazard ratios for 1-vessel disease slightly but attenuated the risk for 2-vessel disease evidently, 2.81 (95% CI = 1.10-7.16) and 2.85 (95% = CI 1.11-7.33), p = 0.026. CONCLUSION: The presence of MCA stenoses was an independent predictor of vascular mortality in these diabetics. More aggressive treatment of risk factors in these subjects merits further evaluation.

Association of testosterone, insulin-like growth factor-I, and C-reactive protein with metabolic syndrome in Chinese middle-aged men with a family history of type 2 diabetes.

CONTEXT: Age-related declines in testosterone and IGF-I are associated with deposition of visceral fat, a component of the metabolic syndrome (MES). OBJECTIVE: Testosterone and IGF-I may interact with familial disposition to diabetes mellitus to increase the association with MES. DESIGN: We conducted a cross-sectional cohort study. SETTING: The study was conducted in a university teaching hospital. SUBJECTS: Study subjects included 179 middle-aged men with a family history of diabetes (FH) (aged 39.1 +/- 8.1 yr) and 128 men without FH (aged 43.8 +/- 8.5 yr). MAIN OUTCOME MEASURES: Clinical characteristics, frequency of MES using the World Health Organization criteria with Asian definitions of obesity (body mass index > or = 25 kg/m2), and serum levels of total testosterone, IGF-I, and high-sensitive C-reactive protein (hs-CRP) were measured. RESULTS: Men with FH had higher frequency of MES than those without FH [39.1 vs. 23.4% (P = 0.004)]. On multivariate analysis, smoking (former and current smokers), low total testosterone, and IGF-I but elevated hs-CRP levels explained 35% of the MES variance in men with FH. The frequency of MES increased with declining tertiles of total testosterone and IGF-I but increasing tertiles of hs-CRP. After adjustment for age and smoking history, subjects with all three risk factors had a 13-fold increase in risk association with MES compared with those without hormonal and inflammatory risk factors. These risk associations were not found in men without FH in whom only smoking (ex and current) and low total testosterone level were independent predictors for MES, which explained 14% of the variance. CONCLUSIONS: Clustering of FH, hormonal abnormalities, and high hs-CRP is associated with MES in Chinese middle-aged men.

Effects of obesity on the conversion from normal glucose tolerance to diabetes in Hong Kong Chinese.

OBJECTIVE: To assess the effects of BMI on progression to diabetes in Hong Kong Chinese and to analyze the optimal cutoff for overweight and obesity in Hong Kong Chinese. RESEARCH METHODS AND PROCEDURES: This is a prospective study with a mean follow-up of 2.1 years (median 1.4 years, range 0.9 to 8.4 years). We recruited 172 nondiabetic high-risk subjects, of whom 115 had normal glucose tolerance (NGT) and 57 had impaired glucose tolerance (IGT). BMI and 75-gram oral glucose tolerance tests were assessed at baseline and then at yearly intervals. RESULTS: The crude rates of progression to diabetes for subjects with NGT or IGT were 8.4% and 11.5% per year, respectively. For subjects with NGT, the progression rate to diabetes differed with different BMI ranges. For subjects with NGT and BMI > or = 25 kg/m2, the crude rates of progression to diabetes or glucose intolerance (diabetes or IGT) were 12.5% per year and 14.6% per year, respectively. The corresponding rates for subjects with NGT and BMI > or = 28 kg/m2 were 14.6% and 18.9% per year, respectively. Among subjects with NGT, those with BMI between 25 and 28 kg/m2 had the highest Youden index and likelihood ratio to predict the conversion to diabetes or glucose intolerance. DISCUSSION: Obese subjects with NGT had higher rates of progression to diabetes than nonobese subjects. We recommend redefining BMI cutoffs, with 23 kg/m2 for overweight and 28 kg/m2 for obesity. This definition may be more sensitive to identify at-risk subjects and more specific to identify "patients" for therapeutic management.

Consensus statement on iodine deficiency disorders in Hong Kong.

This article reviews the available data on the study of iodine deficiency disorders in Hong Kong and to discuss the approach towards preventing such disorders in Hong Kong. The importance of iodine and iodine deficiency disorders is described, and the available data on the dietary iodine intake and urinary iodine concentration in different populations of Hong Kong are summarised and discussed. Dietary iodine insufficiency among pregnant women in Hong Kong is associated with maternal goitrogenesis and hypothyroxinaemia as well as neonatal hypothyroidism. Borderline iodine deficiency exists in the expectant mothers in Hong Kong. Women of reproductive age, and pregnant and lactating women should be made aware and educated to have an adequate iodine intake, such as iodised salt, as an interim measure. A steering group involving all stakeholders should be formed to advise on the strategy of ensuring adequate iodine intake, including universal iodisation of salt in Hong Kong. Continuous surveillance of iodine status in the Hong Kong population is necessary.

Effects of protocol-driven care versus usual outpatient clinic care on survival rates in patients with type 2 diabetes.

OBJECTIVE: To determine whether clinical outcomes in patients with type 2 diabetes were improved by protocol-driven care in a Diabetes Centre compared with usual outpatient care. STUDY DESIGN: Descriptive analysis of a prospective cohort. PATIENTS AND METHODS: During a median 7-year observational period, 91 patients with type 2 diabetes and no cardiovascular or renal complications were monitored by a nurse and a diabetologist in a clinical trial setting according to a structured protocol. Another 81 patients with comparable clinical characteristics were monitored by generalists at the medical clinic in the same hospital. Clinical end points, defined as death and cardiovascular and renal events, were evaluated in 1997 by review of case records. RESULTS: Patients receiving structured care had lower mortality (relative risk [RR] = 0.21; 95% confidence interval [CI] = 0.07, 0.65; P = .006) than the usual-care group, as well as a lower incidence of combined clinical end points (RR = 0.43; 95% CI = 0.22, 0.84; P = .01). In the usual-care group, patients who had no monitoring of glycosylated hemoglobin or plasma lipid levels during the entire observational period (8.6%) had a 14.6-fold (P < .01) and 15.7-fold (P < .01) increased risk of death and combined clinical end points, respectively, compared with those who had at least one measurement (60.5%). CONCLUSION: Management by protocol-driven care model improved survival and clinical outcomes in patients with type 2 diabetes. Definitive studies are required to confirm these findings and compare the cost effectiveness of these care models.