Guidance on the management of familial hypercholesterolaemia in Hong Kong: an expert panel consensus viewpoin.

In 2016, meetings of groups of physicians and paediatricians with a special interest in lipid disorders and familial hypercholesterolaemia were held to discuss several domains of management of familial hypercholesterolaemia in adults and children in Hong Kong. After reviewing the evidence and guidelines for the diagnosis, screening, and management of familial hypercholesterolaemia, consensus was reached on the following aspects: clinical features, diagnostic criteria, screening in adults, screening in children, management in relation to target plasma low-density lipoprotein cholesterol levels, detection of atherosclerosis, lifestyle and behaviour modification, and pharmacotherapy.

Precision-activated T-cell engagers targeting HER2 or EGFR and CD3 mitigate on-target, off-tumor toxicity for immunotherapy in solid tumors.

To enhance the therapeutic index of T-cell engagers (TCEs), we engineered masked, precision-activated TCEs (XPAT proteins), targeting a tumor antigen (human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR)) and CD3. Unstructured XTEN polypeptide masks flank the N and C termini of the TCE and are designed to be released by proteases in the tumor microenvironment. In vitro, unmasked HER2-XPAT (uTCE) demonstrates potent cytotoxicity, with XTEN polypeptide masking providing up to 4-log-fold protection. In vivo, HER2-XPAT protein induces protease-dependent antitumor activity and is proteolytically stable in healthy tissues. In non-human primates, HER2-XPAT protein demonstrates a strong safety margin (>400-fold increase in tolerated maximum concentration versus uTCE). HER2-XPAT protein cleavage is low and similar in plasma samples from healthy and diseased humans and non-human primates, supporting translatability of stability to patients. EGFR-XPAT protein confirmed the utility of XPAT technology for tumor targets more widely expressed in healthy tissues.

Rab35-dependent extracellular nanovesicles are required for induction of tumour supporting stroma.

Communication between diseased cells and the microenvironment is a complex yet crucial element in progression of varied pathological processes. Recent studies in cancer highlight an important role for small extracellular nanovesicles secreted by cancer cells as modulators of cancer-associated stroma, leading to enhanced angiogenesis and metastatic priming. The intrinsic factors regulating extracellular nanovesicle biogenesis and secretion are therefore relevant in studies of nano-communication in the cancer milieu. We generated prostate cancer cells bearing stable knockdown of several candidate vesicle regulating factors and examined the impact on cell health, vesicle secretion and on communication with fibroblastic stromal cells. We highlight that RAB11B and RAB35 regulate phenotypically distinct nanovesicle populations, each accounting for only around 20% of the total. Depleting RAB35, but not RAB11B leaves a remaining population of vesicles whose phenotype is insufficient for driving fibroblast to myofibroblast differentiation, leading to attenuated motile behaviours in 3D in vitro models. Co-implantation of tumour cells with stromal fibroblasts in xenografts similarly showed that RAB11B knockdown had little effect on growth rates in vivo. In contrast, significant attenuation in growth, and attenuation of myofibroblasts at the tumour site was evident when using RAB35-knockdown cells. The study concludes that a RAB35 regulated nanovesicle sub-population is particularly important for communication between cancer and stromal cells, and is required for generating a tumour-supportive microenvironment.

CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation.

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.

RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common Wnt pathway mutations.

Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, ß-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.

WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death.

The WNT pathway mediates intercellular signaling that regulates cell fate in both normal development and cancer. It is widely appreciated that the WNT pathway is frequently dysregulated in human cancers through a variety of genetic and epigenetic mechanisms. Targets in the WNT pathway are being extensively pursued for the development of new anticancer therapies, and we have advanced two WNT antagonists for clinical development: vantictumab (anti-FZD) and ipafricept (FZD8-Fc). We examined the antitumor efficacy of these WNT antagonists in combination with various chemotherapies in a large set of patient-derived xenograft models. In responsive models, WNT blockade led to profound synergy with taxanes such as paclitaxel, and the combination activity with taxanes was consistently more effective than with other classes of chemotherapy. Taxane monotherapy increased the frequency of cells with active WNT signaling. This selection of WNT-active chemotherapy-resistant tumorigenic cells was prevented by WNT-antagonizing biologics and required sequential dosing of the WNT antagonist followed by the taxane. The WNT antagonists potentiated paclitaxel-mediated mitotic blockade and promoted widespread mitotic cell death. By blocking WNT/ß-catenin signaling before mitotic blockade by paclitaxel, we found that this treatment effectively sensitizes cancer stem cells to taxanes. This combination strategy and treatment regimen has been incorporated into ongoing clinical testing for vantictumab and ipafricept.

Metabolic syndrome by the international diabetes federation definition in Hong Kong Chinese.

In this report, we aimed to examine the impact of the new International Diabetes Federation (IDF) definition on the prevalence and clinical characteristics of subjects with metabolic syndrome (MES). Data were obtained from a prevalence survey for cardiovascular risk factors in a Hong Kong Chinese working population. There were 1513 subjects well representing all occupational groups from managers to general laborers [910 (60.1%) men and 603 (39.9%) women (mean age 37.5+/-9.2, median 37.0, range 18-66 years)]. The crude prevalence of MES defined by the IDF criterion was 7.4% (compared to other criteria: NCEP, 9.6%; WHO, 13.4% and EGIR, 8.9%). The age-standardized prevalence of MES by the IDF criterion was 8.8% in women and 7.3% in men. Subjects with MES defined by IDF criterion had higher body mass index and waist compared to those with MES defined by NCEP or WHO criteria, and lower triglyceride compared to those with MES defined by NCEP criterion after adjustment for age, gender and smoking. Non-MES subjects defined by IDF criterion had higher 2h glucose and insulin resistance compared to non-MES subjects defined by WHO. In conclusion, the new IDF criterion for MES is easy to implement in clinical practice. It may be potentially more 'specific' in identifying subjects with MES although compared to the NCEP criterion, it may have missed a proportion of subjects, especially men, who have metabolic derangement. Prospective and interventional studies are needed to validate the prognostic values of this new definition in comparison with other existing definitions.

Association of smoking with increasing vascular involvement in type 2 diabetic Chinese patients.

PURPOSE: To identify the relationship between smoking and the metabolic profile and existing vascular disease in Chinese type 2 diabetic patients. METHODS: 1710 diabetic patients were screened for complications, and biochemical and anthropometric vascular risk factors. As most smokers were male, differences were only compared between male current (n = 196) and never smoking patients (n = 300). RESULTS: The smokers had higher glycosylated haemoglobin levels (8.2 +/- 2.0 vs. 7.6 +/- 1.8%, p < 0.001) than never smokers, despite a greater proportion receiving hypoglycaemic agents (87.5 vs. 79.6%, p = 0.003). Male smokers compared to never smokers had lower HDL-cholesterol levels (1.12 +/- 0.31 vs. 1.20 +/- 0.30 mmol/L, p = 0.006), and elevated albumin-to-creatinine ratio (3.57 [2.68-4.75] vs. 2.47 [1.99-3.05] mg/mmol, p = 0.040). However, diastolic blood pressure was lower in the smoking group (78 +/- 12 vs. 82 +/- 12 mmHg, p = 0.001) even though they received less blood pressure-lowering treatments (23.8 vs. 33.2%, p = 0.034). The prevalence of peripheral vascular disease was increased in the diabetic patients who smoked compared to nonsmokers (7.1 vs. 2.8%, p = 0.039). CONCLUSIONS: Smoking was associated with a more adverse metabolic profile and peripheral vascular disease. As mainland China undergoes rapid modernisation and urbanisation, the observed effects of smoking means tobacco control becomes increasingly important to prevent or minimise potential health impacts and chronic disease.

MicroAlbuminuria Prevalence Study (MAPS) in hypertensive type 2 diabetic patients in Hong Kong.

OBJECTIVES: To assess the prevalence of macroalbuminuria and microalbuminuria, and the level of blood pressure control in patients with type 2 diabetes and hypertension in Hong Kong. DESIGN: Cross-sectional clinic-based epidemiological study. SETTING: Six medical centres (including two public hospital diabetes centres) in Hong Kong. PATIENTS: Recruited from the medical centres from April to November 2002, after excluding those with bacteriuria and haematuria. MAIN OUTCOME MEASURES: Body mass index; blood pressure; levels of blood glucose, macroalbuminuria, and microalbuminuria; treatments for hypertension and diabetes. RESULTS: The as per-protocol recruited population of 437 hypertensive type 2 diabetic patients had a mean age of 61.7 (standard error, 0.5) years. Overall, the prevalence of diabetic nephropathy in this population was high; 18.3% had macroalbuminuria (95% confidence interval, 16.5-20.2%) and 24.9% had microalbuminuria (95% confidence interval, 22.9-27.0%). Predictive factors were advanced age, male sex, poor blood pressure control, and existing cardiovascular complications. Whilst almost all patients (96.1%) were receiving treatment for hypertension, only 25.6% had systolic/diastolic blood pressures below the 130/85 mm Hg target. CONCLUSIONS: In Hong Kong, the prevalence of microalbuminuria and macroalbuminuria is high in type 2 diabetic patients with hypertension, particularly in males and those with poorly controlled systolic blood pressure. Tight glycaemic control, antihypertensive therapy, and use of renin-angiotensin system inhibitors/blockers are necessary to retard the progression of nephropathy to advanced renal disease.

A beta-lactamase with reduced immunogenicity for the targeted delivery of chemotherapeutics using antibody-directed enzyme prodrug therapy.

Antibody-directed enzyme prodrug therapy (ADEPT) delivers chemotherapeutic agents in high concentration to tumor tissue while minimizing systemic drug exposure. beta-Lactamases are particularly useful enzymes for ADEPT systems due to their unique substrate specificity that allows the activation of a variety of lactam-based prodrugs with minimal interference from mammalian enzymes. We evaluated the amino acid sequence of beta-lactamase from Enterobacter cloacae for the presence of human T-cell epitopes using a cell-based proliferation assay using samples from 65 community donors. We observed a low background response that is consistent with a lack of preexposure to this enzyme. beta-Lactamase was found to contain four CD4+ T-cell epitopes. For two of these epitopes, we identified single amino acid changes that result in significantly reduced proliferative responses while retaining stability and activity of the enzyme. The beta-lactamase variant containing both changes induces significantly less proliferation in human and mouse cell assays, and 5-fold lower levels of IgG1 in mice were observed after repeat administration of beta-lactamase variant with adjuvant. The beta-lactamase variant should be very suitable for the construction of ADEPT fusion proteins, as it combines high activity toward lactam prodrugs, high plasma stability, a monomeric architecture, and a relatively low risk of eliciting an immune response in patients.

Susceptibility to IDDM in a Chinese population. Role of HLA class II alleles.

MHC associations with IDDM in a Chinese population were studied to investigate genetic susceptibility to the disorder. The frequency of HLA-DR3 was significantly higher in the diabetic patients (19/49 [38.7%] vs. control subjects, 11/105 [10.5%], Pc less than 1.3 x 10(-3), RR = 5.3 [CI 2.3-12.1]), whereas DR4 was not (11/49 [22.4%] vs. 28/105 [26.7%], NS). The frequency of DR3/4 heterozygosity was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 0/105 [0%], P = 1.7 x 10(-3), RR = 31.5 [CI 3.8-263.6]). The frequency of DR3/9 heterozygosity also was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 2/105 [1.9%], P = 0.03, RR = 6.2 [CI 3.0-12.7]). No significant associations were noted between DQB1 alleles and IDDM. Among DR4-positive subjects, the frequency of DQB1 allele DQB1*0302 was higher in the diabetic patients (10/11 [90.0%] vs. control subjects, 12/24 [50%], Pc less than 0.05, RR = 7.0 [CI 1.3-38.0]), and the frequency of DQB1*0401 was significantly lower in the diabetic patients (2/11 [18.2%] vs. control subjects, 16/24 [66.7%], Pc = 0.04, RR = 0.1 [CI 0.02-0.46]). No DR4 subtype was associated significantly with IDDM. The frequency of DQA1*0501, a DQA1 allele, was higher in diabetic patients (22/41 [53.7%] vs. control subjects, 20/95 [21.1%], Pc less than 3 x 10(-3), RR = 4.3 [CI 2.0-9.3]). The frequency of DQA1*0301, which has been associated consistently with IDDM in other ethnic groups, was not significantly higher in the diabetic patients in this study (27/41 [65.9%] vs. control subjects, 53/95 [55.8%], NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of enalapril and nifedipine on carbohydrate and lipid metabolism in NIDDM.

OBJECTIVE: To compare the effects of nifedipine and enalapril on carbohydrate and lipoprotein metabolism in Chinese non-insulin-dependent diabetes mellitus (NIDDM) patients with hypertension. RESEARCH DESIGN AND METHODS: A 12-week, double-blind, randomized study of plasma lipid levels and glycemic control in patients treated with nifedipine (n = 52) or enalapril (n = 50) was conducted. None of the patients were treated with insulin. Diet and dosages of oral hypoglycemic agents remained unchanged during the 12-week treatment period. RESULTS: Mean arterial pressure was reduced more by nifedipine than by enalapril (23.1 vs. 11.1 mmHg, P < 0.001). Similar reductions in body mass index and plasma triglycerides and increases in apolipoprotein A-I were seen with both treatments, but HbA1 was reduced more during treatment with enalapril than with nifedipine (0.49 vs. 0.20%, P = 0.035) and serum apolipoprotein B (apoB) also declined more with enalapril than with nifedipine (8.2 vs. 2.3 mg/dl, P = 0.009). CONCLUSIONS: Twelve weeks of treatment with enalapril in hypertensive NIDDM patients was associated with greater improvement in glycemic control and greater reduction in serum apoB concentration, although the reduction in blood pressure was less than with nifedipine. These changes in cardiovascular risk profile warrant investigation for a longer term.

Dexfenfluramine in obese Chinese NIDDM patients. A placebo-controlled investigation of the effects on body weight, glycemic control, and cardiovascular risk factors.

OBJECTIVE: To investigate the safety, efficacy, and metabolic effects of dexfenfluramine in obese Chinese NIDDM patients. RESEARCH DESIGN AND METHODS: Thirty-two patients, mean (+/- SD) body weight 76.2 +/- 8.5 kg with corresponding BMI 31.1 +/- 2.1 kg/m2, were randomized into a two-phase study, after a 2-week single-blind run-in period on placebo. Phase 1 was a randomized 3-month double-blind placebo-controlled trial during which either dexfenfluramine or placebo was added to the existing treatment regimens of diet plus or minus sulfonylureas without metformin. Phase 2 was a further 3-month single-blind trial during which the placebo group was given dexfenfluramine without patients' knowledge of changing to active medication, while the active group continued with dexfenfluramine. Body weight, glycemic control, blood pressure, lipids, and quality of life were assessed before and at 3 and 6 months after randomization. A total of 27 patients were also followed for an additional period of 6-12 months (215 +/- 53 days) after dexfenfluramine treatment was withdrawn. RESULTS: During the run-in period, both groups were comparable for all parameters measured. At 3 months, mean changes in BMI were -1.2 +/- 1.0 kg/m2 (dexfenfluramine) vs. -0.1 +/- 0.5 kg/m2 (placebo) (P < 0.001). The mean changes in fasting plasma glucose were -1.14 +/- 0.99 vs. 0.51 +/- 1.34 mmol/l (dexfenfluramine vs. placebo, P = 0.004). HbA(1c) also significantly improved in the dexfenfluramine group (-0.80 +/- 0.53 vs. 0.25 +/- 0.64%, P < 0.001). During the 3-month single-blind dexfenfluramine treatment in the ex-placebo group, there were similar improvements in body weight and glycemic indexes. After cessation of dexfenfluramine therapy at 6 months, significant increases in body weight and glycemic indexes, almost back to the baseline, were observed for both groups. CONCLUSIONS: Dexfenfluramine aids weight loss and improves glycemic control in obese Chinese NIDDM patients over a 3- to 6-month period. These effects are emphasized after withdrawal of treatment and further support the longer-term use of dexfenfluramine for chronic complicated obesity.

Factors predicting the age when type 2 diabetes is diagnosed in Hong Kong Chinese subjects.

OBJECTIVE: To examine the factors predicting age at diagnosis of type 2 diabetes in Hong Kong Chinese. RESEARCH DESIGN AND METHODS: The relationships between age at diagnosis and parental history of diabetes as well as an array of clinical and metabolic factors were examined using a hospital clinic-based diabetes registry involving 3,414 index patients with type 2 diabetes Patterns of age at diagnosis in successive generations were also examined using 21 affected child-parent pairs and 7 affected child-parent-grandparent trios. RESULTS: Approximately 29% of the index patients were diagnosed with type 2 diabetes at < or = 35 years of age (hereby defined as early-onset). Compared with the patients diagnosed at >35 years of age (hereby defined as late-onset) the early-onset patients had higher rates of positive paternal (16 vs. 5%) and maternal (22 vs. 12%) history of diabetes (both at P < 0.01) and had poorer metabolic profiles. In the overall index patients, male sex, higher HbA1c waist-to-hip ratio (WHR), and systolic blood pressure (sBP); lower HDL cholesterol level; and a positive paternal was well as maternal history of diabetes predicted younger age at diagnosis. More senior age and higher BMI and diastolic blood pressure predicted olderq age at diagnosis. Predictors for younger age at diagnosis in the male patients were higher HbA1c and sBP and a positive paternal history of diabetes Predictors for younger age at diagnosis in the female patients were higher HbA1c WHR, and sBP and a paternal as well as maternal history of diabetes. In the affected child parent pairs and clild-parent-grandparent trios there was a decrease in age at diagnosis in successive generations. CONCLUSIONS: Our data indicate that both familial (possibly genetic) and metabolic factors affect the age of onset of type 2 diabetes in the Chinese population. The results also suggest an onset and progression pattern of the disease that is compatible with the phenomenon of anticipation.

Outcomes of screening for diabetes in high-risk Hong Kong Chinese subjects.

OBJECTIVE: To examine the significance of individual risk factors on the development of diabetes in subjects who underwent screening for diabetes. RESEARCH DESIGN AND METHODS: A total of 1,649 Chinese subjects underwent screening for diabetes. They were asymptomatic but had known risk factors for diabetes, including a positive family history of diabetes, a past history of gestational diabetes, obesity, hypertension, and/or dyslipidemia. Another 799 age-matched subjects from the community who had no risk factors for diabetes were used as the comparison group. RESULTS: Of the 1,649 subjects who underwent screening, 241 (14.6%) had diabetes. In these subjects, 989 (60.0%) had 1 risk factor, 502 (30.4%) had 2 risk factors, 141 (8.6%) had 3 risk factors, and 17 (1.0%) had 4 or 5 risk factors for diabetes. Of the 799 control subjects, 29 (3.6%) had diabetes. Compared with the comparison group, the odds ratio (95% CI) of having diabetes after adjustment for age was 5.2 (3.5-7.7) in the 1,649 subjects with known risk factors. The odds ratio of having diabetes increased from 3.7 in subjects with 1 risk factor to 28.4 in subjects with 4 or 5 risk factors. CONCLUSIONS: In men, age, BMI, family history of diabetes, and dyslipidemia, and in women, age, BMI, hypertension, dyslipidemia, total cholesterol, and history of gestational diabetes are associated with increased odds of developing diabetes. These risk factors have additive effects on the odds of having diabetes. Early and regular screening for diabetes and other cardiovascular risk factors is essential in these high-risk individuals.

Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients.

OBJECTIVE: To examine the relationships between central obesity, insulin resistance index, plasma insulin, growth hormone (GH), and cortisol concentrations in 90 young Chinese type 2 diabetic patients (aged 33+/-5 years) and 104 age- and sex-matched control subjects (aged 32+/-9 years). RESEARCH DESIGN AND METHODS: Young Chinese diabetic patients (aged <40 years) were recruited from the Prince of Wales Hospital. Blood pressure, height, weight, and waist and hip circumferences were determined. Venous blood was sampled for measurements of fasting plasma glucose, HbA1c, lipids, creatinine, insulin, GH, and cortisol. A 24-h urine was assayed for urinary albumin excretion (UAE). General and central obesity was represented by BMI and waist circumference, respectively. Insulin resistance index was estimated as a product of fasting plasma insulin and glucose concentrations. RESULTS: Compared with control subjects, diabetic patients were more obese, hyperglycemic, and had worse lipid profile, higher blood pressures, UAE, insulin resistance index, plasma insulin, and cortisol concentrations (all P < 0.001) but lower GH concentrations (P < 0.05). When analyzed as a whole group (n = 194), increasing quartiles of waist circumference were associated with increasing trends of insulin resistance index, plasma insulin, and cortisol concentrations (all P < 0.01) but a decreasing trend of plasma GH concentration (P < 0.05). Using stepwise multiple regression analysis, waist circumference was only associated with sex variable (being higher in men) in the control subjects. In the diabetic group, 51% of waist circumference was independently related to male sex and increased plasma insulin and cortisol concentrations as well as reduced plasma GH levels. CONCLUSIONS: In young Chinese type 2 diabetic patients, hyperinsulinemia, hypercortisolemia, and reduced plasma GH levels were closely associated with central obesity. Based on these findings, we postulate that maladaptive hormonal responses to rapid changes in lifestyle may have led to obesity and type 2 diabetes in these young patients. Alternatively, lifestyle-related obesity may have given rise to these hormonal changes. More studies are required to delineate the nature of these relationships.

Combined use of a fasting plasma glucose concentration and HbA1c or fructosamine predicts the likelihood of having diabetes in high-risk subjects.

OBJECTIVE: To assess the validity of using fasting plasma glucose (FPG) concentrations in conjunction with HbA1c or fructosamine for the screening of diabetes in high-risk individuals. RESEARCH DESIGN AND METHODS: In this study 2,877 Hong Kong Chinese (565 [19.6%] men; 2,312 [80.4%] women) with various risk factors for glucose intolerance underwent a 75-g oral glucose tolerance test (OGTT) for screening of diabetes. The risk factors included a family history positive for diabetes, a history of gestational diabetes or impaired glucose tolerance, and obesity. RESULTS: Using World Health Organization (WHO) criteria, 1,593 (55.4%) had normal glucose tolerance, 657 (22.8%) had impaired glucose tolerance, and 627 (21.8%) had diabetes. When the 1997 American Diabetes Association (ADA) criteria were applied, 394 (13.7%) had diabetes with an FPG > or = 7.0 mmol/l. Using multiple receiver operating characteristic curve analysis, the paired values of an FPG of 5.6 mmol/l and a HbA1c of 5.5% gave an optimal sensitivity of 83.8% and specificity of 83.6% to predict a 2-h plasma glucose (PG) > or = 11.1 mmol/l. Likewise, the paired values of an FPG of 5.4 mmol/l and a fructosamine level of 235 mumol/l (n = 2,408) gave an optimal sensitivity of 81.5% and specificity of 83.2%. An FPG > or = 5.6 mmol/l and an HbA1c > or = 5.5% was 5.4-fold more likely to occur in diabetic subjects (based on the WHO criteria) compared with nondiabetic subjects. For paired parameters less than these values, the likelihood ratio of this occurring in diabetic subjects was only 0.11. Similarly, an FPG > or = 5.4 mmol/l and a fructosamine > or = 235 mumol/l was fivefold more likely to occur in diabetic subjects than in nondiabetic subjects, with both parameters less than these values having a likelihood ratio of 0.04. Using these paired values as initial screening tests, only subjects who had an FPG > or = 5.6 mmol/l and < 7.8 mmol/l and an HbA1c > or = 5.5% (n = 642) required an OGTT to confirm diabetes, thereby saving 77.7% [(2,877-642)/2,877] of the OGTTs performed. Similarly, only subjects who had an FPG > or = 5.4 mmol/l and < 7.8 mmol/l and a fructosamine > or = 235 mumol/l (n = 526) required OGTT to confirm diabetes, meaning that 78.2% [(2,408-526)/2,408] of the OGTTs could have been saved. Based on the 1997 ADA criterion of an FPG cutoff value of 7.0 mmol/l, the corresponding numbers of OGTTs to be saved were 82.6% and 85.5%, respectively. CONCLUSIONS: The paired values of FPG and HbA1c or FPG and fructosamine helped to identify potentially diabetic subjects, the diagnosis of which could be further confirmed by the 75-g OGTT. Using this approach approximately 80% of OGTTs could have been saved, depending on the diagnostic cutoff value of FPG.