Aromatic Amino Acids and Their Interactions with Gut Microbiota-Related Metabolites for Risk of Gestational Diabetes: A Prospective Nested Case-Control Study in a Chinese Cohort.

INTRODUCTION: The aim of this study was to explore associations of aromatic amino acids (AAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high AAA and gut microbiota-related metabolites had interactive effects on GDM risk. METHODS: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women from 2010 to 2012. According to the International Association of Diabetes and Pregnancy Study Group's criteria, 243 women were diagnosed with GDM. Binary conditional logistic regression was performed to examine associations of AAA with GDM risk. Interactions between AAA and gut microbiota-related metabolites for GDM were examined using additive interaction measures. RESULTS: High phenylalanine and tryptophan were associated with increased GDM risk (OR: 1.72, 95% CI: 1.07-2.78 and 1.66, 1.02-2.71). The presence of high trimethylamine (TMA) markedly increased the OR of high phenylalanine alone up to 7.95 (2.79-22.71), while the presence of low glycoursodeoxycholic acid (GUDCA) markedly increased the OR of high tryptophan alone up to 22.88 (5.28-99.26), both with significant additive interactions. Furthermore, high lysophosphatidylcholines (LPC18:0) mediated both interactive effects. CONCLUSIONS: High phenylalanine may have an additive interaction with high TMA, while high tryptophan may have an additive interaction with low GUDCA toward increased risk of GDM, both being mediated via LPC18:0.

Sex-specific effect of perfluoroalkyl substances exposure on liver and thyroid function biomarkers: A mixture approach.

Although studies have investigated the effects of perfluoroalkyl substances (PFASs) on liver and thyroid function, little is known about its combined and sex-specific effect. A total of 688 participants were interviewed and serum PFASs concentration was measured using liquid chromatography/mass spectrometry. Five biomarkers of liver and thyroid function (ALT, GGT, TSH, FT3 and FT4) were chosen as outcomes. A restriction cubic spline function was applied to capture the dose-response relationship between PFASs and liver enzymes and thyroid hormones. Multivariable regression and Bayesian kernel machine regression (BKMR) models were performed to assess the single and overall associations of PFASs with targeted biomarkers. Single-pollutant analyses indicated that increased PFASs concentrations were associated with elevated ALT and GGT levels. BKMR models suggested positive dose-response relationships between PFASs mixtures and ALT and GGT levels. Significant associations were only detected between several PFASs and thyroid hormones, and joint effect of PFASs mixtures on FT3 levels was found at higher concentrations. Meanwhile, sex differences were found in the associations of PFASs with ALT and GGT levels, with significant results only in males. Our findings provide epidemiological evidence for combined and sex-specific effects of PFASs on ALT and GGT levels.

Branched-Chain Amino Acids and Their Interactions With Lipid Metabolites for Increased Risk of Gestational Diabetes.

OBJECTIVE: We aimed to explore associations of branched-chain amino acids (BCAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high BCAAs and lipidomics markers had interactive effects on the risk of GDM. METHODS: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women in Tianjin, China. Blood samples were collected at their first antenatal care visit (median 10 gestational weeks). Serum BCAAs, saturated fatty acids (SFA) and lysophosphatidylcholines (LPC) were measured by liquid chromatography-tandem mass spectrometry analysis. Conditional logistic regression was performed to examine associations of BCAAs with the risk of GDM. Interactions between high BCAAs and high SFA16:0 for GDM were examined using additive interaction measures. RESULTS: High serum valine, leucine, isoleucine, and total BCAAs were associated with markedly increased risk of GDM (OR of top vs bottom tertiles: 1.91 [95% CI, 1.22-3.01]; 1.87 [1.20-2.91]; 2.23 [1.41-3.52]; 1.93 [1.23-3.02], respectively). The presence of high SFA16:0 defined as ≥ 17.1 nmol/mL (ie, median) markedly increased the ORs of high leucine alone and high isoleucine alone up to 4.56 (2.37-8.75) and 4.41 (2.30-8.43) for the risk of GDM, with significant additive interaction. After adjustment for LPCs, the ORs were greatly elevated (6.33, 2.25-17.80 and 6.53, 2.39-17.86) and the additive interactions became more significant. CONCLUSION: BCAAs in early pregnancy were positively associated with the risk of GDM, and high levels of leucine and isoleucine enhanced the risk association of high SFA16:0 with GDM, independent of LPCs.

Predictive values of serum metabolites in early pregnancy and their possible pathways for gestational diabetes: A nested case-control study in Tianjin, China.

AIMS: To investigate the associations and predictive values of serum metabolites in early pregnancy for later development of gestational diabetes mellitus (GDM), and further explore their metabolic pathways to GDM. METHODS: We conducted a 1:1 nested case-control study including 486 pregnant women from Tianjin, China, and collected blood samples at their first registration (median at 10th gestational week). Liquid chromatography-tandem mass spectrometry was used to measure serum metabolites. Orthogonal partial least squares discriminant analysis was used to select specific metabolites associated with GDM, and pathway analysis was used to identify the metabolic pathways related to GDM. RESULTS: A total of 64 serum metabolites were included in this analysis, 17 of which were identified as specific metabolites associated with GDM. Ten metabolites increased and seven metabolites decreased GDM risk. Inclusion of these specific metabolites to the model of traditional risk factors greatly increased the predictive value from 0.69 (95% confidence interval: 0.64-0.74) to 0.92 (0.90-0.95). In addition, we found that glycerophospholipid metabolism, sphingolipid metabolism and primary bile acid biosynthesis were main metabolic pathways related to GDM. CONCLUSION: We identified a set of serum metabolites and their metabolic pathways in early pregnancy associated with GDM, which provided a theoretical basis for further research on the molecular pathways to GDM and early identification of GDM.

Ceramides and their interactive effects with trimethylamine-N-oxide metabolites on risk of gestational diabetes: A nested case-control study.

AIMS: To explore associations between ceramides in early pregnancy and gestational diabetes mellitus (GDM); and interactions between ceramides and trimethylamine N-oxide (TMAO) metabolites for GDM. METHODS: We organized a 1:1 nested case-control study (n = 486) from a prospective cohort of pregnant women. Conditional logistic regression and additive interaction were performed to examine relationships between ceramides and TMAO metabolites for GDM. We defined trimethylamine (TMA) conversion ratio (TMAR) as TMA/its precursors and TMAO conversion ratio (TMAOR) as TMAO/TMA. Copresence of high TMAR and low TMAOR indicated TMA accumulation status. RESULTS: High ceramides 18:0 (per SD), 18:1 (per SD) and low ceramide 24:0 (≤ 3.60 nmol/mL) were associated with increased GDM risk (OR: 1.69, 1.72 & 3.59, respectively). High TMA enhanced the OR of low ceramide 24:0 for GDM from 1.53 (95%CI: 0.88-2.66) to 10.3 (2.83-37.5), high TMAR enhanced it from 1.31 (0.67-2.56) to 24.3 (6.57-89.5) and TMA accumulation enhanced it from 1.42 (0.72-2.77) to 25.5 (6.80-95.7), with all additive interactions being significant. However, the interactions between high ceramide 18 and TMAO metabolites were not significant. CONCLUSIONS: High ceramides 18:0, 18:1 and low ceramide 24:0 in early pregnancy were associated with increased GDM risk. Notably, TMA accumulation greatly amplified the risk-promoting effect of low ceramide 24:0 for GDM.

Circulating Lysophosphatidylcholines in Early Pregnancy and Risk of Gestational Diabetes in Chinese Women.

OBJECTIVES: This study aimed to explore associations of lysophosphatidylcholines (LPCs) in early pregnancy with gestational diabetes mellitus (GDM), and whether LPCs mediated the associations of bile acids with GDM risk or had interactive effects with bile acids on GDM risk. DESIGN: We conducted a 1:1 nested case-control study (n = 486) from a large prospective pregnant women cohort in urban Tianjin, China. Blood samples were collected at their first antenatal care visit (median at 10th gestational week). LPCs were measured by liquid chromatography-tandem mass spectrometry analysis. Conditional binary logistic regression and restricted cubic spline analysis were used to identify cutoff points of these metabolites for GDM risk. RESULTS: Of the 6 detectable LPCs, LPC14:0 less than 0.24 nmol/mL, LPC15:0 at 0.45 nmol/mL or greater, and LPC18:0 at 18.00 nmol/mL or greater were independently associated with GDM risk. Adjustment for LPC18:0 slightly attenuated odds ratios (ORs) of deoxycholic acid (DCA, ≤ 0.36 nmol/mL) and glycoursodeoxycholic acid (GUDCA, ≤ 0.07 nmol/mL) for GDM, and the correlations of DCA and GUDCA with LPC18:0 were weak. However, the presence of DCA at 0.36 nmol/mL or less greatly amplified the adjusted OR of LPC18:0 at 18.00 nmol/mL or greater alone for GDM from 8.18 (2.51-26.7) up to 17.7 (6.64-47.1), with significant additive interaction. Similarly, the presence of GUDCA at 0.07 nmol/mL or less also greatly amplified the adjusted OR of LPC18:0 at 18.00 nmol/mL or greater alone for GDM from 17.2 (1.77-168) up to 73.8 (12.7-429), with significant additive interaction. CONCLUSIONS: LPCs in early pregnancy were associated with GDM risk. Low DCA or GUDCA greatly amplified the effect of high LPC18:0 on GDM, and its molecular mechanism is worth further investigations.

Impacts of gestational diabetes on quality of life in Chinese pregnant women in urban Tianjin, China.

AIMS: This study aimed to examine impacts of gestational diabetes mellitus (GDM) on quality of life (QoL) domains in Chinese pregnant women. METHODS: We recruited 13,358 pregnant women in Tianjin, China. GDM was diagnosed using the criteria of International Association of Diabetes and Pregnancy Study Group. QoL was measured using the 36-Item Short-Form Health Survey. General linear model was used to obtain ß-coefficient and 95% confidence intervals (CI) of GDM for QoL domain and summary scores. RESULTS: 7.25% of the pregnant women developed GDM. Among the QoL domain and summary scores, only general health (GH) score was lower in the GDM group than in the non-GDM group. GDM and advanced maternal age (i.e., ≥ versus <30 years) were negatively associated with GH in multivariable analyses (ß-coefficient: -1.17, 95%CI: -2.17 to -0.17 & -0.79, -1.40 to -0.18, respectively). In subgroup analyses, the ß-coefficient of GDM for GH among women with maternal age ≥30 years was enhanced to -2.17 (-3.94 to -0.40) in multivariable analysis while the ß-coefficient of GDM for GH among women aged <30 years was attenuated to non-significance. CONCLUSIONS: GDM and advanced maternal age were associated with reducing GH, and presence of advanced maternal age markedly increased the effect of GDM on GH.

Trimethylamine N-Oxide Metabolites in Early Pregnancy and Risk of Gestational Diabetes: A Nested Case-Control Study.

OBJECTIVES: This study aimed to investigate the associations between trimethylamine N-oxide (TMAO) and related metabolites in early pregnancy and the risk of gestational diabetes mellitus (GDM). DESIGN: A prospective cohort of 22,302 pregnant women from 2010 to 2012 in Tianjin, China, was used to perform a nested case-control study. A total of 243 women with GDM and 243 women without GDM matched by maternal age (±1 year) were used as cases and controls, respectively. Conditional logistic regression and restricted cubic spline were used to examine the full-range risk associations between individual TMAOs metabolites at the first antenatal care visit with GDM. Trimethylamine conversion ratio (TMAR) was defined as trimethylamine (TMA)/its precursors, and trimethylamine N-oxide conversion ratio (TMAOR) was defined as TMAO/TMA. An additive interaction between high TMAR and low TMAOR indicates a state of TMA accumulation, and a mathematical interaction between high TMAR and high TMAOR indicates accumulation of TMAO. RESULTS: TMA was linearly associated with GDM, whereas TMA precursors and TMAO were inversely associated with GDM with clear threshold effects, i.e., 16 nmol/mL for TMAO, 200 nmol/mL for betaine, 112 nmol/mL for l-carnitine, and 110 and 270 nmol/mL for cholinechloride (a U-shaped relationship). Copresence of TMAR >0.35 and TMAOR ≤0.15 was associated with a markedly higher OR (11.16; 95% CI, 5.45 to 22.8), compared with TMAR >0.35 only (OR = 1.71; 95% CI, 0.42 to 6.95) or TMAOR ≤0.15 only (OR = 2.06; 95% CI, 1.09 to 3.90), with a significant additive interaction. However, the mathematical interaction was nonsignificant. CONCLUSIONS: TMAO metabolites in the early pregnancy were associated with the risk of GDM, whereas TMA was more likely to play a causal role in GDM.

Effects of vitamin D supplementation on cognitive function and blood Aß-related biomarkers in older adults with Alzheimer's disease: a randomised, double-blind, placebo-controlled trial.

OBJECTIVE: Our study aimed to assess the effect of a 12-month vitamin D supplementation on cognitive function and amyloid beta (Aß)-related biomarkers in subjects with Alzheimer's disease (AD). METHODS : This was a randomised, double-blind, placebo-controlled trial. 210 AD patients were randomly divided into intervention and control groups. Participants received 12-month 800 IU/day of vitamin D or starch granules as placebo. Tests of cognitive performance and Aß-related biomarkers were measured at baseline, 6 months and 12 months. RESULTS : Repeated-measures analysis of variance showed significant improvements in plasma Aß42, APP, BACE1, APPmRNA, BACE1mRNA (p<0.001) levels and information, arithmetic, digit span, vocabulary, block design and picture arrange scores (p<0.05) in the intervention group over the control group. According to mixed-model analysis, vitamin D group had significant increase in full scale IQ during follow-up period (p<0.001). CONCLUSIONS: Daily oral vitamin D supplementation (800 IU/day) for 12 months may improve cognitive function and decrease Aß-related biomarkers in elderly patients with AD. Larger scale longer term randomised trials of vitamin D are needed. TRIAL REGISTRATION NUMBER: ChiCTR-IIR-16009549.

Indicators of socio-economic status and risk of gestational diabetes mellitus in pregnant women in urban Tianjin, China.

AIMS: To examine associations between the indicators of socio-economic status (SES) and gestational diabetes mellitus (GDM). METHODS: From 2010 to 2012, 17 659 women underwent glucose challenge test (GCT) and oral glucose tolerance test if GCT ≥ 7.8 mmol/L at 24-28 gestational weeks in 6 urban districts of Tianjin, China. Binary logistic regression was used to obtain adjusted odds ratio (OR) of SES for GDM, as defined by education attainment and family monthly income. RESULTS: A total of 1264 women (7.2%) were found to have GDM. If the women with low-middle income and high school or below used as the reference group, the middle-high income group and the high income group were associated with decreased risks of GDM (OR: 0.85, 95%CI: 0.71-1.00 & 0.80, 0.65-0.98) while tertiary education attainment was associated with decreased risk of GDM (0.75, 0.58-0.97). Women with higher income and/or higher education attainment tended to have a decreased risk of GDM (P for trend: 0.0105). All these significant ORs were attenuated to be non-significant by adjustment for pre-pregnancy body mass index (BMI), but not by adjustment for gestational weight gain (GWG). CONCLUSIONS: In urban Tianjin, indicators of high SES were associated with decreased risk of GDM via decreased pre-pregnancy BMI.

Interactive effect of serum uric acid and total bilirubin for micro-vascular disease of type 2 diabetes in China.

AIMS: Serum uric acid (SUA) and bilirubin at high levels had both pro-oxidant and anti-oxidant properties. The present study aimed to examine additive interactions between SUA and total bilirubin (TBIL) for the risk of micro-vascular disease (MVD) in type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional survey of 6713 inpatients with T2DM was conducted in 81 tertiary care hospitals in China. MVD was defined as having either prior diabetic retinopathy (DR) or diabetic nephropathy (DN). Binary logistic regression was used to estimate odds ratios of SUA and TBIL for MVD. Additive interaction was measured by three indices, i.e., relative excess risk due to interaction, attributable proportion due to interaction and synergy index. RESULTS: Among 6713 inpatients, 408 (6.08%) suffered from MVD. SUA ≥ 283 µmol/l (i.e., its media) was defined as high SUA, and TBIL <11.5 µmol/l (n = 2290 or 34.11%) was defined as low TBIL. Overall, 621 patients were exposed to co-presence of high SUA and low TBIL. The co-presence of both factors greatly increased the effect sizes from 1.03(95%CI: 0.72-1.46) (high SUA alone) or 0.70(95%CI: 0.48-1.05) (low TBIL alone) to 1.90 (95%CI: 1.26-2.87) for MVD in multivariable analysis. The additive interaction of both factors was significant for MVD in both univariable analysis and multivariable analysis. CONCLUSIONS: Co-presence of both high SUA and low TBIL indentified a group of patients at a markedly increased risk of MVD in high-risk Chinese patients with T2DM.

Bile acid metabolites in early pregnancy and risk of gestational diabetes in Chinese women: A nested case-control study.

BACKGROUND: Bile acid metabolism plays an important role in metabolism but it is uncertain whether bile acid metabolites in early pregnancy are associated with risk of gestational diabetes mellitus (GDM). METHODS: We organized a 1:1 case-control study nested in a prospective cohort of 22,302 pregnant women recruited from 2010 to 2012 in China: 243 women with GDM were matched with 243 non-GDM controls on age (±1 year). Conditional logistic regression and restricted cubic spline were used to examine full-range associations of bile acid metabolites with GDM. FINDINGS: All the 9 detectable bile acids were inversely associated with the risk of GDM, among them, 8 in nonlinear and one in largely linear manners in multivariable analysis. Glycoursodeoxycholic acid (GUDCA) at ≤0.07 nmol/mL and deoxycholic acid (DCA) at ≤0.28 nmol/mL had threshold effects and their decreasing levels below the cutoff points were associated with rapid rises in the risk of GDM. In traditional risk factor model, the stepwise procedure identified that GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.280 nmol/mL were still significant (OR: 6.84, 95%CI: 1.10-42.48 & 2.06, 1.26-3.37), while other bile acids were not. Inclusion of the two bile acids in the model increased the area under operating characteristic's curve from 0.69 to 0.76 (95% CI: 0.71-0.80) (P < .05). INTERPRETATION: Serum GUDCA ≤ 0.07 nmol/mL and DCA ≤ 0.28 nmol/mL in early pregnancy were independently associated with increased risk of GDM in Chinese pregnant women. FUNDING: Talent Recruitment Scheme grant of Tianjin Medical University and National Key Research and Development Program, etc.

Regional Differences in the Prevalence of Coronary Heart Disease and Stroke in Patients With Type 2 Diabetes in China.

Background: There are large regional variations in the prevalence and mortality of cardiovascular disease in general populations in China. It remains uncertain whether the prevalence in type 2 diabetes mellitus (T2DM) varies by region in China. Methods: We analyzed data of 219,522 Chinese patients with T2DM retrieved from the China National HbA1c Surveillance System in 2012. We used the Chinese population distribution in 2010 to standardize prevalence of coronary heart disease (CHD), stroke, and composite of both in 30 provinces and seven geological regions. Multivariable logistic regression was performed to obtain ORs and CIs of provinces/geological regions for CHD, stroke, and composite of both. Results: Age and sex standardized prevalence of CHD, stroke, and composite of both was, respectively, 4.59% (95% CI, 4.58 to 4.60), 1.79% (1.79 to 1.80), and 5.85% (5.84 to 5.86), in contrast to 0.60% of CHD, 0.80% of stroke, and 1.37% of composite of both in the general population in China. After adjustment for traditional risk factors, Northeast had the highest risks of CHD, stroke, and composite of both, and North had the second highest risks of CHD, stroke, and composite of both among the seven regions, both being higher than any other regions (all P values < 0.05). The ORs of Northeast vs Southwest were up to 2.60 (2.35 to 2.88) for CHD, 2.49 (2.15 to 2.88) for stroke, and 2.61 (2.38 to 2.86) for composite of both. Conclusions: There were large variations in risks of CHD, stroke, and composite of both in T2DM in China with Northeast and North having the highest risks.

Gender Difference in the Association of Early- vs. Late-Onset Type 2 Diabetes with Non-Fatal Microvascular Disease in China: A Cross-sectional Study.

BACKGROUND: This study aimed to test whether early-onset (defined as <40 years of age) type 2 diabetes mellitus (T2DM) imparted different risks of microvascular disease to Chinese men and women. METHODS: 222,537 Chinese patients with T2DM were recruited in 630 hospitals from 106 cities in 30 provinces of China in 2012 using a cross-sectional design. Logistic regression analysis was performed to obtain odds ratios (ORs) of male vs. female for diabetic retinopathy (DR) and diabetic nephropathy (DN). Additive interaction was used to test whether male gender and early-onset T2DM had interactive effects for DR and DN. RESULTS: More men than women with T2DM had DN (4.5 vs. 3.0%, P < 0.0001), DR (5.3 vs. 5.1%, P < 0.0001), and microvascular disease (either DN or DR) (8.4 vs. 7.1%, P < 0.0001). After adjustment for age and levels of hospitals, the effect sizes of early-onset T2DM for microvascular disease were higher in men than in women, with a 2.67 [95% confidence intervals (CI): 2.51-2.85] fold risk in men and a 2.53 (95% CI: 2.35-2.72) fold risk in women. The risk effect sizes were greatly attenuated by further adjusting for diabetes durations and other traditional risk factors, with a 1.28 (95% CI: 1.19-1.37) fold risk in men and a 1.07 (95% CI: 0.99-1.16) fold risk in women. After adjustment for diabetes durations and other traditional risk factors, using women with late-onset T2DM as the reference, co-presence of early-onset and male gender significantly enhanced the ORs of either early-onset alone (1.10, 95% CI: 1.03-1.19) or male gender alone (0.96, 95% CI: 0.93-0.99) to 1.32 (95% CI: 1.24-1.41), with significant additive interaction. Kaplan-Meier analysis showed that in early-onset T2DM, DN developed 5 years earlier in men than in women. CONCLUSION: Early-onset T2DM increased more risk of microvascular complications in Chinese men than in women, most of increased risks being attributable to longer diabetes durations.

Low triglyceride as a marker for increased risk of cardiovascular diseases in patients with long-term type 2 diabetes: A cross-sectional survey in China.

BACKGROUND: There are inconsistent findings regarding associations between triglyceride levels and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM). This study aimed to test whether the association between triglycerides and CVD depends upon duration of diabetes. METHODS: From April 1, 2012, to June 30, 2012, we conducted a cross-sectional survey of 223 612 patients with T2DM from 630 hospitals in China. Cardiovascular disease was defined as having either prior coronary heart disease or stroke, or diabetic foot. Binary logistic regression was used to estimate odds ratios of triglyceride for CVD. Relative excess risk due to interaction, attributable proportion due to interaction, and synergy index were used to estimate effect size of additive interaction between low triglyceride, ie, <1.7 mmol/L, and duration of diabetes, ie, ≥15 years. RESULTS: Among 223 612 T2DM patients, 31 898 (14.27%) suffered from CVD. A low level of triglyceride was associated with decreased risk of CVD (univariable OR, 0.91, 95% CI, 0.88-0.93; multivariable OR, 0.94, 95% CI, 0.92-0.97) among patients with <15 years of duration of diabetes but increased risk of CVD (univariable OR, 1.12, 95% CI, 1.04-1.21; multivariable OR, 1.18, 95% CI, 1.09-1.27) among those patients with 15 and more years of duration of diabetes with significant additive interactions (relative excess risk due to interaction, 0.39, 95% CI, 0.25-0.52; attributable proportion due to interaction, 0.20, 95% CI, 0.14-0.27; and synergy index, 1.80, 95% CI, 1.43-2.28). CONCLUSIONS: Whereas a high triglyceride level was associated with increased risk of CVD in short-term T2DM, low triglyceride was associated with increased CVD risk in long-term T2DM. Low triglyceride may be a marker of CVD risk in Chinese patients with long-term T2DM.

Long exposure to type 2 diabetes and risk of non-fatal coronary heart disease in Chinese females and males: Findings from a China national cross-sectional study.

AIMS: To investigate the risk of Chinese females versus males for non-fatal coronary heart disease (CHD) due to long exposure to type 2 diabetes mellitus (T2DM). METHODS: 223,612 Chinese patients with T2DM were recruited from China in 2012. Binary logistic regression analysis was performed to obtain odds ratios (OR) of females versus males for non-fatal CHD. Additive interaction was used to test whether female gender and long exposure to T2DM (≥15 years) had a synergistic effect for non-fatal CHD. Significant relative excess risk due to interaction (RERI > 0), attributable proportion due to interaction (AP > 0) or synergy index (SI > 1) suggest a significant additive interaction. RESULTS: More females than males with T2DM had non-fatal CHD (11.3% versus 10.6%, P < .0001). Females had slightly higher risk of non-fatal CHD since 5-10 years of diabetic duration and the effect size became larger since 15 years and onwards. Overall effect of females versus males for non-fatal CHD was 1.04 (95% CI: 1.01-1.08) among patients with <15 years of duration while the effect size increased to 1.17 (95% CI: 1.07-1.28) among patients with ≥15 years of duration. Using males with <15 years of duration as the reference, females with ≥15 years of duration were at 1.82-fold (95% CI: 1.70-1.95) non-fatal CHD risk while males with ≥15 years of duration were only at 1.56 (95% CI: 1.45-1.68) fold non-fatal CHD risk, with significant additive interaction (all three measures < 0.05). CONCLUSIONS: Long exposure to T2DM imparted a larger risk of non-fatal CHD to Chinese females than to Chinese males.

Risk of non-fatal cardiovascular diseases in early-onset versus late-onset type 2 diabetes in China: a cross-sectional study.

BACKGROUND: The age of onset of type 2 diabetes is decreasing. Because non-Chinese patients with early-onset type 2 diabetes (defined here as diagnosis at <40 years) have increased risk of vascular complications, we investigated effects of early-onset versus late-onset type 2 diabetes on risk of non-fatal cardiovascular diseases in China. METHODS: We did a cross-sectional survey using data from the China National HbA1c Surveillance System (CNHSS), including 222,773 Chinese patients with type 2 diabetes in 630 hospitals from 106 cities in 30 provinces of China in 2012. We documented demographic information and clinical profiles. Non-fatal cardiovascular disease was defined as non-fatal coronary heart disease or non-fatal stroke. Prevalence of non-fatal cardiovascular diseases was standardised to the Chinese population in 2011. We did logistic regression analysis to obtain odds ratios (ORs) for the risk of cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Because the CNHSS did not contain patients on diet or lifestyle treatment alone, and did not capture information on smoking or lipid or antihypertensive treatment, we validated our findings in another dataset from a cross-sectional, multicentre observational study (the 3B study) of outpatients with type 2 diabetes to confirm that exclusion of patients with diet treatment only and non-adjustment for lipid-lowering and antihypertensive drugs did not introduce major biases in the main analysis. FINDINGS: Of 222,773 patients recruited from April 1, 2012, to June 30, 2012, 24,316 (11%) had non-fatal cardiovascular disease. Patients with early-onset diabetes had a higher age-adjusted prevalence of non-fatal cardiovascular disease than did patients with late-onset diabetes (11·1% vs 4·9%; p<0·0001). After adjustment for age and sex, patients with early-onset type 2 diabetes had higher risk of non-fatal cardiovascular disease than did those with late-onset type 2 diabetes (OR 1·91, 95% CI 1·81-2·02). Adjustment for duration of diabetes greatly attenuated the effect size for risk of non-fatal cardiovascular disease (1·13, 1·06-1·20). Results of the validation study showed that exclusion of patients with diet only and non-adjustment for lipid-lowering and antihypertensive drugs resulted in marginal changes in ORs for risk of non-fatal cardiovascular disease in patients with early-onset versus late-onset type 2 diabetes. Early-onset type 2 diabetes remained associated with increased risk of cardiovascular disease, attributable to longer duration of diabetes. INTERPRETATION: Chinese patients with early-onset type 2 diabetes are at increased risk of non-fatal cardiovascular disease, mostly attributable to longer duration of diabetes. FUNDING: Novo Nordisk China (for the China National HbA1c Surveillance System [CNHSS]) and Merck Sharp & Dohme China (for the 3B study).

Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes.

There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.

Effect of interpregnancy interval after a mifepristone-induced abortion on neonatal outcomes in subsequent pregnancy.

BACKGROUND: The study evaluated effects of interpregnancy interval (IPI) on neonatal outcomes after mifepristone-induced abortion in the first pregnancy. STUDY DESIGN: This observational cohort study, conducted from 1998 to 2001 at antenatal clinics in Shanghai, Beijing, and Chengdu, China, included 4682 nulliparous women with one mifepristone-induced abortion in their first pregnancy, who were enrolled and followed up until delivery. We compared neonatal outcomes among women with different IPIs between their mifepristone-induced abortion and subsequent pregnancy. RESULTS: When compared to IPI of 18-24 months, there was an increased risk of the neonate being small for gestational age (SGA) [adjusted odds ratio (aOR): 2.01; 95% confidence interval (CI): 1.04-3.88] when IPI was <6 months; this risk was greater among women without a curettage history after abortion (aOR: 2.49; 95% CI: 1.13-5.50). The associations between IPI and preterm delivery (<37 weeks), low birth weight (<2500 g), mean birth weight and ponderal index were not statistically significant. CONCLUSIONS: The results indicate that an IPI <6 months after one mifepristone-induced abortion in first pregnancy is associated with an increased risk of SGA in the subsequent pregnancy.