Microvascular Disease, Cardiovascular Health, and Risk of Coronary Heart Disease in Type 2 Diabetes: A UK Biobank Study.

CONTEXT: The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. OBJECTIVE: To investigate the role of MVD and CVHMs in the development of CHD among T2DM. DESIGN: We included 19,664 participants with T2DM from the UK Biobank who had data on CVH metrics (CVHMs) and were free of CHD during recruitment. CVHMs were defined based on five behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and three biological factors (glycemic control, hyperlipidemia, and hypertension). MVD was defined as the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. HR and 95% CI of CHD were estimated by multivariable Cox regression models. RESULTS: There were 3,252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each of the unfavorable CVHMs was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR=4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. CONCLUSIONS: Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such an association may be amplified by unfavorable CVHMs.

Association Between Glucosamine Use and the Risk of Incident Heart Failure: The UK Biobank Cohort Study and Mendelian Randomization Analysis.

OBJECTIVE: To evaluate the association between regular glucosamine intake and heart failure (HF) and to explore whether the association is mediated by relevant cardiovascular disease. PATIENTS AND METHODS: We included 479,650 participants with data available for supplement use and without HF at baseline from the UK Biobank study. Using 12 single-nucleotide polymorphisms linked to HF, a weighted genetic risk score was calculated. We evaluated the association between glucosamine use and HF by Cox regression models after inverse probability of treatment weighting. A validation and mediation analysis were performed through two-sample Mendelian randomization. The study was from May 18, 2006, to February 16, 2018. RESULTS: During a median follow-up of 9.0 (IQR, 8.3-9.8) years, we documented 5501 incident cases of HF. In multivariable analysis, the HR of glucosamine users for HF was 0.87 (95% CI, 0.81 to 0.94). The inverse associations were stronger in males and participants with unfavorable lifestyle (P<.05 for interaction). Genetic risk categories did not modify this association (P>.05 for interaction). Multivariable Mendelian randomization showed that taking glucosamine was protective against HF (HR, 0.92; 95% CI, 0.87 to 0.96). The mediated proportion of coronary heart disease and stroke were 10.5% (95% CI, 7.6% to 13.4%) and 14.4% (95% CI, 10.8% to 18.0%), respectively. The two-mediator combination accounted for 22.7% (95% CI, 17.2% to 28.2%) of the effect of glucosamine use. CONCLUSION: Regular glucosamine supplementation was associated with a lower risk of HF regardless of genetic risk status, and to a lesser extent, coronary heart disease and stroke mediated this effect. The results may inform novel pathway for prevention and intervention toward HF.

Association of regular glucosamine use with incident dementia: evidence from a longitudinal cohort and Mendelian randomization study.

BACKGROUND: Emerging data suggests the neuroprotective and anti-neuroinflammatory effects of glucosamine. We aimed to examine the association between regular glucosamine use and risk of incident dementia, including dementia subtypes. METHODS: We conducted large-scale observational and two-sample Mendelian randomization (MR) analyses. Participants in UK Biobank having accessible data for dementia incidence and who did not have dementia at baseline were included in the prospective cohort. Through the Cox proportional hazard model, we examined the risks of incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia among glucosamine users and non-users. To further test the causal association between glucosamine use and dementia, we conducted a 2-sample MR utilizing summary statistics from genome-wide association studies (GWAS). The GWAS data were obtained from observational cohort participants of mostly European ancestry. RESULTS: During a median follow-up of 8.9 years, there were 2458 cases of all-cause dementia, 924 cases of AD, and 491 cases of vascular dementia. In multivariable analysis, the hazard ratios (HR) of glucosamine users for all-cause dementia, AD, and vascular dementia were 0.84 (95% CI 0.75-0.93), 0.83 (95% CI 0.71-0.98), and 0.74 (95% CI 0.58-0.95), respectively. The inverse associations between glucosamine use and AD appeared to be stronger among participants aged below 60 years than those aged above 60 years (p = 0.04 for interaction). The APOE genotype did not modify this association (p > 0.05 for interaction). Single-variable MR suggested a causal relationship between glucosamine use and lower dementia risk. Multivariable MR showed that taking glucosamine continued to protect against dementia after controlling for vitamin, chondroitin supplement use and osteoarthritis (all-cause dementia HR 0.88, 95% CI 0.81-0.95; AD HR 0.78, 95% CI 0.72-0.85; vascular dementia HR 0.73, 95% CI 0.57-0.94). Single and multivariable inverse variance weighted (MV-IVW) and MR-Egger sensitivity analyses produced similar results for these estimations. CONCLUSIONS: The findings of this large-scale cohort and MR analysis provide evidence for potential causal associations between the glucosamine use and lower risk for dementia. These findings require further validation through randomized controlled trials.

Preserved Ratio Impaired Spirometry in Relationship to Cardiovascular Outcomes: A Large Prospective Cohort Study.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) findings are a heterogeneous condition characterized by a normal FEV1 to FVC ratio with underlying impairment of pulmonary function. Data relating to the association of baseline and trajectories of PRISm findings with diverse cardiovascular outcomes are sparse. RESEARCH QUESTION: How do baseline and trajectories of PRISm findings impact subsequent cardiovascular events? STUDY DESIGN AND METHODS: In the UK Biobank cohort study, we included participants free of cardiovascular disease (CVD) with spirometry (FEV1 and FVC values) at baseline (2006-2010). Participants with baseline spirometry and follow-up spirometry (2014-2020) were included in the lung function trajectory analysis. Cox proportional hazards multivariate regression was performed to evaluate the outcomes of major adverse cardiovascular events (MACEs), incident myocardial infarction (MI), stroke, heart failure (HF), and CVD mortality in association with lung function. RESULTS: For baseline analysis (329,954 participants), the multivariate adjusted hazard ratios (HRs) for participants had PRISm findings (vs normal spirometry findings) were 1.26 (95% CI, 1.17-1.35) for MACE, 1.12 (95% CI, 1.01-1.25) for MI, 1.88 (95% CI, 1.72-2.05) for HF, 1.26 (95% CI, 1.13-1.40) for stroke, and 1.55 (95% CI, 1.37-1.76) for CVD mortality, respectively. A total of 22,781 participants underwent follow-up spirometry after an average of 8.9 years. Trajectory analysis showed that persistent PRISm findings (HR, 1.96; 95% CI, 1.24-3.09) and airflow obstruction (HR, 1.43; 95% CI, 1.00-2.04) was associated with a higher incidence of MACE vs consistently normal lung function. Compared with persistent PRISm findings, changing from PRISm to normal spirometry findings was associated with a lower incidence of MACE (HR, 0.42; 95% CI, 0.19-0.99). INTERPRETATION: Individuals with baseline or persistent PRISm findings were at a higher risk of diverse cardiovascular outcomes even after adjusting for a wide range of confounding factors. However, individuals who transitioned from PRISm to normal findings showed a similar cardiovascular risk as those with normal lung function.

Microvascular Burden and Incident Heart Failure Among Middle-Aged and Older Adults With Type 1 or Type 2 Diabetes.

OBJECTIVE: To examine the association between microvascular disease (MVD) and risk of heart failure (HF) among individuals with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We included 1,713 and 28,624 participants with T1DM and T2DM, respectively, from the UK Biobank who were free of HF during enrollment. MVD burden reflected by the presence of retinopathy, peripheral neuropathy, and chronic kidney disease (CKD) at baseline was prospectively evaluated for the association with incidence of HF. Hazard ratios (HRs) and 95% CIs of HF were estimated by Cox regression models adjusted for multiple traditional risk factors. RESULTS: There were 145 and 2,515 incident cases of HF recorded among participants with T1DM and T2DM, respectively, during a median follow-up of 11.5 years. The association between the number of MVD and HF was stronger among participants with T1DM than among those with T2DM (P for interaction <0.001). Compared with participants with no MVD, those with all three MVD had an adjusted HR (95% CI) of 11.37 (5.62, 22.99) in T1DM and 3.66 (2.74, 4.88) in T2DM. In T1DM, HRs (CIs) were 2.69 (1.75, 4.14) for retinopathy, 2.11 (1.38, 3.23) for peripheral neuropathy, and 2.21 (1.53, 3.18) for CKD. The corresponding estimates in T2DM were 1.24 (1.13, 1.36), 1.63 (1.36, 1.96), and 1.73 (1.59, 1.89), respectively. CONCLUSIONS: While a heavier burden of MVD was associated with excess risk of HF both in T1DM and T2DM, the association was evidently more pronounced in T1DM.

Favourable Lifestyle Protects Cognitive Function in Older Adults With High Genetic Risk of Obesity: A Prospective Cohort Study.

The relationship between body mass index (BMI) and cognitive impairment remains controversial, especially in older people. This study aims to confirm the association of phenotypic and genetic obesity with cognitive impairment and the benefits of adhering to a healthy lifestyle. This prospective study included 10,798 participants (aged ≥ 50 years) with normal cognitive function from the Health and Retirement Study in the United States. Participants were divided into low (lowest quintile), intermediate (quintiles 2-4), and high (highest quintile) groups according to their polygenic risk score (PRS) for BMI. The risk of cognitive impairment was estimated using Cox proportional hazard models. Higher PRS for BMI was associated with an increased risk, whereas phenotypic obesity was related to a decreased risk of cognitive impairment. Never smoking, moderate drinking, and active physical activity were considered favourable and associated with a lower risk of cognitive impairment compared with current smoking, never drinking, and inactive, respectively. A favourable lifestyle was associated with a low risk of cognitive impairment, even in subjects with low BMI and high PRS for BMI. This study suggest that regardless of obesity status, including phenotypic and genetic, adhering to a favourable lifestyle is beneficial to cognitive function.

Lipid variability and risk of microvascular complications in Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: A post hoc analysis.

BACKGROUND: Greater lipid variability may cause adverse health events among diabetic patients. We aimed to examine the effect of lipid variability on the risk of diabetic microvascular outcomes among type 2 diabetes mellitus patients. METHODS: We assessed the association between visit-to-visit variability (measured by variability independent of mean) in high-density lipoprotein (HDL) cholesterol, low-density lipoprotein-cholesterol (LDL), triglyceride, and remnant cholesterol (RC) measurements among participants involved in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study and the risk of incident microvascular outcomes, including nephropathy, neuropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for potential confounders. RESULTS: There were 2400, 2470, and 2468 cases of nephropathy, neuropathy, and retinopathy during a follow-up period of 22 600, 21 542, and 26 701 person-years, respectively. Higher levels of HDL, triglyceride, and RC variability were associated with an increased risk of incident nephropathy and neuropathy. Compared with the lowest quartile, the fully adjusted HRs (95% CI) for the highest quartile of HDL, triglyceride, and RC variability for nephropathy risk were 1.57 (1.22, 2.01), 1.50 (1.18, 1.92), and 1.40 (1.09, 1.80), respectively; and for neuropathy, the corresponding risks were 1.36 (1.05, 1.75), 1.47 (1.14, 1.91), and 1.35 (1.04, 1.74), respectively. Null association was observed between LDL variability and all microvascular complications. Additionally, all associations of variability in the other lipids with retinopathy risk were null. CONCLUSION: Among individuals with type 2 diabetes mellitus, HDL, triglyceride, and RC variability were associated with increased risks of nephropathy and neuropathy but not retinopathy. TRIAL REGISTRATION: ClinicalTrials.gov., no. NCT00000620.

Waist Circumference and Body Mass Index Variability and Incident Diabetic Microvascular Complications: A Post Hoc Analysis of ACCORD Trial.

BACKGROUND: Obesity is associated with adverse health events among diabetic patients, however, the relationship between obesity fluctuation and risk of microvascular complications among this specific population is unclear. We aimed to examine the effect of waist circumference (WC) and body mass index (BMI) variability on the risk of diabetic microvascular outcome. METHODS: Annually recorded anthropometric data in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used to examine the association of WC and BMI variability defined as variability independent of mean, with the risk of microvascular outcomes, including neuropathy, nephropathy, and retinopathy. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) (Trial registration: ClinicalTrials.gov., no. NCT00000620). RESULTS: There were 4,031, 5,369, and 2,601 cases of neuropathy, nephropathy, and retinopathy during a follow-up period of 22,524, 23,941, and 23,850 person-years, respectively. Higher levels of WC and BMI variability were associated with an increased risk of neuropathy. Compared with the lowest quartile, the fully-adjusted HR (95% CI) for the highest quartile of WC and BMI variability for neuropathy risk were 1.21 (1.05 to 1.40) and 1.16 (1.00 to 1.33), respectively. Also, higher quartiles of BMI variability but not WC variability were associated with increased risk of nephropathic events. The fully-adjusted HR (95% CI) for the highest quartile compared with the lowest quartile of BMI variability was 1.31 (1.18 to 1.46). However, the results for retinopathic events were all insignificant. CONCLUSION: Among participants with type 2 diabetes mellitus, WC and BMI variability were associated with a higher risk of neuropathic events, whereas BMI variability was associated with an increased risk of nephropathic events.

Association of Predicted Lean Body Mass and Fat Mass With Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus: A Post Hoc Analysis of ACCORD Trial.

Background: Lean body mass (LBM) and fat mass (FM) have been shown to have different associations with several chronic diseases but little is known about the sex-specific association of LBM and FM with diabetic nephropathy (DN) risk among participants with diabetes. Methods: Participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study was used in a post hoc analysis to examine the association of predicted LBM index (LBMI) and FM index (FMI) with incident DN risk (defined as a composite outcome of three types of predefined DN). Because of sex differences in body composition, analyses were conducted separately using sex-specific quartiles of predicted LBMI and FMI. Results: Of the 9,022 participants with type 2 diabetes (5,575 men and 3,447 women) included in this study, 5,374 individuals developed DN (3,396 in men and 1,978 in women). Higher quartiles of LBMI were associated with a reduced risk of DN while higher quartiles of FMI were associated with an increased higher risk of DN among men but not women. Compared with the lowest quartile, the fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs)for the highest quartile of predicted LBMI and FMI were respectively 0.83 (95% CI 1.71 - 0.96) and 1.23 (95% CI 1.06-1.43) among men; and 0.92 (95% CI 0.63 - 1.33) and 1.14 (95% CI 0.79 - 1.63) among women. Conclusions: Among participants with diabetes, predicted LBMI was inversely associated with risk of DN while predicted FMI was positively associated with an increased risk of incident DN among men but not women. Trial registration: ClinicalTrials.gov., no. NCT00000620.

Anthropometric Measures and Incident Diabetic Nephropathy in Participants With Type 2 Diabetes Mellitus.

Background: The prevalence of diabetes is on the rise globally coupled with its associated complications, such as diabetic nephropathy (DN). Obesity has been identified as a risk factor for the development of DN but it is still unclear which obesity index is the best predictor of incident DN. Methods: Data from the participants with type 2 diabetes mellitus (T2DM) in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study were used to examine the sex-specific association between waist circumference (WC), waist-to-height ratio (WHtR), and body mass index (BMI) with incident DN risk. Results: Among the 8,887 participants with T2DM (5,489 men and 3,398 women), 5,296 participants (3,345 men and 1,951 women) developed the DN composite outcome during a follow-up period of 24302 person-years. Among men, null associations were observed between all anthropometric measures with incident DN in the multivariate analysis although the 3rd quartile of WHtR showed marginally significant results (P = 0.052). However, among women, both central and general obesity measures were associated with increased risks of incident DN. Compared with participants in the WC <88 cm category, the fully adjusted HR and 95% CI for those in the ≥88 cm of WC was 1.35 (95% CI 1.15-1.57). Compared with the lowest quartile, the fully adjusted HRs and 95% CIs for the 2nd to the 4th quartile of WHtR were 1.09 (95% CI 0.96-1.25), 1.12 (95% CI 0.98-1.28), and 1.14 (95% CI 1.00-1.30) respectively; also, compared with the normal BMI category, the fully adjusted HRs and 95% CIs for class I - class III obese were 1.36 (95% CI 1.10 - 1.67), 1.43 (95% CI 1.16 - 1.78) and 1.32 (95% CI 1.05 - 1.66) respectively. Conclusions: Among participants with T2DM, higher levels of both central and general obesity indexes were associated with DN risk among women but not in men. Women with T2DM should maintain a healthy weight targeted at reducing both central and general obesity to enhance nephroprotection. Trial registration: ClinicalTrials.gov., no. NCT00000620.

Long-Term Increase in Cholesterol Is Associated With Better Cognitive Function: Evidence From a Longitudinal Study.

Background: Higher visit-to-visit cholesterol has been associated with cognitive decline. However, the association between long-term increase or decrease in cholesterol and cognitive decline remains unclear. Methods: A total of 4,915 participants aged ≥45 years with normal cognition in baseline were included. The participants were divided into four groups, namely low-low, low-high, high-low, and high-high, according to the diagnostic thresholds of total cholesterol (TC), non-high-density lipoprotein cholesterol (NHDL-C), low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C) after 4 years of follow-up. Cognitive function was assessed by episodic memory and mental intactness. Binary logistic regression was used to analyse the association of cholesterol variation with cognitive decline. Results: Among the participants, 979 (19.9%) experienced global cognitive decline. The odds ratio (OR) of global cognitive and memory function decline were remarkably lower in participants in the low-high NHDL-C group than those in the low-low group [OR and 95% confidence interval (CI): 0.50 [0.26-0.95] for global cognitive decline, 0.45 [0.25-0.82] for memory function decline]. The lower OR was also significant in females (OR [95% CI]: 0.38 [0.17-0.87] for global cognitive decline; 0.44 [0.19-0.97] for memory function decline) and participants without cardiovascular disease (OR [95% CI]: 0.31 [0.11-0.87] for global cognitive decline; 0.34 [0.14-0.83] for memory function decline). The increases in other cholesterol were also negatively associated with the risk of cognitive decline although not significantly. Conclusions: A longitudinal increase in NHDL-C may be protective for cognition in females or individuals without cardiovascular disease.