Poor Glycemic Control Is an Independent Risk Factor for Low HDL Cholesterol in Patients With Type 2 Diabetes

OBJECTIVE

To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides <400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors.

RESULTS

A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1–1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1–1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05–1.18], P = 0.00017).

CONCLUSIONS

Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes (1,2). Several studies have shown that aggressive comprehensive management of the mixed dyslipidemia associated with the metabolic syndrome and type 2 diabetes is needed to reduce the increased cardiovascular risk (3,4). Despite this evidence, treatments do not completely address all the components of diabetic dyslipidemia and therapeutic targets are still not achieved (5). Nearly half of type 2 diabetic patients have low levels of HDL cholesterol (5), a key component of diabetes-related dyslipidemia and a strong independent risk factor for CVD. HDL cholesterol is inversely correlated with cardiovascular risk, even when LDL cholesterol has been reduced with statin therapy (6–7).An inverse relationship between HDL cholesterol and A1C levels has been described in type 2 diabetic patients (8,9). It is unclear, however, whether this relationship is partly dependent on obesity and/or hypertriglyceridemia, which are known determinants of low HDL cholesterol and frequently found in patients with poorly controlled diabetes. This study was designed to test the hypothesis that glycemic control is independently associated with HDL cholesterol in patients with type 2 diabetes.     

Interpretable Machine Learning Framework Reveals Robust Gut Microbiome Features Associated With Type 2 Diabetes

OBJECTIVETo identify the core gut microbial features associated with type 2 diabetes risk and potential demographic, adiposity, and dietary factors associated with these features.RESEARCH DESIGN AND METHODSWe used an interpretable machine learning framework to identify the type 2 diabetes–related gut microbiome features in the cross-sectional analyses of three Chinese cohorts: one discovery cohort (n = 1,832, 270 cases of type 2 diabetes) and two validation cohorts (cohort 1: n = 203, 48 cases; cohort 2: n = 7,009, 608 cases). We constructed a microbiome risk score (MRS) with the identified features. We examined the prospective association of the MRS with glucose increment in 249 participants without type 2 diabetes and assessed the correlation between the MRS and host blood metabolites (n = 1,016). We transferred human fecal samples with different MRS levels to germ-free mice to confirm the MRS–type 2 diabetes relationship. We then examined the prospective association of demographic, adiposity, and dietary factors with the MRS (n = 1,832).RESULTSThe MRS (including 14 microbial features) consistently associated with type 2 diabetes, with risk ratio for per 1-unit change in MRS 1.28 (95% CI 1.23–1.33), 1.23 (1.13–1.34), and 1.12 (1.06–1.18) across three cohorts. The MRS was positively associated with future glucose increment (P < 0.05) and was correlated with a variety of gut microbiota–derived blood metabolites. Animal study further confirmed the MRS–type 2 diabetes relationship. Body fat distribution was found to be a key factor modulating the gut microbiome–type 2 diabetes relationship.CONCLUSIONSOur results reveal a core set of gut microbiome features associated with type 2 diabetes risk and future glucose increment.     

Prior Glucose-Lowering Medication Use and 30-Day Outcomes Among 64,892 Veterans With Diabetes and COVID-19

OBJECTIVETo identify preinfection risk factors for adverse outcomes among veterans with diabetes and coronavirus disease 2019 (COVID-19) infection.RESEARCH DESIGN AND METHODSWe identified all Veterans Health Administration patients with diabetes and one or more positive nasal swab(s) for severe acute respiratory syndrome coronavirus 2 (1 March 2020–10 March 2021) (n = 64,892). We examined associations of HbA_1c and glucose-lowering medication use with hospitalization, intensive care unit (ICU) admission, and mortality at 30 days using logistic regression models and during 4.4 months of follow-up (range <1–13.1) using proportional hazards models.RESULTSCompared with HbA_1c <7.0%, HbA_1c ≥9.0% was associated with higher odds of hospitalization, ICU admission, and death at 30 days (odds ratio [OR] 1.27 [95% CI 1.19–1.35], 1.28 [95% CI 1.15–1.42], 1.30 [95% CI 1.17–1.44], respectively) as well as higher risk of death over 4.4 months (hazard ratio [HR] 1.22 [95% CI 1.12–1.32]). Insulin use was associated with higher odds of hospitalization, ICU admission, and death (OR 1.12 [95% CI 1.07–1.18], 1.12 [95% CI 1.04–1.22], and 1.18 [95% CI 1.09–1.27], respectively) and higher risk of death (HR 1.12 [95% CI 1.07–1.18]). Sodium–glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP1-RA), or angiotensin receptor blocker use were associated with lower odds of hospitalization (OR 0.92 [95% CI 0.85–0.99], 0.88 [95% CI 0.81–0.96], and 0.94 [95% CI 0.89–0.99], respectively). Metformin and SGLT2i use were associated with lower odds (OR 0.84 [95% CI 0.78–0.91], 0.82 [95% CI 0.72–0.94], respectively) and risk of death (HR 0.84 [95% CI 0.79–0.89], 0.82 [95% CI 0.74–0.92], respectively).CONCLUSIONSAmong veterans with diabetes and COVID-19, higher HbA_1c and insulin use were directly associated with adverse outcomes, while use of a GLP1-RA, metformin, and SGLT2i was inversely associated.     

HDL Cholesterol and Cancer Risk Among Patients With Type 2 Diabetes

OBJECTIVETo investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients.RESULTSDuring a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30–39.9, 40–49.9, 50–59.9, 60–69.9, 70–79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (P_trend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (P_trend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up.CONCLUSIONSThe study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.     

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes

OBJECTIVEEnvironmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.RESEARCH DESIGN AND METHODSAssociation between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes (n = 271) or multiple diabetes-associated islet autoantibodies (n = 384) and children without diabetes who are negative for diabetes autoantibodies.RESULTSAgricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16–0.87, P = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, P = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, P = 0.001) compared with an urban environment known to have lower environmental microbial diversity.CONCLUSIONSThe study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.     

Gut Microbiota Metabolites of Dietary Lignans and Risk of Type 2 Diabetes: A Prospective Investigation in Two Cohorts of U.S. Women

OBJECTIVETo examine urinary levels of enterolactone and enterodiol, intestinal microbial metabolites of dietary lignans, in relation to type 2 diabetes (T2D) risk.RESULTSIn both cohorts, T2D subjects had significantly lower concentrations of both enterolactone and enterodiol than control subjects. After multivariate adjustment for lifestyle and dietary risk factors of T2D, urinary concentrations of enterolactone were significantly associated with a lower risk of T2D (pooled odds ratio [OR] comparing the extreme quartiles 0.62 [95% CI 0.44, 0.88], P for trend = 0.003). Higher urinary concentrations of enterodiol were also marginally significantly associated with a lower T2D risk (pooled OR comparing extreme quartiles 0.67 [95% CI 0.48, 0.96], P for trend = 0.08). When concentrations of both metabolites were combined to reflect total lignan intake, the OR was 0.70 (95% CI 0.53, 0.92) for each SD increment of total lignan metabolites.CONCLUSIONSThese results indicate that lignan metabolites, especially enterolactone, are associated with a lower risk of T2D in U.S. women. Further studies are needed to replicate these findings and to explore potential mechanisms underlying the observed association.     

Visceral Adipose Tissue Is a Better Predictor of Subclinical Carotid Atherosclerosis Compared with Waist Circumference

We investigated whether visceral adipose tissue (VAT) measured by ultrasonography is better than waist circumference (WC) in predicting the presence of subclinical carotid atherosclerosis. We recruited 100 individuals without a history of cardiovascular disease or diabetes mellitus. VAT volume was measured by ultrasonography and common carotid artery intima-media thickness (CCA-IMT) by B-mode ultrasonography. Both VAT and WC were positively associated with body mass index, triglycerides, uric acid, systolic/diastolic blood pressure and high sensitivity C-reactive protein and inversely correlated with high-density lipoprotein cholesterol. However, only VAT was associated with CCA-IMT (r = 0.309, p = 0.002). Multivariate logistic regression analysis revealed that VAT, but not WC, was an independent predictor of carotid plaques after adjustment for cardiovascular risk factors (odds ratio [OR] = 1.017, 95% confidence interval [CI] = 1.003–1.031, p = 0.017), and this association persisted after additional adjustment for WC (OR = 1.024, 95% CI = 1.003–1.031, p = 0.027). Our data suggest that VAT volume measured by ultrasonography may be a better predictor of subclinical carotid atherosclerosis than waist circumference in healthy individuals.     

Cardiometabolic Health Outcomes Associated With Discordant Visceral and Liver Fat Phenotypes: Insights From the Dallas Heart Study and UK Biobank

ObjectiveTo evaluate the cardiometabolic outcomes associated with discordant visceral adipose tissue (VAT) and liver fat (LF) phenotypes in 2 cohorts.Patients and MethodsParticipants in the Dallas Heart Study underwent baseline imaging from January 1, 2000, through December 31, 2002, and were followed for incident cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) through 2013. Associations between VAT-LF groups (low-low, high-low, low-high, and high-high) and outcomes were assessed using multivariable-adjusted regression and were replicated in the independent UK Biobank.ResultsThe Dallas Heart Study included 2064 participants (mean ± SD age, 44±9 years; 54% female; 47% black). High VAT–high LF and high VAT–low LF were associated with prevalent atherosclerosis, whereas low VAT–high LF was not. Of 1731 participants without CVD/T2DM, 128 (7.4%) developed CVD and 95 (5.5%) T2DM over a median of 12 years. High VAT–high LF and high VAT–low LF were associated with increased risk of CVD (hazard ratios [HRs], 2.0 [95% CI, 1.3 to 3.2] and 2.4 [95% CI, 1.4 to 4.1], respectively) and T2DM (odds ratios [ORs], 7.8 [95% CI, 3.8 to 15.8] and 3.3 [95% CI, 1.4 to 7.8], respectively), whereas low VAT–high LF was associated with T2DM (OR, 2.7 [95% CI, 1.1 to 6.7]). In the UK Biobank (N=22,354; April 2014-May 2020), only high VAT–low LF remained associated with CVD after multivariable adjustment for age and body mass index (HR, 1.5 [95% CI, 1.2 to 1.9]).ConclusionAlthough VAT and LF are each associated with cardiometabolic risk, these observations demonstrate the importance of separating their cardiometabolic implications when there is presence or absence of either or both in an individual.     

Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns That Associate With Future Diabetic Complications

OBJECTIVEType 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.RESEARCH DESIGN AND METHODSGenome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.RESULTSWe found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6–6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4–1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.CONCLUSIONSWe identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.     

Association and Familial Coaggregation of Type 1 Diabetes and Eating Disorders: A Register-Based Cohort Study in Denmark and Sweden

OBJECTIVETo ascertain the association and coaggregation of eating disorders and childhood-onset type 1 diabetes in families.RESEARCH DESIGN AND METHODSUsing population samples from national registers in Sweden (n = 2,517,277) and Demark (n = 1,825,920), we investigated the within-individual association between type 1 diabetes and eating disorders and their familial coaggregation among full siblings, half siblings, full cousins, and half cousins. On the basis of clinical diagnoses, we classified eating disorders into any eating disorder (AED), anorexia nervosa (AN) and atypical AN, and other eating disorder (OED). Associations were determined with hazard ratios (HRs) with 95% CIs from Cox regressions.RESULTSSwedish and Danish individuals with a type 1 diabetes diagnosis had a greater risk of receiving an eating disorder diagnosis (HR [95% CI] Sweden: AED 2.02 [1.80–2.27], AN 1.63 [1.36–1.96], OED 2.34 [2.07–2.63]; Denmark: AED 2.19 [1.84–2.61], AN 1.78 [1.36–2.33], OED 2.65 [2.20–3.21]). We also meta-analyzed the results: AED 2.07 (1.88–2.28), AN 1.68 (1.44–1.95), OED 2.44 (2.17–2.72). There was an increased risk of receiving an eating disorder diagnosis in full siblings in the Swedish cohort (AED 1.25 [1.07–1.46], AN 1.28 [1.04–1.57], OED 1.28 [1.07–1.52]); these results were nonsignificant in the Danish cohort.CONCLUSIONSPatients with type 1 diabetes are at a higher risk of subsequent eating disorders; however, there is conflicting support for the relationship between having a sibling with type 1 diabetes and an eating disorder diagnosis. Diabetes health care teams should be vigilant about disordered eating behaviors in children and adolescents with type 1 diabetes.     

Clinical usefulness of different lipid measures for prediction of coronary heart disease in type 2 diabetes: a report from the Swedish National Diabetes Register

OBJECTIVE

We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD).

RESEARCH DESIGN AND METHODS

We conducted an observational study of patients with type 2 diabetes from the Swedish National Diabetes Register. Baseline LDL cholesterol, non-HDL cholesterol, ratio of non-HDL to HDL cholesterol (non-HDL:HDL), and ratio of triacylglycerol to HDL cholesterol (TG:HDL) was measured in 18,673 patients aged 30–70 years, followed for a mean of 4.8 years from 2003 to 2007.

RESULTS

Hazard ratios (HRs) for CHD per 1-SD increment in lipid measures were 1.23 with non-HDL:HDL, 1.20 with non-HDL cholesterol, 1.17 with LDL cholesterol, and 1.15 with TG:HDL (all P < 0.001 when adjusted for clinical characteristics and nonlipid risk factors). The best global model fit was found with non-HDL:HDL. When patients within the lowest tertile of a lipid measure were compared with those with all lipid measures within the highest tertile, the adjusted HR for CHD was 0.62 with non-HDL:HDL <3.5 mmol/L, 0.65 with non-HDL cholesterol <3.3 mmol/L, and 0.70 with LDL cholesterol <2.5 mmol/L (all P < 0.001). The lowest tertile of LDL and non-HDL cholesterol corresponded with treatment targets according to U.S. and European guidelines. HRs for CHD were 0.52, 0.62, and 0.66 with the lowest deciles of non-HDL:HDL, non-HDL cholesterol, and LDL cholesterol ≤1.8 mmol/L (all P < 0.001). Mean TG:HDL was considerably lower in patients within the lowest tertile of non-HDL:HDL, 0.82 ± 0.47, than in those within the lowest tertile of LDL cholesterol (<2.5 mmol/L), 1.49 ± 1.03.

CONCLUSIONS

Non-HDL:HDL had a stronger effect on CHD risk than LDL cholesterol, and low TG:HDL values were more often seen within the lowest non-HDL:HDL tertile than within the lowest LDL cholesterol tertile. LDL cholesterol was not the best predictor of CHD risk in type 2 diabetes.Randomized controlled clinical trials have established the clinical benefits of lowering LDL cholesterol levels for risk reduction of coronary heart disease (CHD) (1). The National Cholesterol Education Program Adult Treatment Panel (ATP) III (2) and the American Diabetes Association (3) have recommended LDL cholesterol <2.5 mmol/L as the primary treatment goal in patients with diabetes and hyperlipidemia.ATP III has also identified non-HDL cholesterol (the sum of LDL and VLDL) <3.3 mmol/L as a secondary treatment target in patients with triacylglycerol >2.3 mmol/L or HDL cholesterol <1.0 mmol/L (2). European guidelines recommend the same targets for LDL and non-HDL cholesterol (4,5), and these as well as those of the U.S. National Cholesterol Education Program (1) and the American Diabetes Association (3) have also recently underlined LDL cholesterol ≤1.8 mmol/L as an optional goal for patients with diabetes and overt cardiovascular disease (CVD).Against this background, we assessed the clinical usefulness of several lipid measures with regard to the risk of CHD in an observational study of 18,673 patients with type 2 diabetes in the Swedish National Diabetes Register (NDR). The main aim was to evaluate LDL cholesterol as a risk factor in comparison with the ratio of non-HDL cholesterol to HDL cholesterol (non-HDL:HDL).     

Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts

OBJECTIVEWe evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes.RESEARCH DESIGN AND METHODSWe prospectively followed 76,530 women in the Nurses’ Health Study (NHS) (1986–2012), 81,569 women in NHS II (1991–2017), and 34,468 men in the Health Professionals Follow-up Study (1986–2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis.RESULTSWe documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12–23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7–9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0–35.6% of the associations between changes in PDI and hPDI and diabetes risk.CONCLUSIONSImproving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.     

Association of Bariatric Surgery With Cancer Incidence in Patients With Obesity and Diabetes: Long-term Results From the Swedish Obese Subjects Study

OBJECTIVEObesity and type 2 diabetes are associated with serious adverse health effects, including cancer. Although bariatric surgery has been shown to reduce cancer risk in patients with obesity, the effect of bariatric surgery on cancer risk in patients with obesity and diabetes is less studied. We therefore examined the long-term incidence of cancer after bariatric surgery and usual care in patients with obesity and diabetes in the matched prospective Swedish Obese Subjects (SOS) study.RESEARCH DESIGN AND METHODSThe SOS study examines long-term outcomes following bariatric surgery or usual care. The current analysis includes 701 patients with obesity and type 2 diabetes at baseline, 393 of whom underwent bariatric surgery and 308 who received conventional obesity treatment. Information on cancer events was obtained from the Swedish National Cancer Register. Median follow-up time was 21.3 years (interquartile range 17.6–24.8 years, maximum 30.7 years).RESULTSDuring follow-up, the incidence rate for first-time cancer was 9.1 per 1,000 person-years (95% CI 7.2–11.5) in patients with obesity and diabetes treated with bariatric surgery and 14.1 per 1,000 person-years (95% CI 11.2–17.7) in patients treated with usual obesity care (adjusted hazard ratio 0.63 [95% CI 0.44–0.89], P = 0.008). Moreover, surgery was associated with reduced cancer incidence in women (0.58 [0.38–0.90], P = 0.016), although the sex-treatment interaction was nonsignificant (P = 0.630). In addition, diabetes remission at the 10-year follow-up was associated with reduced cancer incidence (0.40 [0.22–0.74], P = 0.003).CONCLUSIONSThese results suggest that bariatric surgery prevents cancer in patients with obesity and diabetes and that durable diabetes remission is associated with reduced cancer risk.     

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

OBJECTIVEObservational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.RESEARCH DESIGN AND METHODSUsing 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.RESULTSMR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17–1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.CONCLUSIONSThis MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.     

The Incidence of Diabetes Among 2,777,768 Veterans With and Without Recent SARS-CoV-2 Infection

OBJECTIVETo examine associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection/coronavirus disease 2019 with incident diabetes.RESEARCH DESIGN AND METHODSWe conducted a retrospective cohort study using Veterans Health Administration data. We defined all patients without preexisting diabetes with one or more nasal swabs positive for SARS-CoV-2 (1 March 2020–10 March 2021; n = 126,710) as exposed and those with no positive swab and one or more laboratory tests (1 March 2020–31 March 2021; n = 2,651,058) as unexposed. The index date for patients exposed was the date of first positive swab and for patients unexposed a random date during the month of the qualifying laboratory test. We fit sex-stratified logistic regression models examining associations of SARS-CoV-2 with incident diabetes within 120 days and all follow-up time through 1 June 2021. A subgroup analysis was performed among hospitalized subjects only to help equalize laboratory surveillance.RESULTSSARS-CoV-2 was associated with higher risk of incident diabetes, compared with no positive tests, among men (120 days, odds ratio [OR] 2.56 [95% CI 2.32–2.83]; all time, 1.95 [1.80–2.12]) but not women (120 days, 1.21 [0.88–1.68]; all time, 1.04 [0.82–1.31]). Among hospitalized participants, SARS-CoV-2 was associated with higher risk of diabetes at 120 days and at the end of follow-up in men (OR 1.42 [95% CI 1.22–1.65] and 1.32 [1.16–1.50], respectively) but not women (0.72 [0.34–1.52] and 0.80 [0.44–1.45]). Sex ∗ SARS-CoV-2 interaction P values were all <0.1.CONCLUSIONSSARS-CoV-2 is associated with higher risk of incident diabetes in men but not in women even after greater surveillance related to hospitalization is accounted for.     

Type 2 Diabetes and COVID-19–Related Mortality in the Critical Care Setting: A National Cohort Study in England,March–July 2020

OBJECTIVETo describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting.RESEARCH DESIGN AND METHODSThis was a nationwide retrospective cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease).RESULTSA total of 19,256 COVID-19–related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio [aHR] 1.23 [95% CI 1.14, 1.32]), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18–49 years aHR 1.50 [95% CI 1.05, 2.15], age 50–64 years 1.29 [1.10, 1.51], and age ≥65 years 1.18 [1.09, 1.29]; P value for age–type 2 diabetes interaction = 0.002).CONCLUSIONSType 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.     

Diabetes and Overweight/Obesity Are Independent,Nonadditive Risk Factors for In-Hospital Severity of COVID-19: An International,Multicenter Retrospective Meta-analysis

OBJECTIVEObesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes.RESEARCH DESIGN AND METHODSWe retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis.RESULTSAmong 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44; 95% CI 1.15–1.80) and invasive mechanical ventilatory support (aOR, 1.22; 95% CI 1.03–1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88; 95% CI 0.74–1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity.CONCLUSIONSIn adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.     

C-reactive protein,gamma-glutamyltransferase and type 2 diabetes in a Chinese population

BackgroundWe studied the association of C-reactive protein (CRP), gamma-glutamyltransferase (GGT) and type 2 diabetes in Chinese.MethodA population-based cross-sectional study.ResultsCRP and GGT levels were significantly higher in participants with diabetes than in those without (P < 0.001). Higher CRP levels were positively associated with prevalent type 2 diabetes after adjustment for age, sex, smoking, alcohol consumption, physical activity, family history of diabetes, body mass index, waist circumference, waist/hip ratio, education, systolic blood pressure, triglycerides, high density lipoprotein cholesterol, use of antihypertensive drugs, aspirin and lipid-lowering agents, with multivariable odds ratios (OR) of 1.55 (95% confidence interval (CI), 1.05–2.27, P trend = 0.005, comparing quartile 4 to quartile 1). However, after further adjustment for GGT, the association was completely attenuated (fourth quartile OR 1.23, 95% CI, 0.83–1.82, P trend = 0.127). Moreover, the association of CRP and prevalent type 2 diabetes was stronger in subjects with GGT values above the median than in those with GGT values below the median. Increasing serum GGT quartiles were positively associated with prevalent type 2 diabetes after adjustment for potential confounding variables (P for trend < 0.001).ConclusionCRP may not be an independent risk factor for type 2 diabetes, at least in Chinese people.     

Serum HDL cholesterol uptake capacity in subjects from the MASHAD cohort study: Its value in determining the risk of cardiovascular endpoints

BackgroundThe efficiency of high‐density lipoprotein (HDL) to efflux cholesterol contributes to the reverse cholesterol transport (RCT) pathway as one of HDL’s proposed functions and depends on the ability of HDL to uptake cholesterol. We aimed to investigate cholesterol uptake capacity (CUC) by a newly developed assay in samples from the MASHAD (Mashhad Stroke and Heart Atherosclerotic Disorders) cohort study.MethodThe study population comprised 153 individuals developed CVD diagnosed by a specialist cardiologist, over 6 years of follow‐up, and 350 subjects without CVD. We used a modified CUC method to evaluate the functionality of HDL in serum samples.ResultThe CUC assay was highly reproducible with values for inter‐ and intra‐assay variation of 13.07 and 6.65, respectively. The mean serum CUC was significantly lower in the CVD group compared to control (p = 0.01). Although, there were no significant differences in serum HDL‐C between the groups and there was no significantly association with risk of progressive CVD. Multivariate logistic regression analysis showed that there was a significantly negative association between CUC and risk of CVD after adjustment for confounding parameters (OR = 0.57, 95% CI = 0.38–0.87, p = 0.009). The CUC was also inversely and independently associated with the risk of CVD event using Cox proportional hazards models analysis (HR = 0.62; 95% CI = 0.41–0.94, p = 0.02). We determined the optimum cutoff value of 1.7 a.u for CUC in the population. Furthermore, the CUC value was important in determining the CVD risk stratification derived from data mining analysis.ConclusionsReduced HDL functionality, as measured by CUC, appears to predict CVD in population sample from north‐eastern Iran.     

Predictive value of HDL function in patients with coronary artery disease: relationship with coronary plaque characteristics and clinical events

BackgroundHDL is endowed with several metabolic, vascular, and immunoinflammatory protective functions. Among them, a key property is to promote reverse cholesterol transport from cells back to the liver. The aim of this study was to estimate the association of scavenger receptor class B type I (SR-BI)- and ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux (the two major routes for cholesterol efflux to HDL) with the presence, extent, and severity of coronary artery disease (CAD), vascular wall remodelling processes, coronary plaque characteristics, and the incidence of myocardial infarction in the different subgroups of patients from the CAPIRE study.MethodsPatients (n = 525) from the CAPIRE study were divided into two groups: low-risk factors (RF), with 0–1 RF (n = 263), and multiple-RF, with ≥2 RFs; within each group, subjects were classified as no-CAD or CAD based on the segment involvement score (SIS) evaluated by coronary computed tomography angiography (SIS = 0 and SIS > 5, respectively). SR-BI- and ABCA1-mediated cholesterol efflux were measured using the plasma of all patients.ResultsSR-BI-mediated cholesterol efflux was significantly reduced in patients with CAD in both the low-RF and multiple-RF groups, whereas ABCA1-mediated cholesterol efflux was similar among all groups. In CAD patients, multivariable analysis showed that SR-BI-mediated cholesterol efflux <25^th percentile predicted cardiovascular outcome (odds ratio 4.1; 95% CI: 1.3–13.7; p = .019), whereas ABCA-1-mediated cholesterol efflux and HDL-C levels significantly did not. Despite this finding, reduced SR-BI-mediated cholesterol efflux was not associated with changes in high-risk plaque features or changes in the prevalence of elevated total, non-calcified, and low-attenuation plaque volume.ConclusionSR-BI-mediated cholesterol efflux capacity is lower in patients with diffuse coronary atherosclerosis. In addition, a lower SR-BI-mediated cholesterol efflux capacity is associated with the worst clinical outcomes in patients with CAD, independently of atherosclerotic plaque features.

Key Messages

• Increased cholesterol efflux capacity, an estimate of HDL function, is associated with a reduced CVD risk, regardless of HDL-C levels.
• HDL-C levels are significantly lower in patients with CAD.
• Lower SR-BI-mediated cholesterol efflux capacity is observed in patients with diffuse coronary atherosclerosis and is associated with the worst clinical outcomes in patients with CAD, independently of atherosclerotic plaque features.