Development and Validation of a Claims-Based Model to Predict Categories of Obesity.

We developed and validated a claims-based algorithm that classifies patients into obesity categories. Using Medicare (2007-2017) and Medicaid (2000-2014) claims data linked to 2 electronic health record (EHR) systems in Boston, Massachusetts, we identified a cohort of patients with an EHR-based body mass index (BMI) measurement (calculated as weight (kg)/height (m)2). We used regularized regression to select from 137 variables and built generalized linear models to classify patients with BMIs of ≥25, ≥30, and ≥40. We developed the prediction model using EHR system 1 (training set) and validated it in EHR system 2 (validation set). The cohort contained 123,432 patients in the Medicare population and 40,736 patients in the Medicaid population. The model comprised 97 variables in the Medicare set and 95 in the Medicaid set, including BMI-related diagnosis codes, cardiovascular and antidiabetic drugs, and obesity-related comorbidities. The areas under the receiver-operating-characteristic curve in the validation set were 0.72, 0.75, and 0.83 (Medicare) and 0.66, 0.66, and 0.70 (Medicaid) for BMIs of ≥25, ≥30, and ≥40, respectively. The positive predictive values were 81.5%, 80.6%, and 64.7% (Medicare) and 81.6%, 77.5%, and 62.5% (Medicaid), for BMIs of ≥25, ≥30, and ≥40, respectively. The proposed model can identify obesity categories in claims databases when BMI measurements are missing and can be used for confounding adjustment, defining subgroups, or probabilistic bias analysis.

Obesity as a modifier of the cardiovascular effectiveness of sodium-glucose cotransporter-2 inhibitors in type 2 diabetes.

AIMS: To assess the association between the use of sodium-glucose cotransporter-2 (SGLT2i) and cardiovascular outcomes and death as a function of obesity among patients with type 2 diabetes. METHODS: This new-user, active-comparator cohort study used U.K.'s Clinical Practice Research Datalink linked to Hospital Episodes Statistics repository and Office for National Statistics. The cohort included 34,128 new-users of SGLT2i matched 1:1 to 34,128 new-users of dipeptidyl peptidase-4 inhibitors (DPP-4i) on body mass index and propensity score. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), overall and in body mass index (BMI) categories (≤24.9 kg/m2, 25.0-29.9 kg/m2, 30.0-39.9 kg/m2, ≥40 kg/m2). Secondary outcomes included all-cause mortality and hospitalization for heart failure. RESULTS: SGLT2i were associated with a decreased risk of MACE (HR: 0.78, 95 %CI: 0.69-0.88) compared to DPP-4i. This decreased risk was most pronounced among obese and severely obese patients (HR: 0.77, 95 %CI: 0.66-0.91; HR: 0.67, 95% CI: 0.49-0.91, respectively) but not among overweight patients (HR: 0.94, 95 %CI: 0.73-1.22). Similar patterns were observed for cardiovascular mortality, all-cause mortality, and heart failure. CONCLUSION: Compared with DPP-4i, the cardioprotective effect associated with SGLT2i is stronger among patients with higher BMI.

Glucosamine and lower mortality and cancer incidence: Selection bias in the observational studies.

BACKGROUND: Glucosamine is a widely used supplement to treat joint pain and osteoarthritis despite inconclusive randomized trial results on its effectiveness. In contrast, observational studies associate glucosamine with significant reductions in mortality and cancer incidence. We evaluated the extent of bias, particularly selection bias, to explain these surprising beneficial effects. METHODS: We searched the literature to identify all observational studies reporting on the effect of glucosamine use on major outcomes. RESULTS: We identified 11 observational studies, reporting a mean 16% reduction in all-cause mortality (hazard ratio [HR] 0.84, 95% CI: 0.81-0.87) with glucosamine use, as well as significant reductions in cancer incidence and other major diseases including cardiovascular, respiratory and diabetes. We show that these significant effects can result from selection bias due to collider stratification, as all studies used "prevalent" cohorts, where glucosamine use started before cohort entry, and where subjects agreed to join the cohorts. Our illustration of the bias using the UK Biobank publication involving a half-million subjects shows how a true rate ratio of mortality of 1.0 in the population can result in a biased rate ratio of 0.82 in the prevalent cohort. CONCLUSIONS: The observational studies reporting significant reductions in mortality, cancer incidence and other outcomes with glucosamine were affected by selection bias from collider stratification. In the absence of properly conducted observational studies that circumvent this bias by considering "new users", the studies to date cannot support the prescription of this supplement as a preventive measure for mortality, cancer, and other chronic diseases.

A mediation analysis on the relationship between dietary glycemic load, obesity and cardiovascular risk factors in children.

BACKGROUND/OBJECTIVE: Adiposity may mediate the effect of dietary glycemic load (GL) on lipid profiles in children, as studies have shown an association between dietary GL and adiposity and between adiposity and lipid profiles. Our objective was to evaluate the role of adiposity as a mediator in the association between dietary GL and lipid profiles after 2 years. SUBJECTS/METHODS: The Quebec Adipose and Lifestyle InvesTigation in Youth study included 630 children, 8-10 years old at recruitment with at least one parent with overweight or obesity with 2-year follow-up. Three baseline 24-h dietary recalls were administered by a dietitian at baseline. Child and parent characteristics were obtained through direct measurement (blood lipids, anthropometrics) or questionnaires (socio-economic characteristics). Indicators of adiposity, including body mass index (BMI) z-score and percent body fat, were the mediators of interest. A conventional approach using the Baron and Kenny method was used. A causal approach using marginal structural models (MSM) was used to estimate the controlled direct effect. RESULTS: Mean age at baseline was 9.6 years and 33% were overweight or obese. Both methods revealed that the effect of GL on blood lipids was mediated by adiposity. The weighted MSM did not show evidence of a direct effect (TG: ß =;0.01, 95% CI = -0.01,0.02; HDL: ß = 0.005, 95%CI = -0.002,0.01), whereas the conventional method did for TG but not HDL (TG:ß = 0.04, 95%CI = 0.01,0.07; HDL: ß = -0.01, 95%CI = -0.03,0.01). CONCLUSION: Adiposity contributes substantially to the association between GL and blood lipids. The choice of approach for mediation analysis should be based on the fulfilment of conditions of each method.

Allopurinol and Cardiovascular Events: Time-Related Biases in Observational Studies.

OBJECTIVE: Several observational studies reported that allopurinol, an effective treatment for gout, was associated with important reductions in cardiovascular (CV) events, with calls for large, randomized trials, although some results were conflicting. The present study was undertaken to assess the extent of time-related biases in these observational studies. METHODS: We searched the literature for all observational studies reporting on allopurinol and CV events, focusing on 2 time-related biases. Time-related confounding bias results from studies using cohorts of patients all exposed to allopurinol, with comparisons based on episodes of allopurinol discontinuation, where confounding factors are not updated over follow-up time. Immortal time bias arises from the exposure misclassification of periods of cohort follow-up during which the outcome under study cannot occur. RESULTS: We identified 12 studies, of which 8 were affected by time-related confounding bias or immortal time bias, while the remaining 4 studies avoided these biases. The studies affected by time-related confounding bias resulted in significant reductions in the incidence of CV events with allopurinol use (pooled hazard ratio [HR] 0.88 [95% confidence interval (95% CI) 0.85-0.92]), as did the studies affected by immortal time bias (pooled HR 0.79 [95% CI 0.72-0.87]). The 4 studies that avoided these biases resulted in a pooled HR of 1.07 (95% CI 0.91-1.25). CONCLUSION: Observational studies reporting significantly reduced incidence of CV events with allopurinol use were affected by time-related biases. Overall, studies that avoided these biases did not find a protective effect. The ALL-HEART randomized trial will provide important and accurate evidence on the potential effectiveness of allopurinol on CV outcomes.

Validation of obesity-related diagnosis codes in claims data.

AIM: To determine whether body mass index (BMI) can be accurately identified in epidemiological studies using claims databases. MATERIALS AND METHODS: Using the Mass General Brigham Research Patient Data Repository-Medicare-linked database, we identified a cohort of patients with a BMI measurement for the periods January 1 to June 31, 2014 or January 1 to June 31, 2016, to capture both the International Classification of Disease (ICD)-9 and ICD-10 eras. Patients were divided into two groups, with or without an obesity-related ICD code in the 6 months before or after the BMI measurement date. We created two binary measures, first for composite overweight, obesity, or severe obesity (BMI ≥25 kg/m2 ), and second for obesity or severe obesity (BMI ≥30 kg/m2 ). We calculated accuracy measures (sensitivity, specificity, positive predictive value [PPV] and negative predictive value [NPV]) for each obesity category for the overall cohort, and stratified by type 2 diabetes and ICD-code era. RESULTS: The cohort included 73 644 patients with a BMI measurement in 2014 or 2016, of whom 16 280 had an obesity-related ICD code. The specificity of obesity-related ICD codes (ICD-9 and ICD-10) was 99.7% for underweight/normal weight, 97.4% for overweight, 99.7% for obese and 98.9% for severely obese. For binary categories capturing BMI ≥25 kg/m2 and BMI ≥30 kg/m2 , specificity was 97.0% and 98.2%, and PPV was 86.9% and 97.3%. Sensitivity was low overall (<40%). Codes for patients with type 2 diabetes and codes in the ICD-10 era had higher sensitivity, PPV and NPV. CONCLUSION: Obesity-related ICD codes can accurately identify patients with obesity in epidemiological studies using claims databases.

The modifying effects of adiposity on the cardiovascular safety of sulphonylureas.

AIMS: To determine whether adiposity modified the effect on the cardiovascular safety of sulphonylureas as a first-line therapy compared with metformin among patients with type 2 diabetes. MATERIALS AND METHODS: Using the UK Clinical Practice Research Datalink, we conducted a cohort study among 13 862 new sulphonylurea users matched on body mass index (BMI) and propensity score, in a 1:1 ratio, to new metformin users between April 1, 1998 and December 31, 2016. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of major adverse cardiovascular events (MACE), individual components of MACE (myocardial infarction [MI], ischaemic stroke, cardiovascular mortality), and all-cause mortality, comparing use of sulphonylureas with use of metformin, overall and within BMI categories (≤24.9 kg/m2 , 25.0-29.9 kg/m2 , ≥30 kg/m2 ). RESULTS: Compared with metformin, sulphonylureas were not associated with an increased risk of MACE either overall (HR 1.08, 95% CI 0.94-1.23) or by BMI category. Similar findings were observed for MI and ischaemic stroke. By contrast, sulphonylureas were associated with an increased risk of cardiovascular mortality (HR 1.24, 95% CI 1.04-1.48), primarily among obese patients (HR 1.52, 95% CI 1.08-2.13), and not among normal-weight patients (HR 1.00, 95% CI 0.72-1.39; P-interaction 0.21). Similar results were observed for all-cause mortality (HR 1.47, 95% CI 1.32-1.62), where an increased risk was observed among obese patients (HR 1.83, 95% CI 1.49-2.25), but not normal-weight patients (HR 1.18, 95% CI 0.99-1.42; P-interaction: 0.006). CONCLUSION: The findings of this study suggest that adiposity may have a modifying effect on the association between sulphonylureas and cardiovascular and all-cause mortality compared with metformin.

Effectiveness of Allopurinol in Reducing Mortality: Time-Related Biases in Observational Studies.

OBJECTIVE: The treatment of gout with allopurinol is effective at reducing urate levels and the frequency of flares. Several observational studies have shown important reductions in mortality with allopurinol use, with wide variations in results. We undertook this review to assess the extent of bias in these studies, particularly time-related biases such as immortal time bias. METHODS: We searched the literature to identify all observational studies describing the effect of allopurinol use versus nonuse on all-cause mortality. RESULTS: We identified 12 observational studies, of which 3 were affected by immortal time bias and 3 by immeasurable time bias, while the remaining 6 studies avoided these time-related biases. Reductions in all-cause mortality with allopurinol use were observed among the studies with immortal time bias, with a pooled hazard ratio (HR) of death associated with allopurinol of 0.71 (95% confidence interval [95% CI] 0.50-1.01), as well as in those with immeasurable time bias (pooled HR 0.62 [95% CI 0.56-0.67]). The 6 studies that avoided these biases demonstrated a null effect of allopurinol on mortality (pooled HR 0.99 [95% CI 0.87-1.11]), though the lack of an analysis based on treatment adherence may have attenuated the effect. CONCLUSION: Observational studies are important to provide real-world data on medication effects. The observational studies showing significantly decreased mortality with allopurinol treatment cannot be used as evidence, however, mainly due to time-related biases that tend to greatly exaggerate the potential benefit of treatments. The ALL-HEART randomized trial, which is currently underway and evaluates the effect of adding allopurinol to usual care (compared to no added treatment), will provide reliable evidence on mortality.

Prescribing trends and clinical characteristics of patients starting antiobesity drugs in the United States.

AIM: To assess the trends in the prescribing of antiobesity medications and the characteristics of patients recently initiating antiobesity drugs. MATERIALS AND METHODS: We conducted a population-based cohort study using claims data from commercial health insurances in the United States. Patients initiating an antiobesity drug between January 2004 and December 2018 were included. Trends in the utilization of antiobesity medications were plotted by year, as a proportion of any antiobesity treatment, and as initiation rates per 100 000. Descriptive statistics were used to summarize the characteristics of antiobesity initiators. RESULTS: From 2004 to 2018, 626 216 patients started an antiobesity medication (two per 100 000). Phentermine was the most frequently prescribed (50% in 2018). In recent years (2015-2018), among 227 692 patients who initiated an antiobesity drug, 51% started phentermine, 19% naltrexone-bupropion, and 13% liraglutide 3.0 mg. Compared to other agents, the use of liraglutide 3.0 mg increased between 2015 and 2018. The average age of initiators was 45 years, 81% of initiators were female, 32% had hypertension, 25% had dyslipidaemia, and 6% had type 2 diabetes. Time on treatment was generally short (mean 81 days). CONCLUSION: The overall use of antiobesity medications remained low over the past 15 years and phentermine was the preferred antiobesity agent. Although the use of potentially safer antiobesity agents, for example, liraglutide 3.0 mg, has increased in recent years, phentermine remained the most frequently prescribed agent among middle-aged adults with a moderate burden of comorbidities.

Effects of dietary glycemic index and load on children's cardiovascular risk factors.

PURPOSE: Consumption of foods high in glycemic index (GI) and glycemic load (GL) is associated with cardiovascular (CV) diseases in adulthood. We examined whether GI and GL predict CV risk factors in children after 2 years of follow-up. METHODS: Three 24-hour recalls were administered at baseline, and individual average daily GI and GL scores were calculated in a cohort of 8-10 year-old children. CV risk factors included body mass index z-score (BMIz), percent fat mass, triglycerides (TGs), low-density lipoprotein and high-density lipoprotein (HDL) cholesterol, and systolic and diastolic blood pressure. Main analyses consisted of multiple linear regression adjusted for anthropometric, socioeconomic, and dietary factors. RESULTS: After 2 years, the highest dietary GL tertile compared with the lowest was associated with increased BMIz (mean difference [MD], 1.1; 95% CI, 0.88-1.31), fat mass (MD, 10.8%; 95% CI, 8.62-13.0), TGs (MD, 0.17 mmol/L; 95% CI, 0.07-0.28), and decreased HDL (MD, -0.13 mmol/L; 95% CI, -0.19 to -0.07). The GL-TG and the GL-HDL associations were mediated by BMIz. CONCLUSIONS: GL predicts increased BMIz, percent fat mass, and TGs and decreased HDL in young children after 2 years. Recommendations to decrease CV risk in children should include lowering foods high in GL.

The Cardiometabolic Risk Profile of Underreporters of Energy Intake Differs from That of Adequate Reporters among Children at Risk of Obesity.

Background: Misreporting of energy intake (EI) in nutritional epidemiology is a concern because of information bias, and tends to occur differentially in obese compared with nonobese subjects. Objective: We examined characteristics of misreporters within a cohort of children with a parental history of obesity and the bias introduced by underreporting. Methods: The QUebec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort included 630 Caucasian children aged 8-10 y at recruitment with ≥1 obese parent [body mass index (BMI; in kg/m2) >30 or waist circumference >102 cm (men), >88 cm (women)] and free of diabetes or severe illness. Children on antihypertensive medications or following a restricted diet were excluded. Child and parent characteristics were measured directly or by questionnaire. Three 24-h dietary recalls were administered by phone by a dietitian. Goldberg's cutoff method identified underreporters (URs). Logistic regression identified correlates of URs. We compared coefficients from linear regressions of BMI after 2 y on total EI at baseline 1) in all participants; 2) in adequate reporters (ARs) (excluding URs); 3) in all participants statistically adjusted for underreporting; 4) excluding URs using individual physical activity level (PAL)-specific cutoffs; and 5) in all participants statistically adjusted for underreporting using PAL-specific cutoffs. Results: We identified 175 URs based on a calculated cutoff of 1.11. URs were older, had a higher BMI z score, and had poorer cardiometabolic health indicators. Parents of URs had a lower family income and higher BMI. Child BMI z score (OR: 3.07; 95% CI: 2.38, 3.97) and age (OR: 1.46/y; 95% CI: 1.14, 1.87/y) were the strongest correlates of underreporting. The association between BMI and total EI was null in all participants but became significantly positive after excluding URs (ß = 0.62/1000 kcal; 95% CI: 0.33, 0.92/1000 kcal) and after adjustment for URs (ß = 0.85/1000 kcal; 95% CI: 0.55, 1.06/1000 kcal). Conclusions: URs in 8- to 10-y-old children differed from ARs. Underreporting biases measurement of nutritional exposures and the assessment of exposure-outcome relations. Identifying URs and using an appropriate correction method is essential.

The effectiveness and safety of the Impella ventricular assist device for high-risk percutaneous coronary interventions: A systematic review.

BACKGROUND: Small randomized controlled trials (RCTs) and observational studies have examined the effectiveness and safety of the Impella device, a percutaneous left ventricular assist device, in the setting of high-risk percutaneous coronary intervention (PCI). However, data are sparse and results are conflicting. Our objective was to evaluate the effectiveness and safety of the Impella device in high-risk patients undergoing PCI via a systematic review of the literature. METHODS: We searched Medline, EMBASE, and the Cochrane Library for RCTs and observational studies that evaluated the Impella device in high-risk patients undergoing PCI. Inclusion was restricted to studies in which ≥10 patients received the Impella device; both uncontrolled and controlled (versus intra-aortic-balloon pump [IABP]) studies were included. RESULTS: A total of 20 studies (4 RCTs, 2 controlled observational studies, and 14 uncontrolled observational studies; 1,287 patients) were included, with follow-up ranging from 1 to 42 months. The use of Impella resulted in improved procedural and hemodynamic characteristics in controlled and uncontrolled studies. In controlled studies, the 30-day rates of all-cause mortality and MACE were similar across groups. In most uncontrolled studies, the 30-day rates of all-cause mortality were generally low (range: 3.7%-10%), though rates of MACE were slightly higher (range: 5%-20%). CONCLUSION: The Impella device was found to improve procedural and hemodynamic parameters, but only limited randomized data are available regarding clinical outcomes associated with its use. Large, multicenter RCTs are needed to definitively establish the effectiveness of the Impella device among high-risk PCI patients.

Efficacy and Safety of Smoking Cessation Interventions in Patients With Cardiovascular Disease: A Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Although the efficacy and safety of smoking cessation interventions are well established, their efficacy and safety in patients with cardiovascular disease (CVD) remain unclear. The objective of this study was to evaluate the efficacy and safety of pharmacological and behavioral smoking cessation interventions in CVD patients via a meta-analysis of randomized controlled trials. METHODS AND RESULTS: EMBASE, PsycINFO, MEDLINE, PubMed, and the Cochrane Tobacco Addiction Specialized Register were searched for randomized controlled trials evaluating the efficacy of smoking cessation pharmacotherapies and behavioral therapies in CVD patients. Outcomes of interest were smoking abstinence at 6 and 12 months, defined using the most rigorous criteria reported. Data were pooled across studies for direct comparisons using random-effects models. Network meta-analysis using a graph-theoretical approach was used to generate the indirect comparisons. Seven pharmacotherapy randomized controlled trials (n=2809) and 17 behavioral intervention randomized controlled trials (n=4666) met our inclusion criteria. Our network meta-analysis revealed that varenicline (relative risk [RR]: 2.64; 95% confidence interval [CI], 1.34-5.21) and bupropion (RR: 1.42; 95% CI, 1.01-2.01) were associated with greater abstinence than placebo. The evidence about nicotine replacement therapies was inconclusive (RR: 1.22; 95% CI, 0.72-2.06). Telephone therapy (RR: 1.47; 95% CI: 1.15-1.88) and individual counseling (RR: 1.64, 95% CI: 1.17-2.28) were both more efficacious than usual care, whereas in-hospital behavioral interventions were not (RR: 1.05; 95% CI, 0.78-1.43). CONCLUSIONS: Our meta-analysis suggests varenicline and bupropion, as well as individual and telephone counseling, are efficacious for smoking cessation in CVD patients.