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Background: Weight gain following smoking cessation reduces the incentive to quit, especially among women. Exercise and diet interventions may reduce postcessation weight gain, but their long-term effect has not been estimated in randomized trials., Methods: We estimated the long-term reduction in postcessation weight gain among women under smoking cessation alone or combined with (1) moderate-to-vigorous exercise (15, 30, 45, 60 minutes/day), and (2) exercise and diet modification (≤2 servings/week of unprocessed red meat; ≥5 servings/day of fruits and vegetables; minimal sugar-sweetened beverages, sweets and desserts, potato chips or fried potatoes, and processed red meat)., Results: Among 10,087 eligible smokers in the Nurses' Health Study and 9,271 in the Nurses' Health Study II, the estimated 10-year mean weights under smoking cessation were 75.0 (95% CI = 74.7, 75.5) kg and 79.0 (78.2, 79.6) kg, respectively. Pooling both cohorts, the estimated postcessation mean weight gain was 4.9 (7.3, 2.6) kg lower under a hypothetical strategy of exercising at least 30 minutes/day and diet modification, and 5.9 (8.0, 3.8) kg lower under exercising at least 60 minutes/day and diet modification, compared with smoking cessation without exercising., Conclusions: In this study, substantial weight gain occurred in women after smoking cessation, but we estimate that exercise and dietary modifications could have averted most of it.

Objective: To compare the risk of incident hypertension between initiators of tumor necrosis factor (TNF)-α inhibitors and initiators of nonbiologic disease modifying antirheumatic drugs (hereafter referred to as nonbiologics) in rheumatoid arthritis patients taking methotrexate monotherapy., Methods: We conducted a cohort study using insurance claims data (2001-2012) from the US. We identified initiators of use of either TNF-α inhibitors or nonbiologics. Subsequent exposure to these agents was measured monthly in a time-varying manner. The outcome of interest was incident hypertension, defined by a diagnosis and a prescription for an antihypertensive drug. Marginal structural models estimated hazard ratios (HRs) adjusted for both baseline and time-varying confounders. To validate the primary analysis, we designed a verification analysis to evaluate a known association between leflunomide (a nonbiologic disease modifying agent) and hypertension., Results: We identified 4,822 initiations of TNF-α inhibitor use and 2,400 of nonbiologic use. Crude incidence rates of hypertension per 1,000 person-years of follow-up were 36 (95% CI [confidence interval]: 32, 41) for the TNF-α inhibitor group and 42 (95% CI: 34, 51) for the nonbiologics group. The crude HR of TNF-α inhibitors versus nonbiologics for the risk of incident hypertension was 0.85 (95% CI: 0.67, 1.1). After adjusting for both baseline and time-varying covariates using marginal structural models, the HR was 0.95 (95% CI: 0.74, 1.2). In the verification analysis, the adjusted HR of incident hypertension was 2.3 (95% CI: 1.7, 3.0) in leflunomide initiators compared with methotrexate initiators., Conclusion: Treatment with TNF-α inhibitors was not associated with a reduced risk of incident hypertension compared with nonbiologics in rheumatoid arthritis patients.See Video Abstract at http://links.lww.com/EDE/B36.

Background: Evidence for the effect of weight loss on coronary heart disease (CHD) or mortality has been mixed. The effect estimates can be confounded due to undiagnosed diseases that may affect weight loss., Methods: We used data from the Nurses' Health Study to estimate the 26-year risk of CHD under several hypothetical weight loss strategies. We applied the parametric g-formula and implemented a novel sensitivity analysis for unmeasured confounding due to undiagnosed disease by imposing a lag time for the effect of weight loss on chronic disease. Several sensitivity analyses were conducted., Results: The estimated 26-year risk of CHD did not change under weight loss strategies using lag times from 0 to 18 years. For a 6-year lag time, the risk ratios of CHD for weight loss compared with no weight loss ranged from 1.00 (0.99, 1.02) to 1.02 (0.99, 1.05) for different degrees of weight loss with and without restricting the weight loss strategy to participants with no major chronic disease. Similarly, no protective effect of weight loss was estimated for mortality risk. In contrast, we estimated a protective effect of weight loss on risk of type 2 diabetes., Conclusion: We estimated that maintaining or losing weight after becoming overweight or obese does not reduce the risk of CHD or death in this cohort of middle-age US women. Unmeasured confounding, measurement error, and model misspecification are possible explanations but these did not prevent us from estimating a beneficial effect of weight loss on diabetes., Competing Interests: Authors have no conflicts of interest to declare.

Background: The prevalence of overweight and obesity is rising globally and together they constitute a major risk factor for coronary heart disease (CHD). Previous estimates of direct effects of high body mass index (BMI) on CHD did not consider an interaction between BMI and its mediators and did not include inflammatory biomarkers as potential mediators., Methods: We analyzed data from 9 prospective cohort studies with 58,322 participants and 9,459 CHD events and decomposed the total effects into natural direct and indirect effects using a 2-stage regression model. We examined overweight (BMI = 25 to <30 kg/m) separately. We pooled hazard ratios using random-effects models and calculated the percentages of excess relative risk mediated by blood pressure, cholesterol, glucose, fibrinogen and high-sensitive C-reactive protein., Results: There was no interaction between BMI and its mediators in the multiplicative scale (P < 0.05 for all). Blood pressure was the most important mediator. The percentage of excess relative risk of overweight (versus normal BMI, 20 to <25 kg/m) mediated was 28% for blood pressure, 10% for blood glucose, and 14% for cholesterol. The same percentages for obesity were 37% for blood pressure, 17% for blood glucose, and 6% for cholesterol. The percentage mediated through all three metabolic risk factors together was 47% (95% confidence interval = 33%-63%) for overweight and 52% (38%-68%) for obesity. Fibrinogen mediated 6% to 9% and high-sensitive C-reactive protein mediated 6% to 8% of the excess relative risk for overweight and obese participants., Conclusions: Metabolic mediators explain about half of the adverse effects of high BMI on CHD. The role of inflammatory and prothrombotic biomarkers is much smaller than that of metabolic factors.

Background: Randomized trials have examined short-term effects of lifestyle interventions for diabetes prevention only among high-risk individuals. Prospective studies have examined the associations between lifestyle factors and diabetes in healthy populations but have not characterized the intervention. We estimated the long-term effects of hypothetical lifestyle interventions on diabetes in a prospective study of healthy women, using the parametric g-formula., Methods: Using data from the Nurses' Health Study, we followed 76,402 women from 1984 to 2008. We estimated the risk of type 2 diabetes under eight hypothetical interventions: quitting smoking, losing weight by 5% every 2 years if overweight/obese, exercising at least 30 minutes a day, eating less than three servings a week of red meat, eating at least two servings a day of whole grain, drinking two or more cups of coffee a day, drinking five or more grams of alcohol a day, and drinking less than one serving of soda a week., Results: The 24-year risk of diabetes was 9.6% under no intervention and 4.3% when all interventions were imposed (55% lower risk [95% confidence interval = 47 to 63%]). The most effective interventions were weight loss (24% lower risk), physical activity (19%), and moderate alcohol use (19%). Overweight/obese women would benefit the most, with 10.8 percentage point reduction in 24-year risk of diabetes. The validity of these estimates relies on the absence of unmeasured confounding, measurement error, and model misspecification., Conclusion: A combination of dietary and nondietary lifestyle modifications, begun in midlife or later in relatively healthy women, could have prevented at least half of the cases of type 2 diabetes in this cohort of U.S. women.

Background: A previous analysis of the Osteoarthritis Initiative study reported a dose-response relationship between physical activity and improved physical function in adults with knee osteoarthritis, using conventional statistical methods. These methods are subject to bias when confounders are affected by prior exposure., Methods: We used baseline and 1-, 2-, and 3-year follow-up data from the Osteoarthritis Initiative study of 2545 US adults with knee osteoarthritis recruited between 2004 and 2006 from 4 clinical sites. Physical activity was measured using the Physical Activity Scale for the Elderly, and outcomes were functional performance measured by the timed 20-meter walk test and self-reported knee pain measured by the Western Ontario and McMaster Universities Osteoarthritis Index. We estimated the effect of physical activity on each outcome using inverse probability-weighted (IPW) estimators of marginal structural models. For each outcome, we fitted 2 separate IPW models adjusting for concurrent or lagged confounders., Results: The mean differences in walking speed for the second, third, and fourth quartiles of physical activity relative to the first were 0.48 (95% confidence interval = -0.12 to 1.08), 0.45 (-0.23 to 1.13), and 0.46 (-0.29 to 1.22) meters/min based on the IPW model adjusting for concurrent confounders. When adjusting for lagged confounders, the results were 1.35 (0.64 to 2.07), 1.33 (0.54 to 2.14), and 1.26 (0.40 to 2.12). Both IPW models indicated that physical activity did not affect knee pain., Conclusions: Physical activity has no effect on knee pain and may have either a very small effect or no effect on functional performance in adults with knee osteoarthritis.