Background: Cross sectional measures of body mass index (BMI) are associated with cardiovascular disease (CVD) incidence, but less is known about whether weight change affects the risk of CVD. Methods: We estimated the effect of 2 year weight change interventions on 7 year risk of CVD, by emulating hypothetical target trials using electronic health records. We identified 138.567 individuals in England between 1998 and 2016, aged 45-69 years old, free of chronic diseases at baseline. We performed pooled logistic regression, using inverse-probability weighting to adjust for baseline and time-varying variables. Each individual was classified into a weight loss, maintenance, or gain group. Findings: In the normal weight, both weight loss and gain were associated with increased risk for CVD [HR vs weight maintenance=1.53 (1.18 to 1.98) and 1.43 (1.19 to 1.71 respectively)]. Among overweight individuals, both weight loss and gain groups, compared to weight maintenance, had a moderately higher risk of CVD [HR=1.20 (0.99 to 1.44) and 1.17 (0.99 to 1.38), respectively]. In the obese, weight loss had a lower risk lower risk of CHD [HR =0.66 (0.49 to 0.89)] and a moderately lower risk of CVD [HR =0.90 (0.72 to 1.13)]. When we assumed that a chronic disease occurred 1-3 years before the recorded date, estimates for weight loss and gain were attenuated among overweight individuals and estimates for weight loss were stronger among individuals with obesity. Interpretation: Among individuals with obesity, the weight loss group had a lower risk of CHD and moderately lower risk of CVD. Weight gain increased the risk of CVD across BMI groups.

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