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<h4>Objectives: </h4> To estimate the cost-effectiveness of interventions to reduce body mass index (BMI) using Mendelian randomization. Design We estimated the causal effect of differences in BMI on quality-adjusted life years (QALYs) and total healthcare costs using Mendelian randomization and applied our results to policy-relevant questions. Setting UK Biobank. Participants 310,913 men and women of white British ancestry aged between 39 and 72 years, followed-up for an average of 8.1 years (6.1 years for secondary care healthcare costs). Main outcome measures Predicted average QALYs and total healthcare costs per year, and cost-effectiveness of interventions. Results A unit increase in BMI decreased QALYs by 0.65% of a QALY (95% confidence interval [CI]: 0.49% to 0.81%) per year and increased annual total healthcare costs by 42.23 (95% CI: 32.95 to 51.51) per person. When considering only health conditions usually considered in previous studies (cancer, cardiovascular disease, cerebrovascular disease and type 2 diabetes), we estimated that a unit increase in BMI decreased QALYs by only 0.16% of a QALY (95% CI: 0.10% to 0.22%) per year. Compared to no intervention and over 20 years, a person in England or Wales aged 40-69 years with a BMI over 35 kg/m2 receiving laparoscopic bariatric surgery would have, on average, an increase of 0.92 QALYs (95% CI: 0.66 to 1.17) and a decrease in total healthcare costs of 5,096 (95% CI: 3,459 to 6,852), with a net monetary benefit (at 20,000 per QALY) of 13,936 (95% CI: 8,112 to 20,658). Restricting volume promotions for high fat, salt and sugar products would, across the 21.7 million adults aged 40 to 69 years in England and Wales, increase QALYs by 20,551 per year (95% CI: 15,335 to 25,301), decrease total healthcare costs by 137 million per year (95% CI: 106 million to 170 million), with a net monetary benefit (at 20,000 per QALY) of 546 million per year (95% CI: 435 million to 671 million). Between 1993 and 2017 in England and Wales, the increase in BMI of people aged 40 to 69 years led to a decrease of 1.13% of a QALY per person per year (95% CI: 0.90% to 1.38%) and an increase in annual healthcare costs of 69 per person (95% CI: 53 to 84). Compared to if all people with a BMI above 25 kg/m2 aged 40 to 69 years in England and Wales in 2017 had a BMI of 25 kg/m2, QALYs are decreased by 580,494 in total per year (95% CI: 457,907 to 717,691) and annual healthcare costs are increased by 3.58 billion (95% CI: 2.75 billion to 4.34 billion). Conclusions Mendelian randomization can be used to estimate the impact of interventions on quality of life and healthcare costs. The effect of increasing BMI on health-related quality of life is much larger when accounting for 240 chronic health conditions, compared with only a limited selection.

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