Aims: BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real–world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability. Methods and Results: We investigated the association between BMI variability and 3P–MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA–REG OUTCOME (n = 2333) trials, followed by real–world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non–fatal stroke, non–fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome. After adjusting for cardiovascular risk factors, a +1 SD increase in BMI variability was associated with increased 3P–MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08 — 1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P <0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA–REG OUTCOME trial did not replicate this association. BMI variability's impact on 3P–MACE risk was independent of HbA1c variability. Conclusion: In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P–MACE across cardiovascular outcome trials and real–world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.

Y.C. is employed by Eli Lilly and Company and owns stock. N.C.S. is employed by Lilly Deutschland GmbH and owns stock. A.Y.D. is employed by Novo Nordisk. M.M. and M.P.N. are employed by Boehringer Ingelheim Pharma GmbH & Co.KG.

This manuscript is part of a Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy (SOPHIA) project (www.imisophia.eu). SOPHIA has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 875534. This Joint Undertaking support from the European Union′s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, and Obesity Action Coalition.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Harmony outcome trial: The protocol for this study was approved by an independent committee who manage access to clinical trials (https://www.clinicalstudydatarequest.com/). All study participants have provided informed consent. Tayside Bioresource: The study was approved by the Tayside Regional Ethics Committee and informed consent was obtained from all subjects. EMPA-REG OUTCOMES: The EMPA-REG OUTCOME trial was designed and overseen by a steering committee that included academic investigators and employees of Boehringer Ingelheim. The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by local authorities. An independent ethics committee or institutional review board approved the clinical protocol at each participating center. A full list of participating sites and ethics committees can be found at https://www.nejm.org/doi/suppl/10.1056/NEJMoa1504720/suppl_file/nejmoa1504720_appendix.pdf All the patients provided written informed consent before study entry. REWIND: Ethics review boards gave ethical approval for the analysis of REWIND placebo cohort.

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors.