Aims/hypothesis: For individuals with prediabetes, the current American Diabetes Association (ADA) guidelines recommend a body weight loss >7% to prevent the development of type 2 diabetes (T2D) without any glycemic target goals. However, we have recently shown that weight loss induced prediabetes remission reduces relative T2D risk by 73% within the following two years. Therefore, we investigated relative T2D risk reduction in people with weight loss vs those with weight loss and prediabetes remission in an independent cohort: the randomized controlled Diabetes Prevention Program (DPP). Methods: Individuals who lost >7% of their body weight over the first year were included in this analysis. Of these, 416 were assigned to intensive lifestyle intervention and 64 received placebo. Remission of prediabetes was defined by normalization of fasting and 2h glucose during an oral glucose tolerance test and a normalized HbA1c according to ADA criteria. Non-remission was given when at least one of these criteria was not met. We computed Kaplan-Meier curves and compared them using log-rank tests and future T2D risk was assessed by computing the relative risk between groups. Results: In DPP, 480 individuals achieved a weight loss of >7% and of these 114 additionally achieved prediabetes remission. Over the period of 6 years, those who achieved weight loss and remission had a 66% lower relative risk to develop T2D compared to those who only met the 7% weight loss goal [RR=0.34, 95% CI (0.15, 0.76)]. Similarly, weight loss responders had a lower relative future T2D risk compared to weight loss non-responders [RR=0.28, 95% CI (0.13, 0.64)]. Importantly, there was not a single T2D case in weight loss responders for up to 4 years after the intervention. Conclusions/interpretation: The combination of achieving weight loss goals and prediabetes remission is most effective in reducing future T2D risk. Thus, beside weight loss goals, interventions in individuals with prediabetes should be continued until prediabetes remission is achieved and this ought to be adapted in current clinical praxis guidelines.

ALB received lecture / advisory board fees from Bayer; lecture fees from NovoNordisk, Boehringer Ingelheim, Daiichi Sankyo, Lilly paid to University Hospital Tübingen: ALB is co-founder of Eternygen GmbH

The analysis for this paper was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). DPP was supported by NIDDK and other agencies. German Federal Ministry for Education and Research (01GI0925) via the German Center for Diabetes Research (DZD e.V.); Ministry of Science, Research and the Arts Baden-Württemberg; Helmholtz Munich. ALB was supported by a research grant from the German Research Foundation (GRK2816; BI 1292/9-1; BI 1292/10-1; BI1292/ 12-1). RJvS was funded by Helmholtz Munich and the Helmholtz Association via a Helmholtz Young Investigator Group (VH-NG-1619) and by the Cluster of Excellence (EXC-2124/1-03.007). The study funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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:

The study used data of DPP which can be requested here: https://repository.niddk.nih.gov/studies/dpp/

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

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

Yes

In general data of the DPP cohort can be requested from the Diabetes Prevention Program website.