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Background  There is a controversy over the association between obesity and the risk of renal events in patients with type 2 diabetes mellitus (T2DM). Furthermore, whether body weight (BW) loss following sodium glucose cotransporter 2 inhibitor (SGLT2i) treatment associated with risk of adverse renal events is unknown.    Methods  We used medical data from a multi-center healthcare provider in Taiwan, enrolling 8992 T2DM patients with a baseline/following-up BW data available after around 12 weeks of SGLT2i treatment, from June 1, 2016 to December 31, 2018. Patients were followed up until the occurrence of composite renal outcome (estimated glomerular filtration rate decline > 40% or end-stage kidney disease) or the end of study period, whichever occurred first.    Results  Participants were divided into six baseline BMI categories: < 18.5 (n = 55); 18.5–22.9 (n = 985); 23.0–24.9 (n = 1389); 25.0–29.9 (n = 3941); 30.0–34.9 (n = 1973); and ≥ 35.0 kg/m 2  (n = 649). There were 38.9%, 23.5%, 24.7%, 8.4%, 2.7%, and 1.8% of patients experienced no-BW loss, initial BW loss of 0.0–2.4%, 2.5–4.9%, 5.0–7.4%, 7.5–9.9%, and ≥ 10.0%, associated with SGLT2i treatment, respectively. Compared with patients with normal BMI (BMI: 18.5–22.9 kg/m 2 ), underweight (BMI: < 18.5 kg/m 2 ) was associated with a higher risk of composite renal outcome (adjusted hazard ratio (aHR) [95% confidence intervals (CI)]: 2.17; [1.16–4.04]), whereas pre-obese (BMI: 25.0–29.9 kg/m 2 ) associated with the lowest risk of composite renal outcome (0.52; [0.40–0.68]) after multivariate adjustment. Compared with those without BW loss after SGLT2i treatment, BW loss of 0.0–2.4% (0.55; [0.43–0.70]) and 2.5–4.9% (0.78; [0.63–0.98]) were associated with a lower risk, whereas BW loss ≥ 10.0% associated with a higher risk of composite renal outcome (1.61; [1.06–2.46]) after multivariate adjustment.    Conclusion  A modest BW loss of 0–5% associated with SGLT2i treatment was associated with a favorable renal outcome. Caution should be taken for whom are underweight at baseline or have a pronounced BW loss ≥ 10.0% associated with SGLT2i treatment, which was associated with a worse renal outcome.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12933-021-01361-z.

The risk of consequent nephropathy following initial weight loss in diabetic patients treated with sodium glucose cotransporter 2 inhibitors