We would like to thank Yang et al. (1) for their interest in our recent publication in Diabetes Care (2). Our analysis demonstrated the U-shaped associations between body weight change and major cardiovascular events, including myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, and all-cause death in patients with type 2 diabetes mellitus (T2DM). We also showed that these U-shaped associations were consistently observed in various subgroup analyses according to age, sex, obesity, T2DM duration, and T2DM medication (2).
Since patients with T2DM who had experienced severe weight loss showed more frequent history of chronic obstructive pulmonary disease and cancer than other groups in our data, Yang et al. (1) raised the possibility of confounding effects from comorbidities and suggested additional analysis. In response to this suggestion, we first need to present sensitivity analysis results in which we excluded patients with chronic diseases, including cancer, chronic kidney disease, chronic obstructive pulmonary disease, hyperthyroidism, and peripheral artery disease. In this analysis, we confirmed that both directions of weight change were significantly associated with increased risks in myocardial infarction (hazard ratio [HR] [95% CI] 1.24 [1.15–1.33], 1.11 [1.06–1.15], 1.07 [1.01–1.12], and 1.15 [1.05–1.26] in the severe weight loss, moderate weight loss, moderate weight gain, and severe weight gain groups, respectively), ischemic stroke (HR [95% CI] 1.19 [1.12–1.27], 1.08 [1.04–1.11], 1.09 [1.04–1.14], and 1.27 [1.18–1.36] in the aforementioned order), atrial fibrillation (HR [95% CI] 1.26 [1.17–1.36], 1.09 [1.04–1.13], 1.02 [0.97–1.07], and 1.11 [1.02–1.21] in the same order), heart failure (HR [95% CI] 1.39 [1.32–1.46], 1.13 [1.10–1.16], 1.10 [1.07–1.14], and 1.34 [1.26–1.42] in the same order), and all-cause death (HR [95% CI] 1.64 [1.57–1.70], 1.18 [1.15–1.21], 1.28 [1.24–1.33], and 1.71 [1.63–1.80] in the same order). We acknowledge that we cannot completely exclude the possibility of unmeasured confounding factors, as described in the discussion section of the study published, given the observational nature of the study design (2). Nonetheless, as Yang et al. (1) addressed in their letter, the consistency of U-shaped associations in explorative analyses implies the robustness of the findings. The sensitivity analyses shown in this response letter support our observation.
Yang et al. (1) also mentioned that this study, albeit a large one, could not dispel the necessity for future randomized trials. We definitely agree with the concern and thus already described in our article that randomized controlled trials are the best way to resolve the unanswered question (2). However, it should be considered that large randomized clinical, well-controlled trials demanding either weight gain or weight loss in patients with T2DM are not practically possible and, more importantly, should be unethical. In addition, discriminating intentional and unintentional weight loss is often difficult in real-world clinical practice (3). Taken together, we again would like to emphasize that our article provides valuable information that weight loss in T2DM patients, which is not necessarily induced by intensive care and nutrient management, could be associated with increased risks of major cardiovascular events despite improvement in metabolic profiles.
See accompanying article, p. e187.
Duality of Interest. H.K.K. reports research grants from Johnson & Johnson, Handok Inc., GSK, Daewoong Pharmaceutical, Yuhan Corp., Hanmi Pharmaceutical, Chong Kun Dang Pharmaceutical, Boryung Pharmaceutical, and JW Pharmaceutical. No other potential conflicts of interest relevant to this article were reported.