Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study
BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2023-076388 (Published 13 February 2024) Cite this as: BMJ 2024;384:e076388Linked Editorial
Liver steatosis linked to type 2 diabetes outcomes
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To the Editors,
Professor Park and colleagues' recent work highlights an increase in the risk difference of CVD among T2DM patients with NAFLD as compared with non-T2DM subjects based on a large nationwide population [1]. While insightful, concerns arise regarding the analysis and interpretations.
First, as a study addressing CVD risk, the relevant crucial confounders [2] such as the use of antiplatelet drugs, statins, ARBs, β-blockers, and anti-diabetes medications (including SGLT2 inhibitors and GLP-1 receptor agonists), which influence CVD risk, weren't adequately adjusted for. Propensity score matching could be considered to address this in such a large population.
Moreover, it is important to note that even classified in the same Grade, the severity of NAFLD in T2DM patients is higher than in non-T2D patients, as inferred from the higher mean values of TG, BMI, GGT and WC in Table 1 (providing the fatty liver index for each group would be more helpful). This could be attributed to insulin resistance, a cardinal pathophysiological feature of T2DM, which emerges as a significant contributing factor to the severity of NAFLD [3]. However, there is no HOMA-IR data in this study. This presents a situation where two variables :1) the different severity of NAFLD; and 2) with or without T2DM are present in one analysis, making it inconclusive to suggest whether T2DM itself or the severe form of NAFLD in T2DM patients ultimately contributes to the increased risk difference of CVD. If NAFLD indeed could cause an increased risk of CVD in T2DM, the observed increase in CVD risk associated with NAFLD in T2DM may not be directly linked to T2DM itself but rather to the more severe form of NAFLD prevalent in this group.
Given these factors and the fairly large population of T2DM patients, it is still premature to suggest that screening and intervention for NAFLD are required to reduce the CVD risk and all cause mortality in patients with T2DM. Further research, including RCTs and thorough consideration of confounding factors and causal pathways, is warranted to provide more conclusive evidence.
References:
1. Kim, K.-S., Hong, S., Han, K. & Park, C.-Y. Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study. BMJ e076388 (2024) doi:10.1136/bmj-2023-076388.
2. Holman, R. R. et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. The Lancet Diabetes & Endocrinology 5, 877–886 (2017).
3. Huang, D. Q. et al. Shared Mechanisms between Cardiovascular Disease and NAFLD. Semin Liver Dis 42, 455–464 (2022).
Competing interests: No competing interests
Re: Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study
Dear Editor
The recent study by Kyung-Soo Kim et al. [1]offers an extensive examination of a substantial Korean population. However, the potential for generalizing the findings to other populations is limited due to cultural, genetic, and lifestyle differences. [2] The study's design and execution could have greatly benefited from the inclusion of patient and public involvement, which may enhance its relevance and broader acceptance.
Furthermore, a notable omission is that of a cost-effectiveness analysis regarding NAFLD interventions or treatments and their cardiovascular outcomes. Conducting such an analysis would be instrumental in understanding the broader economic and health impacts. [3] Concerns arise from the study's reliance on self-reported data—for example, alcohol consumption and physical activity—due to the potential introduction of biases. Enriching the study with a nuanced exploration of coexisting conditions or multimorbidities and their impact on health outcomes would provide more comprehensive findings.
In terms of statistical analysis, while the study makes adjustments for basic demographic and personal characteristics, a more thorough examination of variable interactions or additional stratified analyses would yield deeper insights into risk dynamics. The study uses a variance inflation factor to assess collinearity; however, elaborating on how collinearity might influence model interpretation could offer significant benefits to the study's analytical depth. [4]
1. Kim KS, Hong S, Han K, Park CY. Association of non-alcoholic fatty liver disease with cardiovascular disease and all-cause death in patients with type 2 diabetes mellitus: nationwide population-based study. BMJ. 2024;384:e076388.
2. Wan B, Caffo B, Vedula SS. A unified framework on generalizability of clinical prediction models. Front Artif Intell. 2022;5:872720:1-13.
3. Albright RH, Fleischer AE. A primer on cost-effectiveness analysis. Clin Podiatr Med Surg. 2023;41(2):313-321.
4. Yoo W, Mayberry R, Bae S, Singh K, He QP, Lillard JW Jr. A study of effects of multicollinearity in the multivariable analysis. Int J Appl Sci Technol. 2014;4(5):9-19.
Competing interests: No competing interests