Introduction

A possible synergistic association between non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) might contribute substantially to cardiovascular (CV) risk in affected patients. This association needs to be explored further on large-scale, using population based, longitudinal studies.

Aim

To evaluate the risk of NAFLD for cardiovascular disease (CVD) and all-cause death in patients with T2DM.

Profile of the Study Participants

Individuals who had participated in the National Health Screening Programme in 2009 (n=7796763) were included in this study.
Based on NAFLD status the study subjects were categorized as:
- No NAFLD: Fatty liver index <30
- Grade 1 NAFLD: 30≤ fatty liver index<60
- Grade 2 NAFLD: Fatty liver index ≥60

Methods

Study Design

A nationwide population-based study conducted in Korea.
Assessments
Anthropometric measures and laboratory measures were evaluated.
General information of the study participants was obtained using standardized questionnaires.

Outcomes

Incident CVD [myocardial infarction (MI), ischemic stroke] or all-cause death
Results
The median follow-up period for the study was 8.13 years. At baseline, 6.49% (n=505763) participants had T2DM; 22.04% had grade 1 NAFLD and 11.11% had grade 2 NAFLD.

The prevalence of grade 1 NAFLD (34.06% vs. 21.2%) and grade 2 NAFLD (26.73% vs. 10.02%) was higher in individuals with T2DM vs. those without T2DM (Fig 1).

Fig. 1: Prevalence of NAFLD in the study participants

The incidence rates of CVD (6.77% vs. 2.24%) and of death (8.38% vs. 2.71%) were higher is individuals with T2DM vs. without T2DM.
The incidence rates for CVD, MI, ischemic stroke, and all-cause death increased in the order of no NAFLD, grade 1 NAFLD, and grade 2 NAFLD, with the incidence rates being higher in individuals with T2DM vs. those without T2DM (Table 1).
The five-year absolute risk for CVD, MI, ischemic stroke, and all-cause death increased in the order of no NAFLD, grade 1 NAFLD, and grade 2 NAFLD in patients without and with T2DM. Particularly, patients with T2DM without NAFLD had a higher five-year absolute risk for CVD, MI, ischemic stroke, and all-cause death vs. patients without T2DM with grade 2 NAFLD (Table 1).

Table 1: Risk of CVD as per T2DM and NAFLD status

Disease and death by NAFLD	Incidence rate*	Adjusted† HR (95% CI)	Five-year absolute risk (95% CI)	Risk Difference (95% CI)
Cardiovascular disease without T2DM
No NAFLD	2.26	1 (ref)	1.03 (1.02 to 1.04)	1 (ref)
Grade 1 NAFLD	3.83	1.23 (1.22 to 1.25)	1.23 (1.22 to 1.25)	0.21 (0.19 to 0.22)
Grade 2 NAFLD	3.77	1.44 (1.42 to 1.47)	1.42 (1.40 to 1.45)	0.40 (0.37 to 0.42)
Cardiovascular disease with T2DM
No NAFLD	8.28	1 (ref)	3.34 (3.27 to 3.41)	1 (ref)
Grade 1 NAFLD	9.19	1.10 (1.07 to 1.13)	3.94 (3.87 to 4.02)	0.61 (0.51 to 0.70)
Grade 2 NAFLD	8.34	1.25 (1.22 to 1.29)	4.66 (4.54 to 4.78)	1.32 (1.17 to 1.47)
MI without T2DM
No NAFLD	0.99	1 (ref)	0.40 (0.40 to 0.41)	1 (ref)
Grade 1 NAFLD	1.74	1.27 (1.24 to 1.29)	0.50 (0.49 to 0.51)	0.10 (0.09 to 0.11)
Grade 2 NAFLD	1.85	1.52 (1.48 to 1.57)	0.60 (0.58 to 0.61)	0.19 (0.18 to 0.21)
MI with T2DM
No NAFLD	3.41	1 (ref)	1.29 (1.24 to 1.33)	1 (ref)
Grade 1 NAFLD	3.79	1.07 (1.03 to 1.12)	1.49 (1.44 to 1.53)	0.20 (0.14 to 0.26)
Grade 2 NAFLD	3.54	1.20 (1.15 to 1.25)	1.73 (1.65 to 1.80)	0.44 (0.35 to 0.53)
Ischemic stroke without T2DM
No NAFLD	1.35	1 (ref)	0.65 (0.64 to 0.66)	1 (ref)
Grade 1 NAFLD	2.22	1.21 (1.19 to 1.24)	0.77 (0.76 to 0.78)	0.12 (0.11 to 0.13)
Grade 2 NAFLD	2.05	1.39 (1.36 to 1.42)	0.87 (0.85 to 0.89)	0.22 (0.20 to 0.24)
Ischemic stroke with T2DM
No NAFLD	5.27	1 (ref)	2.18 (2.13 to 2.24)	1 (ref)
Grade 1 NAFLD	5.79	1.12 (1.08 to 1.15)	2.63 (2.56 to 2.69)	0.44 (0.36 to 0.52)
Grade 2 NAFLD	5.15	1.30 (1.25 to 1.35)	3.16 (3.06 to 3.27)	0.98 (0.85 to 1.10)
All-cause death without T2DM
No NAFLD	3.03	1 (ref)	1.25 (1.24 to 1.26)	1 (ref)
Grade 1 NAFLD	3.90	1.22 (1.21 to 1.24)	1.50 (1.48 to 1.51)	0.25 (0.23 to 0.26)
Grade 2 NAFLD	3.63	1.75 (1.72 to 1.78)	2.09 (2.06 to 2.12)	0.84 (0.81 to 0.87)
All-cause death with T2DM
No NAFLD	11.64	1 (ref)	3.68 (3.61 to 3.74)	1 (ref)
Grade 1 NAFLD	10.14	1.14 (1.12 to 1.17)	4.25 (4.18 to 4.33)	0.58 (0.49 to 0.67)
Grade 2 NAFLD	8.77	1.61 (1.57 to 1.65)	5.91 (5.78 to 6.05)	2.24 (2.08 to 2.39)

*Incidence per 1000 person years.

†Adjusted for age, sex, smoking status, alcohol consumption, physical activity, low income, hypertension, dyslipidemia, body mass index, diabetes mellitus, and estimated glomerular filtration rate.

As per Kaplan Meier analyses presence of NAFLD was associated with a significantly higher risk of CVD, MI, ischemic stroke, and all-cause death in patients with and without T2DM (all P<0.001). The risk was highest in patients with grade 2 NAFLD followed by grade 1 NAFLD.
The incidence rate of CVD for patients with T2DM and no NAFLD in the age group 20-29 years was 0.40 per 1000 person years, but the same was as high as 23.25 per 1000 person years in those aged ≥70 years with T2DM and grade 2 NAFLD. Overall, the hazard ratios (HRs) for CVD, MI, ischemic stroke, and all-cause death were higher in the order of grade 1 NAFLD and grade 2 NAFLD as compared to those for the no NAFLD group in all age groups.
There was an increase in 5-year absolute risk for CVD, MI, ischemic stroke, and all-cause death in the order of no NAFLD, grade 1 NAFLD, and grade 2 NAFLD across all age groups, and the same increased with age. The risk was also higher in patients with T2DM vs. those without T2DM.

Conclusions

NAFLD seemed to increase the risk of CVD and all-cause death in patients with T2DM, even in patients with mild NAFLD.
Patients with T2DM vs. those without T2DM had higher risk differences for CVD and all-cause death between no NAFLD and grade 1 or grade 2 NAFLD.
NAFLD screening and prevention are essential to mitigate the risk of CVD and all-cause death in patients with T2DM.

BMJ 2024;384:e076388http://dx.doi.org/10.1136/bmj‑2023‑076388.