Liver Stiffness Independently Predicts Mortality in Patients With Diabetes

A cohort study published in JAMA Network Open found that liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) independently predicted all-cause mortality in patients with diabetes, even after adjusting for traditional cardiovascular risk factors. The analysis of 4102 adults from the National Health and Nutrition Examination Survey between 2017 and 2018 revealed that LSM outperformed the widely used Fibrosis-4 (FIB-4) index in identifying high-risk patients.¹

Elevated Mortality Risk With Liver Fibrosis

Among 808 patients with diabetes (14.5%) in the cohort, 24 died during a mean follow-up of 23 months. In a multivariable analysis adjusting for coronary artery disease, smoking, hemoglobin A_1C (HbA_1C), and diastolic blood pressure, each 1-kPa increment in LSM was associated with a 6% increase in the hazard of death (adjusted HR, 1.06; 95% CI, 1.04-1.09; P < .001). The coexistence of diabetes with advanced liver fibrosis (LSM of 9.7 kPa or higher) was associated with a 6.41-fold higher adjusted mortality risk compared with absence of both conditions (95% CI, 1.03-39.85; P = .047).¹

Patients with stage 3 fibrosis (LSM, 9.7-19.9 kPa) had a 4.24-fold higher mortality risk (95% CI, 1.03-17.43; P = .046), while those with cirrhosis (LSM, 20 kPa or higher) had an 11.13-fold higher risk compared with patients without clinically significant fibrosis, even after adjusting for age, sex, body mass index (BMI), and HbA_1C (95% CI, 2.14-58.05; P = .007). The combination of uncontrolled diabetes (HbA_1C of 8% or higher) and elevated LSM (8 kPa or higher) was particularly concerning, with an 11.71-fold higher mortality risk (95% CI, 4.47-30.67; P < .001) compared with controlled diabetes and low LSM.¹

Limitations of FIB-4 in Diabetes

Although the FIB-4 index was associated with mortality in univariate analysis, it lost statistical significance after adjusting for other clinical covariates. Among patients with diabetes classified as low risk by FIB-4 (less than 1.30), 24.1% had LSM of 8 kPa or higher, with a mortality rate of 4.0% (95% CI, 1.1%-13.9%) compared with 0.4% in those with negative results on both tests. These patients with elevated LSM despite reassuring FIB-4 values had a 39.36-fold higher mortality risk (95% CI, 4.03-384.74; P = .004) compared with those negative on both tests, highlighting FIB-4’s limitations in this population.¹

Recent studies confirm that FIB-4 underperforms in patients with diabetes and obesity. In a large cohort analysis, diabetes and BMI of 30 kg/m² or higher materially increased the probability of liver stiffness of 8 kPa or higher at a given FIB-4 value. At a FIB-4 of 1.30, the probability of significant fibrosis was substantially higher in individuals with diabetes or obesity compared with those without these risk factors.²

The American Diabetes Association and multiple hepatology societies currently recommend using FIB-4 as a first-line screening tool, followed by VCTE for patients with FIB-4 of 1.30 or higher. However, the JAMA Network Open study suggests this sequential approach may miss high-risk patients in the diabetes population, prompting calls for earlier or more widespread use of VCTE in this group.^1,3,4

VCTE Performance and Clinical Utility

VCTE provides 2 measurements: liver stiffness (expressed in kPa, correlating with fibrosis) and controlled attenuation parameter (CAP, expressed in decibels per meter, correlating with steatosis). In the JAMA Network Open study, LSM was independently associated with mortality in patients with diabetes after adjusting for atherosclerotic cardiovascular disease (ASCVD) risk score. The combination of LSM and ASCVD risk significantly improved mortality risk estimation compared with either measure alone.¹

Multiple guidelines now recommend VCTE as the preferred second-line test following FIB-4. Studies demonstrate that VCTE has high sensitivity and specificity for identifying advanced fibrosis and has prognostic accuracy like liver biopsy for predicting liver-related events. However, access to VCTE remains limited, particularly in rural settings and for patients with Medicaid coverage.^4,5

Guidance for Pharmacists

Pharmacists should recognize liver disease as an underappreciated contributor to mortality risk in patients with diabetes. When reviewing medication profiles for patients with diabetes, pharmacists should inquire about liver disease screening and assessment. Patients who report abnormal liver enzymes or hepatic steatosis on imaging but have not undergone fibrosis assessment may benefit from discussion with their prescriber about FIB-4 calculation or VCTE referral.¹

For patients with known liver fibrosis, pharmacists should prioritize medications with favorable hepatic safety profiles and avoid hepatotoxic agents when possible. Several diabetes medications have demonstrated benefits in metabolic dysfunction–associated steatotic liver disease (MASLD), including pioglitazone, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors. Pharmacists can advocate for preferential use of these agents in patients with concurrent diabetes and liver disease.¹

Pharmacists should also counsel patients on lifestyle modifications that address both diabetes and liver disease. Weight reduction of 7% to 10% can lead to regression of hepatic fibrosis. Alcohol consumption assessment is critical, as even moderate intake may accelerate fibrosis progression in patients with MASLD. Given that the study found lower use of metformin and glucagon-like peptide-1 receptor agonists among deceased patients while they were alive, pharmacists should work to optimize diabetes medication regimens in high-risk individuals.¹

REFERENCES

1. Bril F, Huynh K, Bolla PR. Liver stiffness measurement and all-cause mortality in individuals with diabetes. JAMA Netw Open. 2026;9(3):e260762. doi:10.1001/jamanetworkopen.2026.0762

2. Shaheen AA, Baguley E, Swain MG, et al. Diabetes and obesity reduce FIB-4 accuracy in MASLD referral pathways. JHEP Rep. 2026;8(4):101735. doi:10.1016/j.jhepr.2026.101735

3. Cusi K, Abdelmalek MF, Apovian CM, et al. Metabolic dysfunction-associated steatotic liver disease (MASLD) in people with diabetes: the need for screening and early intervention. A consensus report of the American Diabetes Association. Diabetes Care. 2025;48(7):1057-1082. doi:10.2337/dci24-0094

4. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835. doi:10.1097/HEP.0000000000000323

5. European Association for the Study of the Liver. EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol. 2021;75(3):659-689. doi:10.1016/j.jhep.2021.05.025