BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promising effects on liver histology in phase 2 trials enrolling patients with metabolic dysfunction-associated steatotic liver disease. However, the impact of GLP-1RAs on the long-term risk of major adverse liver-related outcomes (MALOs) remains uncertain.
OBJECTIVE: We performed a meta-analysis of observational cohort studies to quantify the magnitude and direction of the association between GLP-1RA use and MALOs in people with type 2 diabetes (T2D).
DESIGN: We systematically searched eligible cohort studies comparing GLP-1RA new users versus users of other glucose-lowering medications. The primary outcome was the cumulative incidence rates of MALOs. Secondary outcomes included hepatic decompensation events, hepatocellular carcinoma (HCC) and liver-related mortality. Random-effects models were used to calculate incidence rate ratios (IRRs).
RESULTS: 11 retrospective cohort studies with aggregate data on 1 467 220 patients with T2D (647 903 GLP-1RA new users, 819 317 non-users) were included. GLP-1RA use was significantly associated with a lower risk of MALOs (IRR 0.71, 95% CI 0.57 to 0.88) and hepatic decompensation (IRR 0.70, 95% CI 0.52 to 0.94). Association with reduced risk of HCC was also observed (IRR 0.82, 95% CI 0.61 to 1.11). Compared with other antidiabetic medications, GLP-1RAs showed superior effectiveness versus SGLT2 inhibitors in preventing MALOs (IRR 0.93, 95% CI 0.87 to 0.99), versus DPP-4 inhibitors in preventing hepatic decompensation (IRR 0.74, 95% CI 0.66 to 0.83) and versus insulin therapy in preventing HCC (IRR 0.32, 95% CI 0.13 to 0.80).
CONCLUSIONS: GLP-1RA use is associated with a lower risk of liver-related complications and hepatic decompensation in people with T2D. These findings suggest a role of GLP-1RAs in preventing liver-related complications beyond their beneficial cardiometabolic effects.
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Endocrine | |
| Gastroenterology | |
| Internal Medicine |  |
Highly important results of a large patient cohort of MASLD on major adverse liver-related outcomes (MALOs) in patients with type 2 diabetes (T2D) in a meta-analysis involving 1,467,220 patients. Although there are very limited therapeutic options approved for managing MASLD, these kind of emerging evidence enable us to combat this enigmatic disease more effectively in future. The study also underscores the importance of appropriately using newer anti-diabetic agents including GLP-1RA and incretin polyagonists, especially in patients with T2D who have worse prognosis and MALOs. We also need to have more evidence on the combination therapy with GLP-1RA and SGLT-2i group of drugs in MASLD and T2D due to the potential benefits in outcomes due to enhanced weight loss and metabolic outcomes. With the emergence of more RCT-based evidence, we can hope to soon have better therapeutic armamentarium against MASLD including those from ethnic minorities across the globe.
This heterogeneous meta-analysis compares different GP-1RA drugs with other conventional antidiabetic drugs based on observational study results. Despite the high I2 inconsistency of the results, this provides substantive evidence that GLP-1RA is associated with a reduction in risk for developing major liver adverse events, which may help to prioritize using GLP-1RA over other alternatives in patients with MASLD and diabetes.
Clinicians recognize that cardiometabolic complications among patients with diabetes include MASH (metabolic dysfunction-associated steatohepatitis). There is clearly a need for new treatments to address this condition as a way to prevent cirrhosis and its complications. These results suggest such a role for GLP-1 agonists.