Highlights
- SGLT2 inhibitors significantly reduced the risk of Major Adverse Cardiovascular Events (MACE) by 56% compared to sulfonylureas in patients with T2DM and MASLD.
- Compared to thiazolidinediones and DPP-4 inhibitors, SGLT2 inhibitors demonstrated a 39% and 41% lower MACE risk, respectively.
- The risk of cardiovascular mortality was reduced by nearly 80% with SGLT2 inhibitors compared to other OAD classes.
- Mediation analysis indicates that regression of MASLD accounts for approximately 8.7% of the total cardiovascular benefit observed with SGLT2 inhibitors.
Background: The Intersection of Metabolic Liver Disease and Cardiovascular Risk
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has emerged as the most prevalent chronic liver condition worldwide. Its pathophysiological link with type 2 diabetes mellitus (T2DM) is well-established, with the two conditions often co-existing and exacerbating one another. For patients navigating this dual diagnosis, the primary driver of mortality is not typically end-stage liver disease, but rather cardiovascular disease (CVD).
While the management of T2DM has evolved rapidly with the introduction of several oral antidiabetic drug (OAD) classes, the optimal therapeutic strategy for patients who also present with MASLD has remained a subject of clinical debate. Thiazolidinediones (TZDs) have historically been favored for their insulin-sensitizing and liver-specific benefits, whereas sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors offer distinct systemic profiles. Given the heightened cardiovascular vulnerability of this population, identifying which OAD provides the most robust cardioprotection is a critical clinical priority.
Study Design: Emulating a Clinical Trial with Real-World Data
To address this gap, researchers conducted a target trial emulation using the Korean National Health Information Database. Target trial emulation is a sophisticated methodological approach designed to apply the rigors of a randomized controlled trial (RCT) to large-scale observational data, thereby minimizing common biases such as immortal time bias and prevalent user bias.
The study cohort included 71,071 patients with concurrent T2DM and MASLD, defined by a Fatty Liver Index (FLI) of 30 or higher. The study compared four treatment initiations: SGLT2 inhibitors, thiazolidinediones, DPP-4 inhibitors, and sulfonylureas, all typically used in combination with metformin. The primary endpoint was the occurrence of Major Adverse Cardiovascular Events (MACE), a composite of cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke. Over a total of 331,726 person-years of follow-up, the researchers utilized adjusted subdistribution hazard ratios (aSHR) to evaluate outcomes while accounting for competing risks.
Key Findings: Superiority of SGLT2 Inhibitors Across the Board
The results of this nationwide study provide compelling evidence for the cardiovascular superiority of SGLT2 inhibitors in the T2DM-MASLD population. When compared to sulfonylureas, the most traditional comparator in this class, SGLT2 inhibitors were associated with a dramatic reduction in MACE risk (aSHR, 0.44; 95% CI, 0.31-0.62). This finding aligns with broader cardiovascular outcome trials (CVOTs) but highlights the specific efficacy in those with significant hepatic steatosis.
Comparative Efficacy Against Newer OADs
One of the most clinically relevant aspects of this study was the head-to-head comparison of SGLT2 inhibitors against other modern OADs. SGLT2 inhibitors demonstrated a significant advantage over thiazolidinediones (aSHR, 0.61; 95% CI, 0.39-0.96) and DPP-4 inhibitors (aSHR, 0.59; 95% CI, 0.42-0.96). While TZDs are known to improve hepatic histology, this study suggests that the systemic cardiovascular benefits of SGLT2 inhibitors—likely driven by hemodynamic improvements and metabolic reprogramming—outweigh the liver-specific effects of TZDs in terms of hard cardiovascular endpoints.
A Remarkable Impact on Cardiovascular Mortality
The reduction in cardiovascular mortality was perhaps the most striking finding. SGLT2 inhibitors were associated with an 87% lower risk of cardiovascular death compared to sulfonylureas (aSHR, 0.13; 95% CI, 0.03-0.50). Similar significant reductions were observed when compared to TZDs (aSHR, 0.19) and DPP-4 inhibitors (aSHR, 0.22). These data suggest that for patients with MASLD, SGLT2 inhibitors may be life-saving interventions rather than merely glucose-lowering agents.
Mediation Analysis: The Role of Liver Health
A unique feature of this study was the mediation analysis, which sought to determine how much of the cardiovascular benefit was directly attributable to the improvement of MASLD itself. The researchers found that regression of MASLD (as measured by changes in the FLI) accounted for 8.7% of the total cardiovascular benefit when comparing SGLT2 inhibitors to sulfonylureas. While this indicates that the majority of the cardioprotection stems from extra-hepatic mechanisms (such as osmotic diuresis, natriuresis, and reduced cardiac afterload), it also confirms that improving liver health is an integral component of the SGLT2 inhibitor’s therapeutic value.
Expert Commentary: Mechanistic Insights and Clinical Implications
The findings by Jang et al. emphasize a shift toward a more holistic, organ-protective approach in diabetes management. For clinicians, the choice of OAD in a patient with MASLD should no longer be viewed solely through the lens of glycemic control. The systemic nature of MASLD means that these patients are in a constant pro-inflammatory and pro-atherogenic state. SGLT2 inhibitors appear to uniquely interrupt this state.
Mechanistically, SGLT2 inhibitors promote a shift in fuel metabolism from glucose to ketones and fatty acids, which may reduce hepatic lipid accumulation and systemic inflammation. Furthermore, their ability to reduce visceral adiposity and blood pressure provides a multi-pronged defense against MACE. While TZDs remain a valid option for those specifically targeting advanced fibrosis (MASH), the broad cardiovascular protection of SGLT2 inhibitors makes them a formidable first-line choice for the majority of patients with metabolic liver disease.
However, the study is not without limitations. As an observational study, despite the target trial emulation framework, the potential for residual confounding remains. Additionally, the use of the Fatty Liver Index, while validated, is a surrogate marker for hepatic steatosis and does not provide the granularity of a liver biopsy or advanced imaging like MRI-PDFF. Future research should focus on whether these benefits extend to patients with advanced cirrhosis and how SGLT2 inhibitors might interact with emerging GLP-1/GIP receptor agonists in this population.
Conclusion: Shaping the Future of Metabolic Care
The study titled “Outcomes of Oral Antidiabetic Drugs in Metabolic Dysfunction-Associated Steatotic Liver Disease” provides robust evidence that SGLT2 inhibitors should be the preferred OAD for cardiovascular risk reduction in patients with concurrent T2DM and MASLD. By demonstrating superior outcomes over sulfonylureas, DPP-4 inhibitors, and even thiazolidinediones, this research supports a precision medicine approach where the presence of liver steatosis guides the selection of antidiabetic therapy. As clinical guidelines continue to evolve, SGLT2 inhibitors are likely to occupy a more central role in the management of the metabolic-liver-cardiovascular axis.
References
Jang H, Kim Y, Lim YK, Lee DH, Joo SK, Koo B, Lee W, Romeo S, Kim W; Innovative Target Exploration of NAFLD (ITEN) consortium. Outcomes of Oral Antidiabetic Drugs in Metabolic Dysfunction-Associated Steatotic Liver Disease: A Nationwide Target Trial Emulation Study. Clin Mol Hepatol. 2026 Jan 6. doi: 10.3350/cmh.2025.1006. Epub ahead of print. PMID: 41492191.
