SGLT2 Inhibitors, GLP-1 RAs Show Cardiorenal and Hepatic Benefits in Type 2 Diabetes
New studies show SGLT2 inhibitors and GLP-1 receptor agonists reduce risks of kidney failure, cardiovascular events, and liver complications in patients with type 2 diabetes, with particularly strong benefits in those with cirrhosis.
SGLT2 inhibitors were associated with significantly lower risks of kidney failure, cardiovascular events, mortality, and hepatic decompensation in patients with type 2 diabetes and liver cirrhosis, according to a nationwide retrospective cohort study published in JAMA Network Open. Separately, a systematic review and meta-analysis published in Hepatology revealed that both GLP-1 receptor agonists and SGLT2 inhibitors are associated with lower risks of liver-related events and hepatocellular carcinoma in patients with type 2 diabetes.
The retrospective cohort study used Taiwan's National Health Insurance Database from May 2016 through December 2023. Adults diagnosed with both type 2 diabetes and liver cirrhosis who newly initiated SGLT2 inhibitors (dapagliflozin, empagliflozin, or canagliflozin) or DPP4 inhibitors (alogliptin, linagliptin, sitagliptin, saxagliptin, or vildagliptin) were included. The study included 24,259 patients (mean age, 64.68 years; 33.9% female). Of these patients, 9689 patients (39.9%) received SGLT2 inhibitors and 14,570 (60.1%) received DPP4 inhibitors. Median follow-up was 2.3 years.
Compared with DPP4 inhibitor therapy, SGLT2 inhibitor use was associated with significantly improved outcomes: end-stage kidney disease (adjusted hazard ratio, 0.34; 95% CI, 0.25-0.47), acute kidney injury (adjusted hazard ratio, 0.66; 95% CI, 0.59-0.74), major adverse cardiovascular events (adjusted hazard ratio, 0.67; 95% CI, 0.62-0.71), all-cause mortality (adjusted hazard ratio, 0.58; 95% CI, 0.53-0.63), and hepatic decompensation (adjusted hazard ratio, 0.65; 95% CI, 0.57-0.74). Reductions were also observed across individual cardiovascular end points.
Type 2 diabetes and liver cirrhosis frequently coexist and can worsen one another through shared metabolic and inflammatory pathways. Insulin resistance and chronic hyperglycemia contribute to fat accumulation, fibrosis progression, and portal hypertension, while cirrhosis alters glucose metabolism and can impair insulin clearance, increasing the risk of worsening diabetes control. Patients with both conditions face higher risks of complications, including renal dysfunction, cardiovascular disease, infections, and mortality.
The systematic review and meta-analysis included a total of 36 cohort studies representing over 5.3 million patients with type 2 diabetes mellitus. GLP-1 receptor agonists were associated with a 23% lower risk of hepatocellular carcinoma compared with other glucose-lowering therapies. GLP-1 receptor agonists also reduced non-HCC liver-related events by 21%. SGLT-2 inhibitors showed similar hepatoprotective effects, with significant reductions in both HCC incidence and overall liver-related complications.
Among patients with chronic liver disease, GLP-1 receptor agonists were the only drug class associated with a significant reduction in hepatic decompensation. These findings suggest that GLP-1 receptor agonists may have a protective role in slowing liver disease progression in patients with type 2 diabetes and pre-existing liver conditions.
DPP-4 inhibitors did not confer liver protection; they were not linked to reduced HCC risk and were associated with a higher likelihood of liver-related events compared with other therapies.
The researchers noted that the Taiwan cohort study was observational and cannot establish causality and may be subject to residual confounding despite statistical weighting. Findings were derived from a Taiwanese population, which may limit generalizability to other health systems and demographic groups. Additionally, detailed clinical measures such as cirrhosis severity, laboratory parameters, and lifestyle factors were not fully captured.
"This cohort study provides new evidence supporting the use of SGLT2 inhibitors in patients with type 2 diabetes and liver cirrhosis, demonstrating significant associations with reductions in the risks of end-stage kidney disease, acute kidney injury, and major adverse cardiovascular events, as well as hepatic decompensation events," the study authors wrote. "Importantly, these protective associations were consistent across the full spectrum of cirrhosis causes, including viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis, and remained robust after multivariable adjustment."