The use of SGLT2 inhibitors in people with type 2 diabetes (T2D) who also have liver cirrhosis led to reductions in the risks for end-stage kidney disease (ESKD), acute kidney injury (AKI), and major adverse cardiovascular events (MACE), new research found.

“This study is one of the largest nationwide cohort analyses to specifically evaluate SGLT2i use in patients with coexisting [T2D] and liver cirrhosis,” said first author Mu-Chi Chung, MD, of the Division of Nephrology and Division of Clinical Toxicology at Taichung Veterans General Hospital in Taichung, Taiwan.

In addition to the significant reductions in the primary outcomes — ESKD, AKI, and MACE events — “we also observed a significant reduction in hepatic decompensation events (35% lower risk), including ascites, peritonitis, and esophageal variceal bleeding,” Chung told Medscape Medical News.

“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,” Chung and colleagues reported in research published recently in JAMA Network Open.

Cardiorenal Benefits Extend to Those With Cirrhosis

T2D and cirrhosis commonly coexist, with nearly a third of patients with cirrhosis having T2D, and those with T2D having about double the risk of developing cirrhosis. 

Both conditions are also associated with increased risks for kidney and cardiovascular complications. Although important cardiorenal benefits of SGLT2 inhibitors have been established in T2D, evidence on whether those benefits extend to patients with cirrhosis is lacking.

To better investigate this question, the authors conducted a retrospective cohort study, evaluating data from Taiwan’s National Health Insurance Database between May 2016 and December 2023. They identified 24,259 patients with T2D and cirrhosis who had initiated treatment with either SGLT2 inhibitors or DPP-4 inhibitors. 

Of the patients, 34% were female, about 40% received SGLT2 inhibitors, and 60% received DPP-4 inhibitors. Their mean age was about 65. 

Importantly, the study included cirrhosis related to all causes, with 20.64% having cirrhosis due to hepatitis B, 15.10% due to hepatitis C, and 6.74% due to alcohol-related liver disease.

For the primary outcomes, after a multivariate adjustment for diabetes duration, age, sex, comorbidities, and concomitant medications, and over a median follow-up of 2.3 years, those treated with SGLT2 inhibitors had significantly reduced risks for ESKD (hazard ratio [HR], 0.34), AKI (HR, 0.66), and MACE (HR, 0.67; all outcomes P < .001). 

Additionally, those treated with SGLT2 inhibitors had a significantly lower risk for all-cause mortality (HR, 0.58) and hepatic decompensation events (HR, 0.65).

The primary outcome results were consistent in a propensity score-matched analysis in which baseline characteristics were well balanced between the groups, including rates of hyperlipidemia or cerebrovascular disease, hepatitis C infection, stroke, and hypoglycemia.

‘Triple Protection’

While previous studies have shown SGLT2 inhibitors to have liver benefits, including reductions in metabolic dysfunction-associated steatotic liver disease, cirrhosis progression, and composite liver-related outcomes, previous concerns about their use in cirrhosis have included “that the natriuretic effects of SGLT2is might exacerbate kidney injury in patients already prone to hepatorenal syndrome or those using heavy diuretics,” Chung noted. 

“However, our data suggest that SGLT2is actually preserve kidney function through reducing AKI and ESRD risk. These findings suggest SGLT2is may mitigate kidney complications in this high-risk population by reducing diuretic-associated kidney injury.”

SGLT2 inhibitors have shown further benefits when combined with GLP-1 receptor agonists, said Chung, and while the current study did not evaluate those combinations, he noted the potential benefits in the context of cirrhosis.

“Given that both classes address shared metabolic and inflammatory pathways, it is plausible that a combination could offer even greater protection against hepatic steatosis and cardiovascular complications in cirrhotic patients,” he said.

“This remains an important area for future prospective research.”

Ultimately, “for clinicians, the key takeaway is that SGLT2is appear to be both safe and highly beneficial for patients with [T2D] and liver cirrhosis,” Chung added.

“They offer a ‘triple protection’ for the heart, kidneys, and liver in a population that previously had very limited evidence-based treatment options.”

Findings Add to Evolving Evidence

Commenting on the study, Mohamed Elsaid, PhD, of the Division of Medical Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, agreed that the study provides important insights into the hepatic effects of SGLT2 inhibitors.

“These findings are very exciting and provide us with new evidence suggesting that SGLT2is retain their cardio- and renal-protective effects in patients with [T2D] and cirrhosis,” he told Medscape Medical News.

“This is very important as patients with cirrhosis are often excluded from clinical trials. It also adds to the current evolving evidence on SGLT2’s hepatic benefits,” he said, noting that “we are still far from conclusive evidence.”

Concerns include that “the majority of evidence we have on the effects of SGLT2is in cirrhosis comes from observational studies, which are prone to bias and confounding.”

“In addition, we lack evidence on SGLT2is’ effects in patients without diabetes, as historical data have been on [T2D], given the clinical indication,” Elsaid pointed out.

Another key question needing investigation is how other T2D drugs compare with SGLT2 inhibitors, he added.

“This is essential, as the use of different comparators has yielded mixed results, especially regarding benefits for hepatic decompensation,” Elsaid explained. 

Encouraging developments include that SGLT2 inhibitors are currently approved across the full heart failure spectrum, regardless of diabetes status, as well as for patients with chronic kidney disease, even in the absence of diabetes, he added.

“Evaluating SGLT2is in those patients, regardless of diabetes status, will provide us with needed evidence on the benefits of SGLT2is in patients with cirrhosis without diabetes.”

Chung and Elsaid had no disclosures to report.