SGLT2 Inhibition Promising for Patients With Cirrhosis and on Diuretics

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.