Researchers from the Sant Pau Research Institute (IR Sant Pau) have conducted a clinical trial demonstrating that the combination of two widely available drugs, carvedilol and simvastatin, significantly improves the control of portal hypertension in patients with hepatic cirrhosis.
The study, published in the scientific journal Hepatology, lists Dr. Edilmar Alvarado and Dr. Anna Brujats as first authors and Dr. Cándido Villanueva as senior author. All of them are investigators of the Digestive Pathology group at IR Sant Pau and hepatologists at Hospital de Sant Pau. The collaborating team also includes researchers from the hepatology group at Hospital Sant Pau—Dr. Berta Cuyás, Dr. María Poca, Dr. Xavier Torras, and Dr. Angels Escorsell, among others—researchers in experimental immunology—Dr. E. Cantó—pharmacy—Ainhoa Rodríguez Arias—and biochemistry—Álvaro García-Osuna.
The research stems from a clear clinical need: to find new strategies capable of effectively reducing portal pressure in people with advanced cirrhosis. According to Dr. Alvarado, “These patients continue to have a very high risk of gastrointestinal bleeding, among other complications of portal hypertension, even with standard treatment, and we needed to explore simple options that could improve their prognosis.”
Cirrhosis is a disease in which the liver gradually becomes hardened and scarred, hindering the flow of blood through it. As a result, the blood arriving from the digestive tract via the portal vein encounters more resistance as it passes through the liver, and pressure in this major vessel rises abnormally. This phenomenon, known as portal hypertension, is one of the main drivers of complications in advanced liver disease.
When portal pressure becomes too high, dilated veins form in the esophagus and stomach—the so-called varices—which are extremely fragile and can rupture, causing potentially life-threatening gastrointestinal bleeding. Portal hypertension also contributes to the accumulation of fluid in the abdomen (ascites) and to kidney problems. Reducing it significantly has proven crucial for improving survival and quality of life in these patients.
In clinical practice, this pressure is measured through the hepatic venous pressure gradient (HVPG), a procedure that reliably quantifies the severity of portal hypertension and helps determine whether a pharmacologic treatment is effective.
To prevent gastrointestinal bleeding, nonselective beta-blockers such as propranolol or nadolol have been used for decades, as they reduce the amount of blood reaching the liver. However, in many patients these drugs do not sufficiently lower portal pressure.
Recently, carvedilol has proved more effective because, in addition to blocking beta-receptors, it also acts on alpha-1 receptors in blood vessels. This dual action causes greater relaxation of intrahepatic vessels, more effectively reducing resistance to blood flow.
Still, in a substantial proportion of patients treated only with carvedilol, the goal of lowering portal pressure is not achieved. Dr. Alvarado explains the team’s reasoning: “We knew that statins could improve blood vessel function and reduce inflammation in the liver. We thought that administering a statin alongside carvedilol could create a complementary effect and increase treatment efficacy by further reducing portal pressure.”
Although several statins are available, simvastatin was chosen because it has the most prior research in cirrhosis, where it had shown the ability to improve liver blood vessel function safely.
With this hypothesis, the Sant Pau team launched a randomized, double-blind, placebo-controlled clinical trial. A total of 82 patients with advanced cirrhosis and high-risk varices were recruited, all of whom had shown an insufficient response to traditional beta-blockers.
First, the researchers confirmed that portal pressure had not decreased adequately with standard treatments. From that point on, all patients started taking carvedilol, and were then randomly assigned to receive either simvastatin or a placebo for 4 to 6 weeks, without doctors or patients knowing who received which treatment.
The impact of treatment was measured through HVPG. In addition, the researchers took measurements after a nutritional supplement, a moment when portal pressure typically increases and bleeding risk intensifies, to determine whether the combination could better blunt this effect. Blood samples were also collected to analyze inflammatory cytokines and oxidative stress markers, to assess whether the benefits extended beyond portal pressure reduction.
“We designed the study with real-life patient situations in mind—from the impact of meals to the inflammatory processes that accompany cirrhosis,” Dr. Alvarado explains.
The results confirmed the initial hypothesis. Carvedilol alone and in combination with simvastatin both reduced portal pressure, but the decrease was significantly greater in the group receiving the two drugs. In absolute terms, HVPG fell from 18.6 to 15.7 mmHg with the combination (versus a reduction from 18.9 to 16.9 mmHg with placebo).
Additionally, 37% of patients treated with carvedilol plus simvastatin achieved a clinically meaningful pressure reduction (≥ 20%), compared with only 15% in the control group. The combination also blunted the increase in portal pressure after the nutritional supplement (12% versus 23%) and more strongly reduced several inflammatory blood markers. All of this occurred with good tolerance and a similar incidence of adverse events in both groups.
For Dr. Alvarado, these findings are promising: “This is a simple strategy using inexpensive, widely available drugs that could have a real impact on preventing decompensations associated with portal hypertension.”
This study opens the door to new therapeutic strategies in cirrhosis. Larger trials will be needed to confirm these results and to assess long-term effects on bleeding prevention and patient survival. But, as Dr. Alvarado concludes, “We have shown that even with well-known treatments, if we combine them effectively, we can take a meaningful step forward in caring for patients with cirrhosis.”
Alvarado-Tapias E, Brujats A, Puente A, Ardevol A, Rodriguez-Arias A, Fajardo J, Pavel O, Garcia-Guix M, Aracil C, Poca M, Cuyàs B, Cantó E, Montañés R, Garcia-Osuna A, Escorsell À, Torras X, Villanueva C. Hemodynamic effects of carvedilol plus simvastatin in cirrhosis with severe portal hypertension and suboptimal response to β-blockers: A double-blind, placebo-controlled, randomized trial. Hepatology 2025;82:140–54. <a href=”https://doi.org/10.1097/HEP.0000000000001148″>https://doi.org/10.1097/HEP.0000000000001148
