Statins Reduce Risk of Hepatocellular Carcinoma

Statin use substantially reduces the risk of hepatocellular carcinoma (HCC) and should be considered as a standard of care in patients at high risk for the disease, according to the results of a systematic medical literature review and meta-analysis conducted by Cleveland Clinic investigators.

Their findings were presented at the American College of Gastroenterology’s (ACG) 2019 annual meeting.

“Our review included 20 studies from Asia, Europe and the United States that represented more than 2.6 million patients,” says gastroenterologist Carlos Romero-Marrero, MD, the study’s principal author. “We found that patients who were taking statins were 43% less likely to develop HCC. Given this finding, statins should be considered as preventive therapy in patients at high risk of HCC.”

Probing the association between statin use and HCC risk

Hepatocellular carcinoma is the most common type of primary liver cancer and the fourth leading cause of cancer-related death globally, accounting for nearly one million fatalities per year. HCC results from chronic, DNA-damaging and gene-mutating liver inflammation, most often due to hepatitis B or C viral infections, alcohol abuse or nonalcoholic fatty liver disease.

The incidence of HCC in the U.S. has been on the rise in recent decades, a trend that mirrors the increasing incidence of end-stage liver disease related to hepatitis C infection, alcohol abuse and nonalcoholic steatohepatitis.

Although strides have been made in early detection and treatment of many cancers, the management of HCC patients is complicated by the fact that most present with advanced disease at diagnosis.

“For many cancers, early identification and screening of the at-risk population has improved the early detection rates, and by incorporating treatment early, we have increased patient survival,” says Dr. Romero-Marrero. “But the truth is that the vast majority [~70%] of HCC cases present at a later stage, when treatment is no longer effective.”

The three-year cost of care for a U.S. patient with HCC has been estimated at more than $150,000.

In addition to statins’ well-documented ability to reduce lipid levels, making them a cardioprotective staple, they are known to have proapoptotic, antiangiogenic, antiproliferative and immunomodulatory effects, suggesting a possible role in cancer prevention. In the last two decades, there has been considerable research investigating statins’ potential impact on HCC risk, but variables in approach and outcome reporting among observational and randomized controlled trials have made it difficult to draw firm conclusions.

The current study aimed to synthesize and clarify the existing evidence regarding a statin/HCC association by examining high-quality published through May 2019.

A total of 20 studies — three randomized controlled trials, six cohorts and 11 case-controls — representing 2,668,497 patients, of whom 24,341 had HCC, were included in the meta-analysis. The studies were selected for review either because they presented an odds ratio (OR) with a 95% confidence interval (CI) or included data from which an OR with a 95% CI could be calculated. The meta-review’s limitations included inconsistencies in controlling for confounding factors, such as various HCC risk factors, and lack of details on statin therapy dosage and duration in most studies.

The analysis found a significant reduction of HCC risk among statin users (43% overall) compared to non-statin users (pooled OR 0.573 [95% CI: 0.491 – 0.668, P<0.05, I2= 86.57%]). In studies performed in Asia, Europe, and the U.S., statin use was associated with 48%, 29% and 46% risk reductions, respectively.

The means by which statins confer the HCC-protective effect are unclear. Hypotheses include statins’ ability to inhibit:

• Mevalonate synthesis, which may reduce the growth and proliferation of neoplastic cells, disrupt the growth of malignant cells and increase apoptosis.
• Hepatitis C viral RNA replication.
• Inflammation and angiogenesis.

Dr. Romero-Marrero notes that this is the first meta-analysis that incorporated studies from Asia (nine), Europe (six) and North America (five), “which helped us eliminate the possibility of geographical bias and made the association [between statin use and HCC] more universal.”

Redefining statin safety in patients with liver disease

Patients at high risk of developing HCC are those with liver cirrhosis from any cause, as well as patients with hemochromatosis, hepatitis B or advanced liver fibrosis related to hepatitis C, Dr. Romero-Marrero says. In patients with chronic liver disease, statin use traditionally has been considered unsafe because of the drugs’ potential to elevate liver-associated enzymes and cause liver injury, but the results of recent studies are redefining this position.

“We now have extensive data showing that patients with chronic liver disease tolerate statins reasonably well, and that patients who take statins not only decrease their risk of liver cancer but also have improved survival and decreased risk of portal hypertension-related complications,” says Dr. Romero-Marrero. “So what the patients need to know is that there’s a protective role of statins against liver cancer. We strongly feel that patients with cirrhosis and chronic liver disease should discuss with their doctors whether statin therapy is appropriate for them.”

Optimal statin dosage still undefined

According to Dr. Romero-Marrero, several unknowns remain about the protective effects of statins against HCC, including the effects of various individual statins and their optimal dosages. The meta-analysis found that as the daily statin dose increased, the chances of HCC development decreased significantly. This could indicate that higher doses provide stronger protection, the researchers say.

“What we still don’t know is whether the effect is similar with different statins, and what exact dosages of statins confer this decreased risk,” he says.

Prospective studies need to be conducted to answer some of these important questions, he adds, “but even in the absence of prospective studies, our data is strong enough to highly consider the use of statins in patients at high risk for HCC.”