Metformin, Statins May Reduce Hepatocellular Carcinoma Risk After HCV Treatment Failure

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Findings from a recent study are providing insight into the potential protective effect of metformin and statins for reducing hepatocellular carcinoma (HCC) risk among patients with chronic hepatitis C virus (HCV) who fail antiviral therapy.¹

Study results were published in Clinical and Molecular Hepatology and showed patients with diabetes using metformin and patients with hyperlipidemia using statins who failed HCV interferon-based therapy had a lower risk of developing HCC.¹

The most common type of primary liver cancer, HCC occurs most frequently in people with chronic liver diseases, including cirrhosis caused by HCV infection.² Although direct-acting antivirals (DAAs) can cure more than 95% of HCV cases, some patients do not respond to treatment and remain susceptible to health risks posed by their infection.³

“Although the chemopreventive effects of metformin in patients with diabetes and statins in patients with hyperlipidemia reduce the risk of HCC in patients with CHC, which has been proven after achieving SVR, the impact on HCC risk reduction remains unclear in patients with CHC who have failed antiviral therapy,” Pei-Chien Tsai, of the department of internal medicine at Kaohsiung Medical University Hospital in Taiwan, and colleagues wrote.¹

To investigate the effects of metformin and statins on HCC risk, investigators collected data from the Taiwanese Chronic Hepatitis C Cohort (T-COACH) for patients ≥ 20 years of age who were diagnosed with chronic HCV through liver histology or by testing positive for anti-HCV or HCV RNA for > 6 months and had undergone antiviral interferon-based therapy for ≥ 4 weeks. The final analysis included 2779 patients.¹

Investigators classified patients as having diabetes if they had a history of diabetes on treatment with oral hypoglycemic agents with or without insulin, fasting glucose ≥ 126 mg/dL, or 2-hr plasma glucose ≥ 200 mg/dL. Patients who had taken metformin for ≥ 84 days were considered metformin users.¹

Participants were considered to have hyperlipidemia if they had a history of hyperlipidemia and used medication. Diagnosed hyperlipidemia statin users were defined as patients with a hyperlipidemia diagnosis who had taken statins for ≥ 84 days.¹

New-onset HCC was defined as HCC occurring in patients 1.5 years after the end of antiviral treatment, with follow-up continuing until HCC occurrence, death, liver transplantation, or the end of the study period on December 31, 2019.¹

Among the entire study population, the mean age was 56.1 years, 52.7% of patients were female, and 63.1% were infected with HCV genotype 1. Additionally, 22.3% of patients had diabetes and 21.8% had hyperlipidemia. Among the patients with diabetes, 53.5% were metformin users. Among patients with hyperlipidemia, 82.5% were statin users.¹

Overall, 238 (8.6%) patients died before the development of HCC and 480 (17.3%) developed new-onset HCC during a total of 18,668 person-years of follow-up. The annual incidence of HCC was 257.1 cases per 10,000 person-years.¹

Investigators noted HCC risk was significantly greater among metformin non-users than in metformin users (adjusted sub-distribution hazard ratio [aSHR], 1.59; 95% CI, 1.07-2.36; P = .022) and in patients without diabetes (aSHR, 1.51; 95% CI, 1.12-2.04; P = .007). However, there was no difference in HCC risk between metformin users and patients without diabetes (aSHR, 1.05; 95% CI, 0.76-1.44; P = .763).¹

Additionally, investigators pointed out patients with hyperlipidemia using statins had a significantly lower HCC risk than patients without hyperlipidemia (3.8% vs 12.5%; aSHR, 0.50; P <.001), but there was no difference compared to patients who were statin non-users.¹

Of note, the unfavorable effect of non-metformin use on HCC risk was primarily observed among patients without cirrhosis. However, the favorable effect of statins for reduced risk of HCC was present in patients with and without cirrhosis.¹

Investigators were careful to outline several potential limitations to these findings, pertaining mainly to the lack of consideration for specific details about metformin and statin use, no differentiation between the effects of lipophilic and hydrophilic statins, potential influence of other oral hypoglycemic agents, and inability to account for differences in interferon preparations.¹

“Our research offers significant insights in the era of DAAs for a small subset of patients who do not achieve SVR with DAAs, are non-compliant with treatment, or have contraindications to DAAs,” investigators concluded.1 “Additionally, this study on the chemopreventive effects of metformin and statins on HCC risk could serve as a benchmark for future research on the long-term risk of HCC among HCV patients and other patients with active liver diseases.”

References:

1. ^{Tsai PC, Huang CF, Yeh ML, et al. Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy. Clin Mol Hepatol. doi:https://doi.org/10.3350/cmh.2024.0038}
2. ^{Mayo Clinic. Liver Cancer. Diseases & Conditions. April 28, 2023. Accessed May 2, 2024. https://www.mayoclinic.org/diseases-conditions/hepatocellular-carcinoma/cdc-20354552}
3. ^{World Health Organization. Hepatitis C. Newsroom. April 9, 2024. Accessed May 2, 2024. https://www.who.int/news-room/fact-sheets/detail/hepatitis-c}