Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease

Abstract

Background and Aims In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear. Approach and Results We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti‐DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow‐up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow‐up. Most common treatments were metformin monotherapy (19.7%), metformin‐sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93–0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85–1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7‐fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62–0.78). Conclusions In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Hepatocellular Carcinoma Due to Nonalcoholic Fatty Liver Disease: Current Concepts and Future Challenges

“…Also, duration of DM, level of glycemic control, use of sulfonylureas, or insulin treatment possibly in combination increases the risk of HCC, while metformin has a protective effect on HCC development. 104 , 108 Yang et al demonstrated similar results that DM is associated with increased risk of HCC in NAFLD-related cirrhosis patients. 106 …”

Metformin: A promising drug for human cancers (Review)

“…Studies have found that metformin has weight loss, anti-aging, and anti-cardiovascular effects ( 2 ). In recent years, studies have reported an antitumoral effect of the drug, which has been confirmed in various malignant tumor cells such as liver ( 3 ), ovarian ( 4 ) and lung cancer cells. The present study summarizes knowledge on the anti-tumoral effects of metformin and its mechanism in order to provide evidence for the repurposing of this drug for tumor treatment.…”

Stationäre Patienten mit der Nebendiagnose Diabetes mellitus: klinische Relevanz

“…Neue Befunde zum positiven Einfluss einer guten glykämischen Kontrolle und insbesondere der Therapie mit Metformin, GLP-1-Rezeptor-Agonisten (GLP-1: „glucagon-like peptide 1“) und SGLT-2-Hemmern (SGLT-2: „sodium glucose linked transporter 2“) auf den Verlauf chronischer Lebererkrankungen und das HCC-Risiko haben in der klinischen Praxis noch nicht ausreichend Resonanz gefunden (Tab. 3 , [ 13 , 14 , 32 , 43 , 44 ]). Klinische Bedeutung kommt auch der Tatsache zu, dass bei Leberzirrhose die gemessenen HbA 1c -Spiegel in der Tendenz falsch-niedrig sind und andere mit chronischen Lebererkrankungen, ihren Komplikationen und ihrer Behandlung assoziierte Faktoren die Verlässlichkeit des Screenings und Monitorings von Patienten mit Diabetes und Lebererkrankungen durch HbA 1c -Messung erheblich einschränken.…”

“…NAFLD erhöht das Risiko für Diabetes mellitus Typ 2 abhängig vom Fibrosegrad im Durchschnitt 2,2fach [ 45 ]. Metformin, Glitazone, GLP-1-Rezeptor-Agonisten und SGLT-2-Inhibitoren beeinflussen Parameter der Leberhistologie bei NAFLD positiv [ 32 , 43 , 44 ] Hepatitis C Diabeteshäufigkeit 17,5–38 % Hämochromatose Diabeteshäufigkeit 10,5–22 % Leberzirrhose Diabeteshäufigkeit 37–71 % BMI Body-Mass-Index; GLP‑1 „glucagon like peptide 1“; HCC hepatozelluläres Karzinom; NAFLD nichtalkoholische Fettlebererkrankung; NODM „new-onset diabetes mellitus“; SGLT‑2 „sodium glucose linked transporter 2“ …”