1051
SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS ASSOCIATED WITH LOWER RISK OF HEPATOCELLULAR CARCINOMA AND HEPATIC DECOMPENSATION IN TYPE 2 DIABETES MELLITUS
Date
May 21, 2024
Background: Epidemiological data on the use of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and hepatocellular carcinoma (HCC) are limited. We aimed to investigate the association of SGLT-2i use with HCC and hepatic decompensation in patients with diabetes mellitus (DM).
Methods: This was a retrospective cohort study of adult patients with newly diagnosed type 2 DM (T2DM) (hemoglobin A1c ≥6.5% or fasting plasma glucose of ≥7mmol/L) based on a territory-wide electronic healthcare database in Hong Kong between 2000 and 2014. The primary outcome was HCC development. The secondary outcome was hepatic decompensation, which was defined as occurence of ascites, variceal bleeding, hepatic encephalopathy, and/or hepatorenal syndrome. The primary exposure was SGLT-2i use (including empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin), defined as medication use within 6 months from the index date, and was treated as a time-varying variable by identifying drug use at each yearly interval of the follow-up period to address potential immortal time bias. Patients were followed from index date (i.e. DM diagnosis) till occurrence of outcomes, liver transplantation, death or end of study (December 2022). Exclusion criteria were prior HCC, liver transplantation and human immunodeficiency virus infection. Multivariable Cox proportional hazards model was used to derive the adjusted hazard ratios (HRs) of the outcomes with SGLT-2i use by adjusting for 24 covariates including age, sex, diabetic complications, body mass index, smoking, alcoholism, HbA1c, dyslipidemia, diabetic complications, liver-related disorders (chronic hepatitis B and C infection, and liver cirrhosis), other comorbidities, and concomitant use of medications (Table 1). Dose-response relationship was investigated in terms of cumulative defined daily dose (cDDD).
Results: There were 272,291 eligible subjects (mean age: 58.7+/-11.6 years; male:143,264 [52.6%]), and 34,050 (12.5%) were SGLT-2i users (Table 1). During a median follow-up of 11.7 years (IQR:9.6-15.4), there were 2,737 (1.0%) and 4,901 (1.8%) cases of HCC and hepatic decompensation, respectively. The aHR of HCC with SGLT-2i use was 0.69 (95%CI: 0.53-0.90). Compared with SGLT-2i ≤30 cDDD, the aHRs of HCC were 0.49 (95%CI 0.32-0.76), 0.44 (95%CI 0.37-0.52), and 0.49 (95%CI 0.35-0.69) for SGLT-2i 31-90, 91-180, and >180 cDDD, respectively (p-trend <0.001). The aHR of hepatic decompensation with SGLT-2i use was 0.50 (95%CI: 0.40-0.63). Compared with SGLT-2i ≤30 cDDD, the aHRs of hepatic decomopensation were 0.56 (95%CI 0.43-0.74), 0.38 (95%CI 0.33-0.43), and 0.41 (95%CI 0.32-0.54) for SGLT-2i 31-90, 91-180, and >180 cDDD, respectively (p-trend <0.001).
Conclusion: SGLT-2i use was associated with lower risk of HCC and hepatic decompensation with a dose-response relationship among T2DM patients.
Methods: This was a retrospective cohort study of adult patients with newly diagnosed type 2 DM (T2DM) (hemoglobin A1c ≥6.5% or fasting plasma glucose of ≥7mmol/L) based on a territory-wide electronic healthcare database in Hong Kong between 2000 and 2014. The primary outcome was HCC development. The secondary outcome was hepatic decompensation, which was defined as occurence of ascites, variceal bleeding, hepatic encephalopathy, and/or hepatorenal syndrome. The primary exposure was SGLT-2i use (including empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin), defined as medication use within 6 months from the index date, and was treated as a time-varying variable by identifying drug use at each yearly interval of the follow-up period to address potential immortal time bias. Patients were followed from index date (i.e. DM diagnosis) till occurrence of outcomes, liver transplantation, death or end of study (December 2022). Exclusion criteria were prior HCC, liver transplantation and human immunodeficiency virus infection. Multivariable Cox proportional hazards model was used to derive the adjusted hazard ratios (HRs) of the outcomes with SGLT-2i use by adjusting for 24 covariates including age, sex, diabetic complications, body mass index, smoking, alcoholism, HbA1c, dyslipidemia, diabetic complications, liver-related disorders (chronic hepatitis B and C infection, and liver cirrhosis), other comorbidities, and concomitant use of medications (Table 1). Dose-response relationship was investigated in terms of cumulative defined daily dose (cDDD).
Results: There were 272,291 eligible subjects (mean age: 58.7+/-11.6 years; male:143,264 [52.6%]), and 34,050 (12.5%) were SGLT-2i users (Table 1). During a median follow-up of 11.7 years (IQR:9.6-15.4), there were 2,737 (1.0%) and 4,901 (1.8%) cases of HCC and hepatic decompensation, respectively. The aHR of HCC with SGLT-2i use was 0.69 (95%CI: 0.53-0.90). Compared with SGLT-2i ≤30 cDDD, the aHRs of HCC were 0.49 (95%CI 0.32-0.76), 0.44 (95%CI 0.37-0.52), and 0.49 (95%CI 0.35-0.69) for SGLT-2i 31-90, 91-180, and >180 cDDD, respectively (p-trend <0.001). The aHR of hepatic decompensation with SGLT-2i use was 0.50 (95%CI: 0.40-0.63). Compared with SGLT-2i ≤30 cDDD, the aHRs of hepatic decomopensation were 0.56 (95%CI 0.43-0.74), 0.38 (95%CI 0.33-0.43), and 0.41 (95%CI 0.32-0.54) for SGLT-2i 31-90, 91-180, and >180 cDDD, respectively (p-trend <0.001).
Conclusion: SGLT-2i use was associated with lower risk of HCC and hepatic decompensation with a dose-response relationship among T2DM patients.
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