4 | DISCUSSION
Our study indicated that in people with T2DM and compensated cirrhosis, insulin users showed higher risks of all-cause mortality, cardiovascular events, HCC, decompensated cirrhosis, hepatic failure, and hypoglycemia than insulin nonusers, even after excluding persons with hypoglycemia.
Insulin treatment is frequently used in persons with diabetes and liver cirrhosis. Elkrief et al. reported that of 348 persons with hepatitis C-related cirrhosis, 62% were on insulin therapy [19]. Gentile et al. found that acarbose significantly improved fasting and postprandial glucose levels in 100 persons with compensated cirrhosis and insulin-treated T2DM [20]. They also compared the metabolic profiles of lispro and regular human insulin in persons with diet-unresponsive T2DM and compensated nonalcoholic liver disease and found that lispro caused lower postprandial glucose levels and hypoglycemic rates [6]. Insulin requirements in persons with liver cirrhosis vary; persons with decompensated cirrhosis may need less insulin compared with persons diagnosed as having compensated cirrhosis [5]. Therefore, insulin therapy in people with liver cirrhosis requires close monitoring of blood glucose levels to avoid the risks of hypoglycemia or hyperglycemia. Our study disclosed that the use of insulin was associated with a significantly higher risk of severe hypoglycemia in persons with compensated cirrhosis compared with oral antidiabetic agents.
People with liver cirrhosis have a 5–10 times higher risk of death than the general population [21], and diabetes can increase their mortality risk [22]. Insulin was reported to be associated with a high risk of mortality in persons with T2DM; [23] our study also showed that among persons with compensated liver cirrhosis, insulin users demonstrated a higher risk of all-cause mortality than insulin nonusers. Although hypoglycemia may increase the risk of death, we observed similar results even after excluding persons with hypoglycemia. Moreover, because insulin users in this study showed increased risks of major cardiovascular events, cirrhotic decompensation, and liver failure, these conditions may also increase the risk of death.
People with liver cirrhosis were reported to have a low prevalence of cardiovascular diseases [24], which may be because of their short life expectancy and low levels of clotting factors in their blood. Coexisting T2DM may increase the risk of cardiovascular diseases; however, their prevalence is still lower than that of general population with T2DM only [24]. Insulin therapy was reported to increase the risk of cardiovascular complications in persons with T2DM [8]. Our study also illustrated that insulin use in persons with compensated liver cirrhosis was associated with a higher risk of MACE, and these hazards persisted even after excluding persons with hypoglycemia. Excess exposure to insulin and hyperinsulinemia are thought to increase basal insulin signaling, which can contribute to insulin resistance and cause atherosclerosis [25].
T2DM [5,19,26] and suboptimal glycemic levels [26] in persons with liver cirrhosis were reported to increase the risks of liver-related complications. However, the favorable impact of optimal glycemic management in persons with liver cirrhosis has not been demonstrated yet. Our study compared the progression of cirrhotic complications between insulin users and nonusers with compensated cirrhosis and observed that insulin users seemed to have higher risks of variceal bleeding, ascites, hepatic encephalopathy, and hepatic failure than insulin nonusers. Insulin stimulates adrenergic hormones and releases endothelin-1 [27]. It was reported to have vasoconstrictor effects on isolated arterioles [28], which may increase systemic vascular resistance and portal pressure. Cirrhosis can aggravate insulin resistance and disturb the molecular mechanisms of insulin on hepatocytes. Exogenous insulin and consequent hyperinsulinemia may activate some signaling molecules (such as PHLPP1 and Grb14) and influence hepatocyte apoptosis [29,30]. These factors may exacerbate the progression of liver cirrhosis and hepatic failure.
HCC occurs primarily in persons with cirrhosis, and diabetes can exacerbate this risk [5]. The use of insulin was reported to increase the risk of HCC; [10,26] our study supports this finding because our results showed that insulin users had a higher risk of HCC than insulin nonusers. Through the activation of the insulin-like growth factor signaling pathway, exogenous insulin and hyperinsulinemia may accelerate hepatocarcinogenesis in persons with liver cirrhosis.
This study has some limitations. First, this was a nationwide cohort study using a sample of Chinese ethnicity only; therefore, the results cannot be generalized to other ethnicities. Second, the administrative claims dataset does not have information on body weight, physical activity, alcohol consumption, and cigarette smoking. It does not contain data on blood biochemical and hemoglobin A1C results, which are used to assess the severity of liver cirrhosis and the treatment situation of T2DM. Instead, we used clinical diagnoses to divide persons into those with compensated and decompensated liver cirrhosis and used DCSI and diabetes duration to distinguish the severity of T2DM. We performed propensity score matching to balance critical variables between insulin users and nonusers to maximally reduce the bias from known confounders. However, the above mentioned unmeasured factors may affect our results. Third, because the number of insulin pens is counted instead of units of insulin in insulin prescription in our health system, we cannot accurately calculate the doses of insulin used. The patients’ adherence to prescribed insulin injections or oral antidiabetic drugs also cannot be adequately measured using this health insurance database. Moreover, physicians’ and patients’ preferences for either insulin or oral antidiabetic drugs may be confounders in this study. Finally, a cohort study is always subject to some inevitable bias, and randomized controlled studies are warranted to verify our results.
Although insulin is the recommended treatment for persons with T2DM and liver cirrhosis, few clinical studies have evaluated its long-term effects and safety. In this cohort study, insulin use in people with T2DM and compensated cirrhosis was associated with higher risks of hypoglycemia, cardiovascular events, liver-related complications, and mortality than insulin nonusers. Therefore, in persons with compensated liver cirrhosis, the use of insulin may require special attention.