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.