Primary Care Corner with Geoffrey Modest MD: Statin Use Lowers Cirrhosis Risk in Hep B

By Dr. Geoffrey Modest

A new study looked at a large number of patients with chronic hepatitis B (CHB) who were on a statin, finding improved hep B outcomes (see Huang Y. Am J Gasstroenterol 2016). This blog follows a recent one I sent out: see https://stg-blogs.bmj.com/bmjebmspotlight/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ , which reviewed a recent study showing statin benefit in those with hepatitis c, also comments on the benefit of statins in NAFLD, and mentions that the data on hep B is more mixed. Details of the current study from Taiwan, where 15-20% of the population has CHB, half of which is by perinatal transmission:

• Population-based cohort study in Taiwan, with 298,761 patients with chronic hepatitis B (but without concomitant hep C, biliary cirrhosis, or alcoholic liver disease) and 6,543 on statins
• Mean age 50, 53% male, 5 year follow-up on cirrhosis and same for decompensated cirrhosis, more comorbidities in the non-statin group (including more cardiovascular and pulmonary diseases)
• Compared on 1:1 ratio with non-statin taking patients, with propensity scoring (to mathematically attempt to eliminate confounders). Also controlled for “inception point” of when statins started, to make sure that the comparisons between patients happened at the same approx time (to decrease likelihood that they were treated differently because of treatment changes over time)

Results:

• Those on statins had:
  • 57% lower risk of developing cirrhosis [RR=0.43 (0.34-0.52, p<0.001)]: in 30,000 person-years of follow-up, 173 of those on statins developed cirrhosis (incidence rate 0.561/100 person-years), vs 400 not on statins (1.338/100 person-years)
  • 53% lower risk of developing decompensated cirrhosis [RR=0.47 (0.34-0.64, p<0.001)]: in 30,000 person-years of follow-up, 59 on those of statins developed decompensated cirrhosis (incidence rate 0.190/100 person-years), vs 126 not on statins (0.411/100 person-years)
  • Adjusted for age, gender, comorbidity index (which includes MI, CHF, PVD, rheumatic disease, chronic pulmonary disease, dementia, renal disease, cancers, HIV), hypertension, diabetes, hyperlipidemia, hepatocellullar carcinoma, obesity, NAFLD, aspirin use, diabetes medication, CHB treatment, non-statin lipid meds, and triglyceride meds: those on statins had
    • 49% lower risk  of developing cirrhosis [RR=0.51 (0.41-0.63, p<0.001)]
    • 47% lower risk of developing decompensated cirrhosis [RR=0.53 (0.43-0.66, p<0.001)]
  • In looking at the length of time taking statins, there was a dose response for the adjusted hazard ratios:
    • Cirrhosis
      • 15% lower if statin use 28-90 days (nonsignificant)
      • 53% lower if 91-365 days (p<0.001)
      • 80% lower if >365 days (p<0.001)
    • Decompensated cirrhosis
      • 7% lower if statin use 28-90 days (nonsignificant)
      • 39% lower if 91-365 days (borderline significant  at p=0.053)
      • 77% lower if >365 days (p=0.001)
    • The Kaplan-Meyer curves for both of the above showed widening curves over 12 years, with the major divergence in the first 6 years of follow-up
  • Also, overall mortality over 12 years of follow-up was lower in those on statins (13% vs 17%, with p<0.001)

Commentary:

• The reason I bring up this article is that I still hear clinicians who feel that it is dangerous to prescribe statins in those with underlying chronic liver disease. As mentioned in the prior blog noted above, there are some reassuring data for NAFLD and Hep C. This huge trial, I think, pretty clearly adds Hep B to the mix. Although these are mostly retrospective/observational studies, and therefore not rock-solid RCTs, they pretty much show that statins at least are not harmful to an already-inflamed liver, and may well be beneficial. Of course, with observational studies, there always is the issue of unequal treatment in the different groups (were those on statins perceived to be less sick with their CHB and therefore getting more aggressive cardiovascular treatment??), but the use of propensity-matched scoring for lots of potential confounders and making sure that people were compared during the same time-frame (to minimize differences in overall treatment during differing time periods) do strengthen the conclusions.
• There is reasonable biologic plausibility: studies have shown that simvastatin lowers portal pressure in patients with cirrhosis, and improves portal hypertension and sinusoidal endothelial dysfunction in rats (presumably by increasing nitric oxide and decreasing hepatic vascular resistance). And reduction in portal pressure correlates with protection from complications from cirrhosis. Also statins seem to inhibit fibrosis through several mechanisms (e.g. decreasing procollagen I and a-smooth muscle actin, connective tissue growth factor, etc.) and may directly decrease hepatitis B viral replication
• The dose-response curve (the longer on statins, the more protective) also strengthens the likely conclusion that statins are protective against disease progression
• And statins may be particularly useful in those with chronic inflammatory conditions such as hepatitis, since these patients are more predisposed to cardiovascular disease
• So, it seems to me, that for the major international causes of chronic liver disease (hep B, hep C, NAFLD), we should not hold off using statins for fear of increasing the liver problems. That being said, I do check and follow liver function tests a bit more closely, though I have never found any problems in these patient groups.