Treatment of severe hypertriglyceridaemia – Authors' reply

Abstract

Authors’ reply In their Correspondence, David Preiss and colleagues point out the challenges involved in proposal of clinical recommendations when highgrade evidence from randomised controlled trials is not available. Here, the issue is whether statins or fi brates should be used as fi rst-line treatment to prevent pancreatitis in patients with severe hypertriglyceridaemia (defi ned as triglyceride concentrations >10 mmol/L). One approach, as adopted by Preiss and colleagues, is to extrapolate data from randomised controlled trials done in other populations, specifically results from their important metaanalysis of 21 statin trials and seven fibrate trials, which show that statins reduced pancreatitis risk by about 25% and that fi brates had no effect. However, this meta-analysis essentially excluded patients with severe hypertriglyceridaemia— the overa l l mean basel ine triglyceride concentration across individuals in these trials was about 1·8 mmol/L, with upperlimit exclusion concentrations between 2·5 and 6·8 mmol/L. As would be expected, the largely normotriglyceridaemic cohorts had a low 5 year incidence of pancreatitis— pancreatitis occurred in roughly one (0·27%) of 370 patients in the statin trials and roughly one (0·35%) of 280 patients in the fi brate trials. The reduced pancreatitis risk in patients given statin treatment is reassuring, since most clinical advice, including from us, is that statins are first-line treatment in patients with mild-to-moderate hypertriglyceridaemia. But the relevance of Preiss and colleagues’ observations for patients with severe hypertriglyceridemia is not clear. Furthermore, their generalisation that fibrates are ineffective is not necessarily supported by their data, since patients with severe hypertriglyceridaemia (a metabolically and clinically distinct population) were excluded from their meta-analysis. Retrospective studies report that at least 15% of patients with severe hypertriglyceridaemia have a history of pancreatitis, with 5 year rates of pancreatitis in patients of at least 3·5%. This is because chylomicrons are the predominant lipoprotein species when triglyceride concentrations are higher than 10 mmol/L compared with minimal fasting chylomicronaemia in patients with mild-to-moderate hypertriglyceridaemia. Pancreatitis risk in patients with chylomicronaemia is markedly reduced after lower triglyceride concentrations are achieved. The opinion of most experienced practitioners is that fi brates are the most eff ective means, more eff ective than statins, to reduce plasma triglycerides in patients with severe hypertriglyceridaemia—in this biochemical range, fibrates are expected to reduce triglyceride concentrations by 30–50% and statins by 20–30%. Indeed Preiss and colleagues seem to accept a role for fibrates in patients when triglyceride concentrations are higher than 20 mmol/L. Expert opinion is imperfect, but it should carry at least as much weight as extrapolation of evidence from normotriglyceridaemic cohorts. Thus, at least until defi nitive randomised trials are done, we maintain that fibrates should be fi rst-line drugs to reduce pancreatitis risk in patients with severe hypertriglyceridaemia.