Diabetes & Metabolic Syndrome: Clinical Research & Reviews
Original ArticleAssociation between triglyceride and high-density lipoprotein cholesterol change following fibrate therapy
Introduction
Epidemiology studies have established low HDL-C and hypertriglyceridaemia, in addition to raised LDL-C as factors associated with cardiovascular disease [1], [2], [3], [4], [5], [6]. Furthermore, an inverse relationship between TG and HDL-C is often seen [7]. TG and HDL-C metabolism is closely linked through CETP and it has been proposed that high TG levels leading to TG enrichment of HDL-C particles could increase the rate of HDL-C catabolism [8], [9].
Fibrates bind and activate PPAR-α which alters the regulation of gene transcription of proteins involved in fatty acid and lipoprotein metabolism [10], [11], [12]. Fibrate treatment leads to a modest decrease in LDL-C, a variable increase in HDL-C and a greater reduction in TG levels [13]. Following mixed outcomes from randomised controlled studies there is debate on whether fibrates have a clinical role, except in patients with marked hypertriglyceridaemia. However, subgroup analyses of these trials have demonstrated significant benefit in patients with the metabolic syndrome. A meta-analysis of 18 trials (45,058 individuals) with fibrates was carried out by Jun et al. in 2010 and significant decreases were observed in major cardiovascular and coronary events [14]. Sub-group analyses suggested lower coronary events in individuals with higher mean baseline TG levels (≥2 mmol/l) compared to the complementary group. Interestingly, despite the well described inverse relationship between baseline TG and HDL-C, no significant difference in outcome was seen in the subgroup of patients with lower baseline HDL-C (<1 mmol/l vs ≥1 mmol/l).
Miller et al. in 2007 investigated the effect that lowering TG levels had on HDL-C following various therapies including treatment with statins, fibrates and niacin [15]. The inverse relationship between TG and HDL-C levels was observed pre-treatment. They revealed that TG reduction was inversely correlated with HDL-C increase, and this pattern remained significant even after the regression analysis was adjusted for several variables such as types of treatment and patient characteristics. Whilst they demonstrated that fibrate therapy led to HDL-C increase in the total cohort, they did not specifically analyse this in relation to TG change in patients on fibrates. The above lipid-regulating drugs not only act through distinct mechanisms but they are also prescribed to patients with different baseline lipid characteristics. It is thus important to study the response to each drug class separately; examining the relation between changes in TG and HDL-C.
There remain unanswered questions in the clinical outcomes amongst subgroups of patients on fibrate therapy, such as why the group with high baseline TG showed greater benefit whilst those with low HDL-C did not [14]. Fibrates, through their action on PPAR-α affect both, TG and HDL-C levels. Despite this, and the well-established inverse relation between baseline TG and HDL-C, a literature search has not identified a study characterising the relation between HDL-C and TG change specifically in patients on fibrate therapy.
Analysis of the data from our metabolic clinics at the Heart of England NHS Foundation Trust in 2012 showed that a greater increase in HDL-C following fibrate treatment was associated with lower HDL-C baseline levels [16]. Interestingly this phenomenon was absent in patients on concurrent statin therapy. We now wished to turn our attention to TG change and its relation to HDL-C in patients on fibrate treatment.
More specifically, the aims of this study were to determine the following after fibrate treatment:
- (1)
TG change in the total cohort as well as patient subgroups.
- (2)
The baseline predictors of TG change.
- (3)
The association between changes in TG and other lipids (HDL-C and TC).
- (4)
Pattern of TG change; whether the change in TG follows the same pattern as the change in HDL-C that we reported in a previous study [16], particularly in patients on concurrent statin therapy.
Section snippets
Subjects, materials and methods
Patients commencing on fibrates between 2002 and 2008 in the lipid clinics run by the Heart of England NHS Foundation Trust were identified from the electronic patient record databases by using appropriate search keywords. Data were collected from 248 case notes (Good Hope Hospital 150 patients, Birmingham Heartlands Hospital: 98 patients). Demographic data included the following: males 181/248 (73.0%), type 2 diabetes 84/247 (34.0%), hypertension 128/239 (53.6%).
Lifestyle advice was provided
Results
The baseline lipid data suggested that fibrates were principally used on both hospital sites to treat patients with hypertriglyceridaemia; pre-treatment TG (mean/SD): 7.82/0.68 mmol/l (Good Hope Hospital), 8.54/0.75 mmol/l (Birmingham Heartlands Hospital), no significant difference between these TG distributions, p (t test) = 0.49. The distribution of pre-treatment TG levels in the total cohort were as follows; median = 5.9 mmol/l, range = 0.7–58.1 mmol/l, 10th/25th/75th/90th percentiles = 2.5/4.0/9.1/15.9
Discussion
We had previously reported that HDL-C increase following fibrate treatment was only observed in patients with a baseline HDL-C <1 mmol/l. Further, no significant change in HDL-C was seen in patients on concurrent statin treatment [16]. We now aimed to investigate the pattern of change in TG following fibrate treatment and compare it to our previous observations of change in HDL-C in the same cohort. We can state at the outset that the pattern of change was very different. We will now speculate
Competing interests
All authors (M.W. Collins, C.S. König, A. Abbas, C. Jewkes, A.F. Jones and S. Ramachandran) declare no conflicts or interest, actual or potential, financial or otherwise, in connection with this submitted manuscript.
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