Hypertriglyceridemia in Type 4 Hyperlipidemia Clinical Trial
Official title:
Rosiglitazone And Fenofibrate Additive Effects on Lipids (RAFAEL)
The design of the study will be randomized, double blind trial, which will examine the effects of Rosiglitazone on the fasting triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and plasma concentrations of apolipoproteins A-I, A-II, and C-III as compared to Fenofibrate and placebo. This study will also assess the synergistic effect of Rosiglitazone and Fenofibrate on the same parameters. Data from this study will help clarify whether Rosiglitazone favorably impacts plasma lipid and lipoprotein concentrations through improving insulin sensitivity and glycemic control, or by directly influencing the synthesis of the apolipoproteins that are responsible for very-low-density lipoprotein (VLDL) and HDL metabolism.
Treatment of patients with type 2 Diabetes Mellitus (DM) consists of reducing hyperglycemia
through diet, exercise, oral drug therapy or insulin (1). The Thiazolidinedione (TZDs),
which include Troglitazone (withdrawn by the FDA), Rosiglitazone, and Pioglitazone, correct
hyperglycemia by increasing insulin sensitivity in both the liver (2, 3) and skeletal
muscles (4,5). Although TZDs improve glycemic control in type 2 diabetic subjects, when
these agents are administered to non-diabetic subjects they do not affect fasting plasma
glucose levels. Nolan et al. (6) observed no effect on the plasma glucose levels of
non-diabetic subjects treated with Troglitazone 200 mg twice daily.
Clinical trials using TZDs in type 2 diabetic subjects have observed that these agents also
favorably impact plasma lipid and lipoprotein concentrations. A recent study comparing the
efficacy of adding Metformin (850 mg, once or twice daily) or Troglitazone (200 mg, once or
twice daily) to Glyburide (10 mg, twice daily) on glycemic control in type 2 diabetic
patients (n=22), reported that after 4 months of treatment, Metformin did not induce
significant changes in LDL-C, LDL size, HDL-C, Triglycerides or Plasminogen Activator
Inhibitor-1 (PAI-1), but decreased C-reactive protein (CRP) by 33%. Interestingly,
Troglitazone increased the size of LDL and the mean LDL-C level (+10%), but decreased the
Triglyceride (-22%) and CRP (-60%) concentrations (7). Following eight weeks of treatment
with Rosiglitazone (4mg, twice daily) in 243 type 2 diabetic patients, the mean HDL-C
increased by 6% and TG by 2%. The increase in the LDL-C concentration (9%) was accompanied
by a shift in small, dense LDL to large, buoyant LDL in 52% of the treated subjects. The
shift in LDL size occurred independent of a significant Triglyceride reduction, which is in
contrast to several studies reporting that increases in LDL size are significantly
correlated with a decrease in the plasma concentrations of total and very low density
lipoproteins (VLDL) Triglycerides (8-10).
The mechanism involved in the plasma lipid and lipoprotein changes induced by TZDs remains
unclear. It is possible that these agents indirectly alter plasma lipid and lipoprotein
levels indirectly by improving insulin sensitivity and glycemic control, or directly by
influencing lipoprotein synthesis and/or catabolism.
In type 2 Diabetes Mellitus, hepatic synthesis of Triglycerides is increased and peripheral
catabolism is decreased. The primary metabolic defect causing the hypertriglyceridemia is
peripheral insensitivity to the action of insulin, accompanied by hyperinsulinemia. The
insulin insensitivity inhibits the synthesis and activity of lipoprotein lipase and
consequently impairs peripheral catabolism of Triglyceride-rich lipoproteins (VLDL and
Chylomicrons) (11-12). Since hepatocytes remain sensitive to the action of insulin, the
hyperinsulinemia suppresses beta-oxidation and shunts free fatty acids entering the liver
into the synthesis of Triglycerides. Therefore, hepatic production of Triglycerides (i.e.
VLDL) is increased at the same time peripheral catabolism is impaired. The result is
hypertriglyceridemia with a reciprocal decease in HDL-C concentration. By reducing insulin
resistance and plasma insulin levels, TZDs would decrease hepatic Triglyceride production
and enhance peripheral catabolism of Triglycerides, resulting in plasma reduction and a
reciprocal increase in the HDL-C level.
Recently, it has been recognized that circulating levels of Triglyceride and HDL-C are
influenced by the activities of Peroxisome Proliferator Activator Receptors (PPARs). PPARs
constitute a super family of nuclear hormone receptors and are ligand-activated
transcription factors. When activated, they transmit signals from intra-cellular
lipid-soluble factors (e.g. fatty acids, hormones, vitamins) to genes in the nucleus by
binding to DNA at specific response elements (13). Three distinct PPARs, termed alpha, beta,
and gamma modulate intracellular lipid and glucose metabolism through controlling gene
expression when activated (14). Specifically when PPAR-alpha is activated, gene expression
for the synthesis of ApoC-III, lipoprotein lipase, ApoA-I and ApoA-II are impacted. ApoC-III
is a specific inhibitor of peripheral lipoprotein lipase and competes with ApoE for space on
the surface of VLDL. Reduced amounts of ApoC-III will result in a larger representation of
ApoE on the VLDL particle, and as a consequence, the ApoE mediated hydrolysis of
Triglycerides is enhanced. Activation of PPAR-alpha leads to decrease production of
ApoC-III, which in turn results in enhanced clearance of Triglycerides. Activation of
PPAR-alpha also increases the synthesis of lipoprotein lipase, which increases Triglyceride
catabolism. Gene expression for the synthesis of ApoA-I and ApoA-II is also enhanced by
activation of PPAR-alpha, resulting in increase in HDL concentration. Fibric acid
derivatives (Gemfibrozil and Fenofibrate) induce their Triglyceride lowering and HDL-C
augmenting properties by binding to the PPAR-alpha nuclear receptor.
TZDs are PPAR-gamma ligands that stimulate the gene expression of GLUT1 and GLUT4 (cellular
glucose transport proteins) leading to increased insulin sensitivity in the target cells
(15,16). The three PPAR receptors possess some degree of structural homology. Therefore,
while TZDs have high affinity to PPAR-gamma, they may also bind to a lesser degree to
PPAR-alpha or beta. Saliel and Olefsky (17) have determined in cell culture studies that
Troglitazone can activate all three PPAR nuclear receptors. Lehmann et al. (18) observed in
vitro that TZDs are high affinity ligands for PPAR-gamma yet also bind to PPAR-alpha (to a
small degree). Binding PPAR-alpha would directly enhance the catabolism of Triglycerides
(i.e. reduced ApoC-III plasma concentrations and increased lipoprotein lipase activity) and
increase HDL-C plasma concentration through enhancing the expression of lipoprotein lipase
and ApoA-I and ApoA-II. Therefore, administration of TZDs to non-diabetic normoglycemic
individuals should not change plasma glucose concentrations, but by binding to PPAR-alpha it
would result in decrease in the plasma concentration of ApoC-III, and an increase in ApoA-I
and ApoA-II, with a subsequent rise in HDL-C and reduction in Triglyceride concentration.
In a recent animal study assessing Rosiglitazone's mode of action on lipids using male
Sprague-Dawley rats, serum total, free and HDL cholesterol concentrations were monitored. In
rats given Rosiglitazone, serum Triglyceride levels decreased in a dose-dependent manner,
dropping to less than 50% of that of the control rats at the highest dose tested (5
mg/kg/d). Serum glucose concentrations did not change after Rosiglitazone treatment, which
is in agreement with previous studies showing that thiazolidinediones do not exert a
hypoglycemic action in the normoglycemic, non-diabetic rat. (18)
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment