Rosiglitazone And Fenofibrate Additive Effects on Lipids (RAFAEL)
Information source: Brooke Army Medical Center
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertriglyceridemia in Type 4 Hyperlipidemia; Non Diabetic Subjects With Normoglycemia
Intervention: Rosiglitazone (Drug); Placebo (Rosiglitazone) (Drug); Placebo (Fenofibrate) (Drug); Fenofibrate (Drug)
Phase: Phase 4
Status: Terminated
Sponsored by: Ahmad Slim Official(s) and/or principal investigator(s): Ahmad m slim, MD, Principal Investigator, Affiliation: Brooke Army Medical Center Laudino Castillo-rojas, MD, Study Chair, Affiliation: Brooke Army Medical Center Jennifer N Slim, DO, Study Director, Affiliation: Brooke Army Medical Center
Summary
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.
Clinical Details
Official title: Rosiglitazone And Fenofibrate Additive Effects on Lipids (RAFAEL)
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Primary outcome: Percent Change in Triglyceride (TG) Levels Post Treatment
Secondary outcome: Post-treatment Percent Change in High-Density Lipoprotein (HDL) LevelsPost-treatment Percent Change in Low-Density Lipoprotein (LDL) Levels Post-treatment Percent Change in Apolipoprotein A-I (Apo AI), Apolipoprotein A-II (Apo AII) and Apolipoprotein C-III (Apo CIII) Levels Mean Levels of Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at Initial Visit and Final Visit
Detailed description:
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)
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion criteria:
1. Fasting plasma glucose <100 mg/dl
2. Fasting LDL <160 mg/dl and Triglyceride <400 mg/dl.
Exclusion criteria:
1. Congestive heart failure
2. Evidence of renal impairment (serum creatinine> 1. 4mg/dL)
3. Liver disease (ALT and/or AST above the upper level of normal)
4. Known diabetes mellitus or impaired fasting glucose (fasting glucose ≥ 100mg/dL)
5. LDL of ≥160mg/dL and/or triglycerides of ≥400mg/dL
6. Pregnant or breast feeding women
7. Prior history of an acute coronary syndrome, myocardial infarction or
revascularization procedures in the past
8. Life-threatening disease with a survival prognosis <3 years
9. Inability to take rosiglitazone and/or fenofibrate
10. Already on statin therapy or have been on statin therapy in the last 3 months
Locations and Contacts
Brooke Army Medical Center, San Antonio, Texas 78234, United States
Additional Information
Related publications: O'Rourke CM, Davis JA, Saltiel AR, Cornicelli JA. Metabolic effects of troglitazone in the Goto-Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus. Metabolism. 1997 Feb;46(2):192-8. Ciaraldi TP, Gilmore A, Olefsky JM, Goldberg M, Heidenreich KA. In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism. 1990 Oct;39(10):1056-62. 5. Troglitazone study group. The metabolic effects of troglitazone in non-insulin dependent diabetes. Diabetes 197; 46:Suppl 1:149A. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994 Nov 3;331(18):1188-93. Chu NV, Kong AP, Kim DD, Armstrong D, Baxi S, Deutsch R, Caulfield M, Mudaliar SR, Reitz R, Henry RR, Reaven PD. Differential effects of metformin and troglitazone on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care. 2002 Mar;25(3):542-9. Erratum in: Diabetes Care 2002 May;25(5):947. Coresh J, Kwiterovich PO Jr. Small, dense low-density lipoprotein particles and coronary heart disease risk: A clear association with uncertain implications. JAMA. 1996 Sep 18;276(11):914-5. Stampfer MJ, Krauss RM, Ma J, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. JAMA. 1996 Sep 18;276(11):882-8. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA. 1996 Sep 18;276(11):875-81. 11. Weinber, R.B. Lipoprotein metabolism: hormone regulation. Hosp. Prac 1987 :June' 15 :125-145. Dunn FL. Hyperlipidemia and diabetes. Med Clin North Am. 1982 Nov;66(6):1347-60. Review. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996 May;37(5):907-25. Review. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998 Nov 10;98(19):2088-93. Review. Bähr M, Spelleken M, Bock M, von Holtey M, Kiehn R, Eckel J. Acute and chronic effects of troglitazone (CS-045) on isolated rat ventricular cardiomyocytes. Diabetologia. 1996 Jul;39(7):766-74. Ciaraldi TP, Huber-Knudsen K, Hickman M, Olefsky JM. Regulation of glucose transport in cultured muscle cells by novel hypoglycemic agents. Metabolism. 1995 Aug;44(8):976-81. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995 Jun 2;270(22):12953-6. Lefebvre AM, Peinado-Onsurbe J, Leitersdorf I, Briggs MR, Paterniti JR, Fruchart JC, Fievet C, Auwerx J, Staels B. Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates. Arterioscler Thromb Vasc Biol. 1997 Sep;17(9):1756-64.
Starting date: September 2008
Last updated: April 8, 2014
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