Effects of Pioglitazone on High-density Lipoprotein (HDL) Function in Persons With Diabetes
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 3

Summary: 
      Metabolic defects contributing to the development of type 2 diabetes (T2D) are relative
      insulin insufficiency and insulin resistance that are associated with a cluster of
      abnormalities that increase the risk for cardiovascular disease including dyslipidemia,
      inflammation, hemodynamic changes and endothelial dysfunction. The dyslipidemia associated
      with T2D is characterized by elevated triglycerides and decreased high-density
      lipoprotein-cholesterol (HDL). The ability of the insulin sensitizing agent pioglitazone
      (ACTOS®) , to improve hyperglycemia in subjects with T2D is now well established.
      Pioglitazone functions as a PPAR-γ (peroxisome proliferator-activated receptor gamma)
      agonists and this class of drugs have demonstrated several other potential benefits, beyond
      glucose homeostasis. Specifically pioglitazone can improve diabetic dyslipidemia by
      increasing HDL cholesterol and lowing triglycerides. A potential beneficial effect on reverse
      cholesterol transport may be mediated by the increased HDL levels. This proposal aims to
      examine the effect of PPAR-γ activation by PIO on various aspects of reverse cholesterol
      transport by testing the hypothesis that PIO treatment affects key steps in the reverse
      cholesterol transport pathway either directly, through induction of protein expression, or
      indirectly, by altering HDL structure and composition leading to increase cholesterol flux
      through this pathway.
    

Detailed description: 
      Thiazolidinediones (TZDs) are pharmacological ligands for the nuclear receptor
      peroxisome-proliferator-activated receptor gamma (PPAR-γ). When activated, the receptor binds
      with response elements on DNA, altering transcription of a variety of genes that regulate
      carbohydrate and lipid metabolism1. The hypoglycemic and insulin sensitizing effects of PIO
      and other TZD compounds are well established2-4. The most prominent effect is increased
      insulin-stimulated glucose uptake by skeletal muscle cells5,6. The receptor is most highly
      expressed in adipocytes, while expression in myocytes is comparatively minor. Therefore, the
      increase in glucose uptake by muscle may largely be an indirect effect mediated through TZD
      interaction with adipocytes7-9. Candidates for the intermediary signal between fat and muscle
      include leptin, free fatty acids, tumor necrosis factor-α, adiponectin, and resistin.

      T2D is associated with a cluster of lipid and lipoprotein abnormalities including reduced
      HDL, elevated triglycerides and a predominance of small dense LDL particles10. Altered
      metabolism of triglyceride rich lipoproteins is crucial in the pathophysiology of diabetic
      dyslipidemia. Alterations include increased hepatic production and delayed clearance from
      plasma of large very low density lipoproteins (VLDL) and intestinal chylomicrons. Increased
      levels of these particles also results in increased production of small dense low density
      lipoprotein (LDL). The reduction in high density lipoprotein (HDL) associated with T2D
      appears related to CETP-mediated transfer of cholesterol from HDL to triglyceride rich
      particles in exchange for triglyceride. The triglyceride rich HDL are hydrolyzed by hepatic
      lipase, reducing particles size, then more rapidly cleared from the circulation11. Reduced
      HDL is due to mostly a decrease in HDL2, however, there are increased levels of small HDL3
      12.

      In addition to their ability to induce insulin sensitivity in T2D subjects, TZDs also have
      certain lipid benefits. HDL cholesterol concentrations are often increased with TZD therapy
      and triglyceride concentrations frequently fall13. A nonrandomized clinical comparison of
      potential differences in lipid effects among TZDs14 demonstrated the beneficial effect on
      lipids was most with pioglitazone (PIO) and least with rosiglitazone (ROSI)15. These
      observations were confirmed in a study investigating the lipid-lowering effects of TZDs
      showing that PIO was associated with significantly greater improvements in triglycerides, HDL
      cholesterol, non-HDL cholesterol, and LDL particle size compared with ROSI 16. The
      mechanism(s) by which these agents exert differential effects on the lipid profile are not
      clearly understood. Whether these differences in lipid effects translate into differences for
      the risk of CVD is not clear. Trials to determine the effects of pioglitazone and
      rosiglitazone on CVD outcomes are underway and should identify any cardiovascular benefits of
      the two drugs.

      Lipid metabolism plays a central role in the development of atherosclerosis. Elevated LDL and
      decreased HDL cholesterol are important risk factors for the development of coronary artery
      disease (CAD). The major cholesterol-carrying lipoprotein in the blood is LDL and many
      studies have shown the independent relationship between LDL cholesterol and atherosclerosis
      in both non-diabetic and diabetic subjects17. The metabolism of HDL, which are inversely
      related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of
      factors regulating HDL synthesis, intravascular remodeling, and catabolism18. The
      anti-atherogenic property of HDL has been attributed, at least in part, to the ability of HDL
      to promote cholesterol removal (efflux) from cells, the first step in the reverse cholesterol
      transport pathway 19.

      Reduced HDL in T2D results from increased clearance of small HDL particles20, and PIO
      treatment of these subjects raises HDL levels by 10-15% through as yet poorly defined
      mechanisms. Studies by Ginsberg and colleagues21, in an elegant study, examined the effects
      PIO treatment in patients with T2D on various aspects of lipoprotein metabolism. PIO raised
      HDL cholesterol levels 14%, but no change in apoA-I production rates, or fall in apoA-I
      synthetic rates were observed during PIO therapy22. ApoA-I synthesis is regulated by several
      transcription factors, including PPAR-α; there is no evidence that PPAR-α plays a role in
      apoA-I synthesis in vivo, although both PIO and ROSI have been reported to stimulate apoA-I
      secretion from HepG2 cells23. The authors suggest that the rise in HDL may have resulted from
      reduced CETP-mediated exchange of VLDL triglycerides for HDL cholesterol, concomitant with
      the PIO-associated fall in VLDL levels or a reduced the mass or activity of HL thus
      increasing HDL levels. There are no published data regarding PPAR-γ agonists on HL activity,
      but the authors found no change in HL mass in preheparin serum by PIO treatment. A final
      possibility proposed by these authors was PPAR-γ signaling may play a role in stimulating
      expression of the gene encoding ABCA1 which could increase the flux of cholesterol from cells
      onto nascent apoA-I.

      Study Aims Characterize the structural and functional changes in plasma lipids and
      lipoproteins in T2D subjects before and after PIO treatment. A major emphasis will compare
      serum HDL function as related to reverse cholesterol transport by plasma lipoproteins at
      baseline and after PIO treatment.

      We hypothesize that increased levels of HDL resulting from PIO therapy will affect particle
      size, density distribution and the lipid and lipoprotein composition of HDL and that such
      changes may alter the activity of several key steps involved in reverse cholesterol
      transport, namely the ability to promote cellular cholesterol efflux, cholesterol
      esterification by LCAT and transport of esterified cholesterol from HDL to the apoB
      containing lipoproteins.
    

Intervention name(s): pioglitazone
Intervention type(s): Drug
Intervention description(s): 30 mg daily for three weeks increase to 45 mg daily for 21 more weeks
Other intervention name(s): ACTOS
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: diabetes; dyslipidemia; pioglitazone; HDL-Cholesterol; Reverse cholesterol transport