A Lesson in Moderation: Applying Pharmacodynamics to Clarify the Relationship Between Thiazolidinediones and Adverse Vascular Outcomes in Type 2 Diabetes (2008)

Thiazolidinediones are agonists of the peroxisome proliferator-activated receptor (PPAR)–gamma.1 Initial in vitro and animal studies provided conflicting data as to how increasing the activity of PPAR-gamma endogenously or by thiazolidinediones affected the progression of atherosclerosis.2–5 Subsequent studies using surrogate markers for and proxy outcomes of atherosclerosis in type 2 diabetes with the 2 agonists of PPAR-gamma on the US market (pioglitazone and rosiglitazone) seemed to suggest a potential benefit.6,7 An ensuing clinical trial showed no significant impact of pioglitazone on the primary endpoint of major vascular complications or death but a benefit in selected secondary endpoints.8 A subsequent analysis supported this observation of a potential protective effect of pioglitazone.9 However, an increase in death, stroke, and myocardial infarction was reported to occur from the thiazolidinedione, muraglitazar, following an analysis of data from clinical trials, a finding that prevented its approval by the Food and Drug Administration (FDA).10 Furthermore, meta and nested case control analyses of rosiglitazone concluded that it increased myocardial infarction and death from cardiovascular causes.11,12 However, an interim analysis of a clinical trial sponsored by the manufacturer showed no increased risk from rosiglitazone,13 a conclusion that was disputed in the accompanying editorial by national experts in the fields of diabetes and pharmacoepidemiology.14,15 These apparent conflicts in the various analyses regarding the safety of this widely prescribed drug have spurred substantial concern in the professional and lay press, Congress, and the FDA, adding yet another layer of confusion to the effect of thiazolidinediones on atherogenesis.16 It is hoped that this commentary will provide a degree of clarity by linking basic biology to the pharmacodynamics of thiazolidinediones and correlating both with reports of vascular complications. The PPAR system has been called the “master regulator of fat metabolism.”17 It is a nuclear receptor complex that, through activation and repression using small accessory coactivator and corepressor molecules, regulates key “nodal” genes to affect the transcription of numerous downstream proteins that affect insulin resistance and the inflammatory response to complement their broader effect on lipid metabolism.18,19 With the present understanding of PPAR-related pathways at the molecular level, certain coactivators can be termed as “beneficial” or “adverse” as they may stimulate adipogensis, insulin sensitization, and atherosclerosis. For example, coactivators such as DRIP 205/TRAP 220 and TIF-2 are responsible for edema and weight gain and may be classified as “adverse” coactivators, whereas SRC-1, involved in lipid metabolism, is viewed as a “beneficial” coactivator. Further stimulation of PPAR not only leads to multiple changes in the array of the gene cascade but also depends on specific repressor genes such as NCoR and SMRT and activator genes such as CBP, SRC-1, TIF-2, SRC-3, PGC-1, and P-300.17,18 Although each ligand may have a different propensity to modulate corepressor and coactivators of PPAR, it is becoming clear that certain coactivators are associated with adverse effects more than beneficial effects and thus should be avoided. For example, rosiglitazone and pioglitazone can specifically recruit the TIF-2 gene in the PPAR cascade and are associated with edema and weight gain.20 Therefore, attempts have been made to develop ligands that do not recruit the TIF-2 gene, and such ligands have been demonstrated to be free from these adverse effects. Similarly, attempts are being made to understand which coactivators might be associated with atherosclerosis, stroke, and myocardial infarction to distinguish them from the coactivators associated with beneficial pharmacological effects such as insulin sensitization, energy expenditure, and salutary lipid effects. The current state of research is toward the development of a ligand that can provide an optimal balance between beneficial and adverse effects. To accomplish this, we and others have carried out investigations of several partial agonists that have shown promising results in animal models and are ready for human testing.21,22 PPAR-gamma expression induces the transcription of machinery that stimulates the uptake of fatty acids, triglycerides, and glucose by fat cells to cause their differentiation and increase adipogenesis.23,24 By promoting intracellular fat manufacture, circulating levels of each of these substrates decrease, producing a decrease in insulin resistance, thereby lowering circulating levels of low-density lipoprotein (LDL) and raising high-density lipoprotein (HDL).19 Because adipose tissue is the primary target for the decrease in insulin resistance, it is unclear whether the changes in circulating levels of lipoproteins provide a net benefit or are an epiphenomenon of the intracellular changes from fat accumulation that may be neutral or prove ultimately harmful.25,26 PPAR-gamma is also highly expressed in macrophage foam cells, and its expression subsequently induces the scavenger receptor CD36 to mediate foam cell internalization of oxidized LDL (oxLDL).3,27 Accumulated oxLDL, in turn, stimulates further intense expression of PPAR-gamma on foam cells and is heavily invested in the pathogenesis of atherosclerosis in diabetes.28 Mechanistically separate from these effects, through an indirect pathway involving the liver, PPAR-gamma activation induces the expression of the adenosine triphosphate (ATP)–binding cassette (ABC)A1 transporter, which enhances cholesterol efflux from macrophages.29 In addition, PPAR-gamma activation also represses transcription of the proinflammatory cytokines involved in atherosclerotic plaque rupture, through a poorly understood process distinct from the other mechanisms described.30 Identification of single-nucleotide polymorphisms (SNPs) of PPAR-gamma lends support to the concept of the existence of an optimal state of activation, corresponding to a low propensity for atherogenesis21 and, furthermore, that either extreme of absent or intense activation provides milieus to promote atherogenesis.31,32 Human and animal models of SNPs associated with either extreme of PPAR-gamma activation produce detrimental conditions of either profound insulin resistance or intense intracellular fat accumulation associated with marked insulin sensitivity.32,33 In contrast, mutations that lower the maximal affinity of PPAR-gamma for response elements in promoter regions of targeted genes have been shown to be protective of cardiac conditions associated with atherosclerosis.27 Figure 1 provides a conceptual framework to understand this purported relationship between the degree of PPAR-gamma activation and atherosclerotic tendency. As represented by Figure 1, polymorphic variations correlate with a continuum of a defective PPAR-gamma state that facilitates acceleration of atherogenesis, a submaximal state of activation that is protective, and a maximally activated state that also fosters atherogenesis. As also described in Figure 1, the relationship between the degree of PPAR-gamma activation may be divergent for the level of insulin sensitivity (linear), in contrast with the propensity for atherogenesis (U-shaped). . Graphic representation of the conceptual relationship between the state of peroxisome proliferator-activated receptor (PPAR)–gamma activation and the potential for atherosclerosis (solid line) combined with their relationship to the level of insulin resistance (dotted line). The 3 states of PPAR-gamma activation correspond to the Pro495Leu, Pro12Ala, and Pro113Gln genetic mutations, respectively. From references 21, 32, 33. The 3 thiazolidinediones that have clinical outcome data available (muraglitazar, rosiglitazone, pioglitazone) are all full agonists of PPAR-gamma.1 The extent of the decrease in insulin resistance associated with each of these agents is closely correlated with their potency.34 Muraglitazar is the most potent thiazolidinedione, with an EC50 of 0.11 μmol/L for activation of human PPAR-gamma. However, the improvement in surrogate outcome measures that accompany the marked decrease in insulin resistance comes at the expense of profound weight gain as fat and an increase in adverse macrovascular events in type 2 diabetes.11 These adverse effects occur despite the additional action that muraglitazar has on PPAR-alpha (hypolipidemic mechanism of fibrates) to produce further favorable effects on circulating lipids.35 Rosiglitazone has a slightly lower potency compared with muraglitazar (EC50 of 0.14 μmol/L).35 Despite reports of an increase in adverse cardiac events from atherosclerosis in animal models with rosiglitazone, subsequent clinical studies reported a benefit, but only as these reflected improvements in surrogate measures.5,7 Studies in diabetic patients assessing clinical outcomes have reported a neutral effect to an increase in adverse macrovascular events.12,13 Pioglitazone is the weakest thiazolidinedione full PPAR-gamma agonist marketed, with an EC50 of 0.49 μmol/L,36 a potency differential with rosiglitazone that is maintained despite the difference in doses (15–45 mg vs 2–8 mg), respectively. Accordingly, the drug has thus far shown to either be neutral on primary outcome measures of cardiovascular toxicity or possibly be beneficial.8,9,12 It is clear that understanding the implications of the mechanism for enhancing insulin sensitivity of the thiazolidinediones is essential to correctly interpret the associated effect on circulating lipids and other surrogate markers indicative of the insulin-resistant state. Specifically, a divergence may occur between the apparent improvements in circulating markers and the effects at the cellular level as a result of the specific way the decrease in insulin resistance is induced. Clinically, this underscores the importance of requiring evidence of drug benefit in clinical outcomes brought about pharmacologically while challenging the assumption of the inextricable link between improvement in intermediate measures and actual clinical benefit. All of these considerations further serve to underscore the importance of having access to and analyzing all clinical trial data for both pioglitazone and rosiglitazone to determine their effects on atherosclerosis, especially because this outcome is also a direct result of the disease being treated by this class of drugs. Indeed, relating the concept of a submaximal state of PPAR-gamma activation being optimal and excess activation being detrimental to the pharmacodynamics of pioglitazone and rosiglitazone may be useful for the best interpretation of the data. Financial disclosure: None declared.