EDITORIAL COMMENT
Physiologic Straws in the WindIn Which Direction Do They Bend?*
Richard Lewanczuk, MD and
Paul W. Armstrong, MD, FACC ,*
Division of Endocrinology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
* Reprint requests and correspondence: Dr. Paul W. Armstrong, Division of Cardiology, Department of Medicine, University of Alberta, 2-51 Medical Sciences Building, Edmonton, Alberta T6G 2H7, Canada. (Email: paul.armstrong{at}ualberta.ca).
Although it has been nearly 10 years since thiazolidinediones were approved, marketed, and broadly incorporated into therapy for diabetes mellitus, remarkably little knowledge exists concerning their physiologic effects in humans. What is known suggests that these agonists of the peroxisome proliferator-activated receptors (PPARs) exert their effects on the gamma subtype thereby affecting a multiplicity of neurohumoral and organ systems (1). In the left portion of Figure 1, a summary of their potential salutary mechanisms is provided. Remarkably and perhaps unadvisedly, it was solely the blood glucose lowering effects, modulated largely through enhancing insulin sensitivity, which led to their approval for clinical use in the U.S. in 1999. Recently, one of the thiazolidinediones (i.e., rosiglitazone) has been implicated—with an intensity nearly matching that associated with the controversy surrounding the deleterious cardiovascular effects of the cyclooxygenase (COX)-2 inhibitors—as a potential cause of myocardial infarction and cardiovascular death, on the basis of a meta-analysis of 42 clinical trials comprising over 27,000 patients (2). Unlike the apparently pure PPAR-delta agonist effects of rosiglitazone, its sister thiazolidinedione pioglitazone seems to act as a partial agonist in vitro and has been found to have more favorable effects on low-density lipoprotein cholesterol and serum triglycerides (1). Moreover, in the only prospective randomized trial (PROactive [PROspective pioglitAzone Clinical Trial In macroVascular Events]) addressing the effect of PPAR-delta agents on cardiovascular outcomes in patients with type 2 diabetes, pioglitazone has been shown to produce a beneficial trend in a composite vascular end point and a significant reduction in the secondary end point comprising death, myocardial infarction, and stroke (3).
Hence, the report of pioglitazone in patients with dyslipidemia by Naoumova et al. (4) reported in this issue of the Journal is of interest. Dyslipidemias have been associated with abnormalities in myocardial blood flow (MBF), and treatment has conversely been associated with improvements in myocardial perfusion (5–7). Familial combined hyperlipidemia encompasses a state of abnormal lipid metabolism but also insulin resistance (8–10). Insulin resistance is similarly associated with abnormalities in MBF as well as with decreased myocardial glucose uptake (11–14). Thus, the state of insulin resistance, from a cardiac perspective, encompasses both resistance to the normal vasodilatory effects of insulin in the coronary circulation as well as resistance to glucose uptake in myocardial cells (11). Factors that improve insulin sensitivity in the heart might therefore be hypothesized to improve both myocardial glucose uptake as well as MBF. Both of these processes would be expected to benefit cardiac function.
The present study consists of a small but well-characterized group of 26 British Caucasians with familial combined hyperlipidemia and persisting hyperlipidemia despite conventional lipid lowering medication with statins. These nondiabetic patients (some of whom had coronary disease), who would be expected to have abnormalities in both myocardial glucose use as well as in MBF, were randomized to pioglitazone or placebo to examine the effects on whole body and myocardial insulin sensitivity and MBF at baseline and after 4 months of treatment.
Results of this study confirm the ability of pioglitazone to improve insulin sensitivity both in the heart as well as at a whole-body level. Furthermore, pioglitazone improved MBF measured by positron emission tomography both at rest and in response to adenosine infusion, suggesting enhanced microvascular function. Although both these metrics showed significant improvement, no correlation between these effects was evident, thereby implying differing mechanisms of benefit on cardiac metabolism versus cardiac perfusion. Despite changes in a variety of lipid fractions, adiponectin, and plasminogen activator inhibitor-1, the authors state—but do not provide data—that only the insulin levels were inversely correlated with enhanced coronary flow reserve, a presumed proxy for endothelial function. Alternatively, changes in other hormones or cytokines not measured in this study but that are known to be associated with changes in insulin sensitivity could be causally linked to the observed improvements. It could also be hypothesized that the benefits in myocardial glucose uptake might also be due to changes in MBF, but this is not supported by the data, because there was no reported correlation between changes in MBF and changes in glucose use. The benefits of pioglitazone on MBF seem multiple, because both baseline flow as well as adenosine stimulated blood flow or coronary reserve were enhanced, indicating both larger artery as well as microcirculatory effects.
Because the study is small and imbalances exist between the 2 treatment groups, its promising findings deserve confirmation in larger, more definitive populations of differing groups, including the cohort enrolled in the PROactive trial, to establish whether the clinical outcomes track the promising physiologic changes. Too often the anticipated alignment between physiologic findings and hopeful hints of clinical efficacy in phase 2 studies has been thwarted by unexpected disassociation of these relationships in large phase 3 studies (15). Although no adverse effects were reported amongst the 14 patients receiving pioglitazone over 16 weeks, a common side effect of this class of agent is fluid retention, thought secondary to increased renal reabsorption of sodium, and/or vasodilatation leading to increased congestive heart failure in susceptible individuals (right portion, Fig. 1) (16,17). Because heart rate increases have previously been noted in normal control subjects, the nonsignificant increase in heart rate—possibly secondary to a lower blood pressure—in the small treatment group in the current study is a straw bending in the wrong direction, deserving of future study (16). Any increase in heart rate does not portend well for patients at risk for cardiovascular disease. Hence, nearly a decade after their introduction into clinical medicine, this class of highly promoted and interesting novel compounds remains both mysterious and, at least for the moment, lingering short of their potential promise.
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* Editorials published in the Journal of American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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1. Yki-Järvinen H. Drug therapy—thiazolidinediones N Engl J Med 2004;351:1106-1118.[Free Full Text]2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes N Engl J Med 2007;356:2457-2471.[Abstract/Free Full Text] 3. Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, PROactive Investigators The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) study J Am Coll Cardiol 2007;49:1772-1780.[Abstract/Free Full Text] 4. Naoumova RP, Kindler H, Leccisotti L, et al. Pioglitazone improves myocardial blood flow and glucose utilization in nondiabetic patients with combined hyperlipidemia: a randomized, double-blind, placebo-controlled study J Am Coll Cardiol 2007;50:2051-2058.[Abstract/Free Full Text] 5. Kaufmann PA, Gnecchi-Ruscone T, Schafers KP, Luscher TF, Camici PG. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia J Am Coll Cardiol 2000;36:103-109.[Abstract/Free Full Text] 6. Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M, Schwaiger M. Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography Circulation 1994;90:808-817.[Abstract/Free Full Text] 7. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease Circulation 1994;89:1530-1538.[Abstract/Free Full Text] 8. McNeely MJ, Edwards KL, Marcovina SM, Brunzell JD, Motulsky AG, Austin MA. Lipoprotein and apolipoprotein abnormalities in familial combined hyperlipidemia: a 20-year prospective study Atherosclerosis 2001;159:471-481.[CrossRef][Web of Science][Medline] 9. Aitman TJ, Godsland IF, Farren B, Crook D, Wong HJ, Scott J. Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia Arterioscler Thromb Vasc Biol 1997;17:748-754.[Abstract/Free Full Text] 10. Ayyobi AF, McGladdery SH, McNeely MJ, Austin MA, Motulsky AG, Brunzell JD. Small, dense LDL and elevated apolipoprotein B are the common characteristics for the three major lipid phenotypes of familial combined hyperlipidemia Arterioscler Thromb Vasc Biol 2003;23:1289-1294.[Abstract/Free Full Text] 11. Voipio-Pulkki LM, Nuutila P, Knuuti MJ, et al. Heart and skeletal muscle glucose disposal in type 2 diabetic patients as determined by positron emission tomography J Nucl Med 1993;34:2064-2067.[Abstract/Free Full Text] 12. Ohtake T, Yokoyama I, Watanabe T, et al. Myocardial glucose metabolism in noninsulin-dependent diabetes mellitus patients evaluated by FDG-PET J Nucl Med 1995;36:456-463.[Abstract/Free Full Text] 13. Yokoyama I, Yonekura K, Ohtake T, et al. Role of insulin resistance in heart and skeletal muscle F-18 fluorodeoxyglucose uptake in patients with non-insulin-dependent diabetes mellitus J Nucl Cardiol 2000;7:242-248.[CrossRef][Web of Science][Medline] 14. Iozzo P, Chareonthaitawee P, Rimoldi O, Betteridge DJ, Camici PG, Ferrannini E. Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with type II diabetes Diabetologia 2002;45:1404-1409.[CrossRef][Web of Science][Medline] 15. APEX AMI Investigators Pexelizumab for acute ST-elevation myocardial infarction in patients undergoing primary percutaneous coronary intervention: a randomized controlled trial JAMA 2007;297:43-51.[Abstract/Free Full Text] 16. Zanchi A, Chiolero A, Maillard M, Nussberger JU. Effects of the peroxisomal proliferator-activated receptor agonist pioglitazone on renal and hormonal responses to salt in healthy men J Clin Endocrinol Metab 2004;89:1140-1145.[Abstract/Free Full Text] 17. Dargie HJ, Hildebrandt PR, Gunter AJ, et al. A randomized, placebo-controlled trial assessing the effects of rosiglitazone on echocardiographic function and cardiac status in type 2 diabetic patients with New York Heart Association functional class I or II heart failure J Am Coll Cardiol 2007;49:1696-1704.[Abstract/Free Full Text]
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