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Diabetes 56:e3 2007
DOI: 10.2337/db07-0146
© 2007 by the American Diabetes Association
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Letter to Editor

Comment on: Boden et al. (2007) Combined Use of Rosiglitazone and Fenofibrate in Patients with Type 2 Diabetes: Prevention of Fluid Retention: Diabetes 56:248–255

J. Karalliedde, and G.C. Viberti

From the Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, Cardiovascular Division, King's College London School of Medicine, Guy's Hospital, King's College London, London, U.K

Address correspondence to Dr. J. Karalliedde, Unit for Metabolic Medicine, 5th Floor Thomas Guy House, Guy's Hospital, St. Thomas Street, London SE1 9RT. E-mail: j.karalliedde{at}kcl.ac.uk

The finding and conclusions of the recent article published by Boden et al. (1) need to be interpreted with caution in view of several factors.

The authors state that the combination of rosiglitazone (RGZ) and fenofibrate (FFB) "completely prevented the water retention and weight gain associated with RGZ." FFB has significant peroxisome proliferator–activated receptor (PPAR)-{alpha} activity (2,3) and is widely used for the treatment of hyperlipidemia.

A small number of patients, n = 13, was studied. Of these, five patients, who were used as the RGZ control group, were taken from a separate previously published study (4). The study was not designed to test the hypothesis of prevention of fluid retention, and indeed the design was totally inadequate for this purpose.

RGZ alone, in the five patients from a different study treated for 2 months, did not affect free fatty acid (FFA) levels. In fact, FFA levels tended to increase. This finding is inconsistent with the published literature, which shows a highly significant FFA-lowering effect of PPAR-{gamma} agonist therapy (5,6).

Table 1 reports data on total body water only. Changes in extracellular fluid volume compartment would be more relevant in the context of PPAR-{gamma}–induced fluid retention. No separation between fat mass accumulation and fluid retention as contributors to weight gain is provided.

Because of the PPAR-{alpha} agonist properties of FFB, the combination of RGZ and FFB would be expected to act as a PPAR-{gamma}/PPAR-{alpha} agonist. Current data suggest that dual PPAR agonists are significantly more likely to result in fluid retention and edema and possible adverse renal and cardiovascular outcomes, particularly congestive heart failure (7,8). These findings have resulted in two pharmaceutical companies halting their dual PPAR-{gamma} and -{alpha} programs (9,10).

We believe that the use of FFB in combination with RGZ should not be advocated as a useful strategy to prevent PPAR-{gamma}–induced fluid retention. Extrapolations from the results of this small, non–ad hoc designed study for the management of fluid retention with thiazolidinediones are unwarranted.

Received for publication February 1, 2007 and accepted in revised form February 1, 2007


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  1. Boden G, Homko C, Mozzoli M, Zhang M, Kresge K, Cheung P: Combined use of rosiglitazone and fenofibrate in patients with type 2 diabetes: prevention of fluid retention. Diabetes 56:248–255, 2007[Abstract/Free Full Text]
  2. Lefebvre P, Chinetti G, Fruchart JC, Staels B: Sorting out the roles of PPAR{alpha} in energy metabolism and vascular homeostasis J Clin Invest 116:571–580, 2006[Medline]
  3. Berger J, Moller DE: The mechanism of action of PPAR. Annu Rev Med 53:409–435, 2002[Medline]
  4. Boden G, Cheung P, Mozzoli M, Fried SK: Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. Metabolism 52:753–759, 2003[Medline]
  5. Miyazaki Y, Glass L, Triplitt C, Matsuda M, Cusi K, Mahankali A, Mahankali S, Mandarino LJ, DeFronzo RA: Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in type II diabetic patients. Diabetologia 44:2210–2219, 2001[Medline]
  6. Fonseca V, Rosenstock J, Patwardhan R, Salzman A: Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 283:1695–1702, 2000[Abstract/Free Full Text]
  7. David M. Kendall, Cindy J Rubin, Pharis Mohideen, Jean-Marie Ledeine, Rene Belder, Jorge Gross, Paul Norwood, Michael O'Mahony, Kenneth Sall, Greg Sloan, Anthony Roberts, Fred T, Fiedorek FT, DeFronzo RA: Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual ({alpha}/{gamma}) peroxisome proliferators–activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a double-blind, randomized, pioglitazone-comparative study. Diabetes Care 29:1016–1023, 2006[Abstract/Free Full Text]
  8. Nissen SE, Wolski K, Topol EJ: Effect of murgalitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294:2581–2586, 2005[Abstract/Free Full Text]
  9. Astrazeneca Discontinues Development of GALIDA TM (Tesaglitazar) [article online]. Available from http://www.astrazeneca.com/pressrelease/5240.aspx. Accessed 4 May 2006
  10. Bristol-Myers Squibb: Bristol Myers Squibb Announces Discontinuation of Development of Muraglitazar, an Investigational Oral Treatment for Type 2 Diabetes [article online]. Available from http://www.bms.com/news/press/data/fg_press_release_6384.html. Accessed 18 May 2006

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G. Boden
Response to Comment on: Boden et al. (2007) Combined Use of Rosiglitazone and Fenofibrate in Patients with Type 2 Diabetes: Prevention of Fluid Retention: Diabetes 56:248-255
Diabetes, May 1, 2007; 56(5): e4 - e4.
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