Skip to main content
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care
  • Subscribe
  • Log in
  • My Cart
  • Follow ada on Twitter
  • RSS
  • Visit ada on Facebook
Diabetes Care

Advanced Search

Main menu

  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
  • More from ADA
    • Diabetes
    • Clinical Diabetes
    • Diabetes Spectrum
    • ADA Standards of Medical Care
    • ADA Scientific Sessions Abstracts
    • BMJ Open Diabetes Research & Care

User menu

  • Subscribe
  • Log in
  • My Cart

Search

  • Advanced search
Diabetes Care
  • Home
  • Current
    • Current Issue
    • Online Ahead of Print
    • Special Article Collections
    • ADA Standards of Medical Care
  • Browse
    • By Topic
    • Issue Archive
    • Saved Searches
    • Special Article Collections
    • ADA Standards of Medical Care
  • Info
    • About the Journal
    • About the Editors
    • ADA Journal Policies
    • Instructions for Authors
    • Guidance for Reviewers
  • Reprints/Reuse
  • Advertising
  • Subscriptions
    • Individual Subscriptions
    • Institutional Subscriptions and Site Licenses
    • Access Institutional Usage Reports
    • Purchase Single Issues
  • Alerts
    • E­mail Alerts
    • RSS Feeds
  • Podcasts
    • Diabetes Core Update
    • Special Podcast Series: Therapeutic Inertia
    • Special Podcast Series: Influenza Podcasts
    • Special Podcast Series: SGLT2 Inhibitors
    • Special Podcast Series: COVID-19
  • Submit
    • Submit a Manuscript
    • Journal Policies
    • Instructions for Authors
    • ADA Peer Review
Brief Reports

Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol

  1. Lena Normén, PHD12,
  2. Jiri Frohlich, MD, FRCPC23,
  3. Julio Montaner, MD4,
  4. Marianne Harris, MD4,
  5. Tom Elliott, MBBS5 and
  6. Greg Bondy, MD, FRCPC23
  1. 1Canadian HIV Trials Network, Pacific Region, Vancouver, British Columbia, Canada
  2. 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  3. 3Healthy Heart Program, St. Paul’s Hospital, Vancouver, British Columbia, Canada
  4. 4BC Centre for Excellence of HIV/AIDS, St. Paul’s Hospital, Vancouver, British Columbia, Canada
  5. 5Department of Endocrinology, University of British Columbia, Vancouver, British Columbia, Canada
  1. Address correspondence and reprint requests to Greg Bondy, MD, FRCPC, Healthy Heart Program, B180-1800 Burrard St., St. Paul’s Hospital, Vancouver, BC, V6Z 1Y6, Canada. E-mail: gbondy{at}providencehealth.bc.ca
Diabetes Care 2004 Sep; 27(9): 2241-2242. https://doi.org/10.2337/diacare.27.9.2241
PreviousNext
  • Article
  • Figures & Tables
  • Info & Metrics
  • PDF
Loading
  • PPAR, peroxisome proliferator-activated receptor
  • TG, triglyceride
  • TZD, thiazolidinedione

Thiazolidinediones (TZDs) are insulin sensitizers widely used in the treatment of type 2 diabetes (1). Fibrates are lipid-lowering drugs that lower triglycerides (TGs) and increase HDL cholesterol (2). Individually, fibrates and TZDs generally raise HDL cholesterol. In this study, we report that certain patients treated with a combination of fibrates (fenofibrate) and a TZD (rosiglitazone) show a paradoxical fall in HDL cholesterol levels.

Chart reviews were performed to identify patients on combination therapy with TZDs and fibrates. Information about age, BMI, sex, type of treatment, duration of either single (fibrate) or combination therapy (fibrate + TZD), and blood lipids was collected. There were nine HIV-positive patients who started combination treatment with fenofibrate and rosiglitazone, of whom all experienced a decrease in serum HDL cholesterol concentrations (Table 1). We compared these changes in HDL cholesterol concentrations with those of HIV-negative patients with type 2 diabetes (n = 12) initiating the same combination therapy of fenofibrate and rosiglitazone as well as with HIV-positive patients on fibrate therapy alone (n = 12). The patients with diabetes had a significant decrease in HDL cholesterol concentrations, whereas HIV-positive patients on fibrate therapy alone had an expected significant increase in HDL cholesterol concentrations. None of the patients had any other changes from concomitant drugs that are also known to affect HDL cholesterol concentrations (including antiretroviral therapy). On cessation of one of the two drugs (either the fibrate or rosiglitazone), HDL cholesterol concentrations returned to the same level that they were before starting combination therapy. Effect of combination therapy on TG concentrations was variable. Fibrate treatment alone decreased TG concentrations by 27 ± 40% (±SD), while it appeared as if combination treatment increased TG concentrations by 48 ± 60%. There was no major change in serum TGs in the group with diabetes (−9 ± 44%).

The finding of a decreased serum HDL cholesterol concentration in patients on a combination of fenofibrate and the TZD rosiglitazone is novel and unexpected. One mechanism could be a drug interaction. This appears unlikely; fenofibrates are metabolized primarily by the hepatic cytochrome P450 4A6 (3), while rosiglitazone is metabolized by the cytochrome P450 2C8 (4). Another explanation may be related to the fact that both drugs bind to the peroxisome proliferator–activated receptor (PPAR) family of receptors. The blood lipid improvement by fibrates is activated through ligand binding to PPARα (5), whereas the effects from rosiglitazone occur through binding to the PPARγ receptor (1,6). However, because both receptors have a distinct tissue expression, competition at the receptor level seems unlikely. PPARα is expressed at high levels in the liver, whereas PPARγ is expressed in many tissues, with the highest concentrations in adipose and skeletal muscle (6).

The observation of a reduced HDL cholesterol level raises some important questions, which we hope will be addressed. First, what is the mechanism behind the paradoxical HDL cholesterol lowering following combination treatment with fibrates and rosiglitazone? Second, how frequent is the reduction in HDL cholesterol following combination treatment in other patient populations? Third, what are the specific characteristics for individuals who respond with decreased serum HDL cholesterol concentrations? The range for the HDL cholesterol change was −4 to −65% in the HIV-positive patients, whereas patients with diabetes had changes between 5 to −50%. Fourth, is the kinetics (turnover) of HDL cholesterol affected by combination treatment, which would be of importance to the potential atherogenic effect of this combination? Until these questions have been answered, we suggest that combinations of fenofibrate and rosiglitazone be used with caution.

View this table:
  • View inline
  • View popup
Table 1—

Comparison of demographics and lab data between groups A-C

Footnotes

  • L.N. has received research support from GlaxoSmithKline. J.F. has received honoraria and funding support from Fournier. J.M. and M.H. have received honoraria and research support from GlaxoSmithKline. T.E. has been on a local advisory board for GlaxoSmithKline. G.B. has received honoraria and consulting fees from and has been on advisory boards for Abbott Laboratories, AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Hoffman-La Roche, Merck Frosst, and Pfizer; has received fees for speaking engagements from Abbott Laboratories, AstraZeneca, Bristol-Meyers Squibb, Fournier, GlaxoSmithKline, Hoffman-La Roche, Lily, Merck Frosst, Pfizer, and Sanofi; and has received grant support from AstraZeneca, Fournier, GlaxoSmithKline, McMasters, Merck Frosst, Pfizer, and Sanofi.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted June 1, 2004.
    • Received May 27, 2004.
  • DIABETES CARE

References

  1. ↵
    Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI: Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 86:280–288, 2001
    OpenUrlCrossRefPubMedWeb of Science
  2. ↵
    Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98:2088–2093, 1998
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Miller DB, Spence JD: Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet 34:155–162, 1998
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    Baldwin SJ, Clarke SE, Chenery RJ: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 48:424–432, 1999
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    Minnich A, Tian N, Byan L, Bilder G: A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 280:E270–E279, 2001
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688, 1999
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
Diabetes Care: 27 (9)

In this Issue

September 2004, 27(9)
  • Table of Contents
  • About the Cover
  • Index by Author
Sign up to receive current issue alerts
View Selected Citations (0)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word about Diabetes Care.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol
(Your Name) has forwarded a page to you from Diabetes Care
(Your Name) thought you would like to see this page from the Diabetes Care web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol
Lena Normén, Jiri Frohlich, Julio Montaner, Marianne Harris, Tom Elliott, Greg Bondy
Diabetes Care Sep 2004, 27 (9) 2241-2242; DOI: 10.2337/diacare.27.9.2241

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Add to Selected Citations
Share

Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol
Lena Normén, Jiri Frohlich, Julio Montaner, Marianne Harris, Tom Elliott, Greg Bondy
Diabetes Care Sep 2004, 27 (9) 2241-2242; DOI: 10.2337/diacare.27.9.2241
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • β-Cell Transplantation Restores Metabolic Control and Quality of Life in a Patient With Subcutaneous Insulin Resistance
  • Hematocrit and the Incidence of Type 2 Diabetes in the Pima Indians
Show more Brief Reports

Similar Articles

Navigate

  • Current Issue
  • Standards of Care Guidelines
  • Online Ahead of Print
  • Archives
  • Submit
  • Subscribe
  • Email Alerts
  • RSS Feeds

More Information

  • About the Journal
  • Instructions for Authors
  • Journal Policies
  • Reprints and Permissions
  • Advertising
  • Privacy Policy: ADA Journals
  • Copyright Notice/Public Access Policy
  • Contact Us

Other ADA Resources

  • Diabetes
  • Clinical Diabetes
  • Diabetes Spectrum
  • Scientific Sessions Abstracts
  • Standards of Medical Care in Diabetes
  • BMJ Open - Diabetes Research & Care
  • Professional Books
  • Diabetes Forecast

 

  • DiabetesJournals.org
  • Diabetes Core Update
  • ADA's DiabetesPro
  • ADA Member Directory
  • Diabetes.org

© 2021 by the American Diabetes Association. Diabetes Care Print ISSN: 0149-5992, Online ISSN: 1935-5548.