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Clinical and Population Studies

Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors

Aramesh Saremi, Dawn C. Schwenke, Thomas A. Buchanan, Howard N. Hodis, Wendy J. Mack, MaryAnn Banerji, George A. Bray, Stephen C. Clement, Robert R. Henry, Abbas E. Kitabchi, Sunder Mudaliar, Robert E. Ratner, Frankie B. Stentz, Nicolas Musi, Devjit Tripathy, Ralph A. DeFronzo, Peter D. Reaven
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https://doi.org/10.1161/ATVBAHA.112.300346
Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:393-399
Originally published January 16, 2013
Aramesh Saremi
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Dawn C. Schwenke
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Thomas A. Buchanan
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Howard N. Hodis
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Wendy J. Mack
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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MaryAnn Banerji
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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George A. Bray
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Stephen C. Clement
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Robert R. Henry
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Abbas E. Kitabchi
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Sunder Mudaliar
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Robert E. Ratner
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Frankie B. Stentz
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Nicolas Musi
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Devjit Tripathy
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Ralph A. DeFronzo
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Peter D. Reaven
From the Phoenix Veterans Affair (VA) Health Care System, Phoenix, AZ (A.S., D.C.S., P.D.R.); University of Southern California Keck School of Medicine, Los Angeles, CA (T.A.B., H.N.H., W.J.M.); SUNY Health Science Center, Brooklyn, NY (M.B.); Pennington Biomedical Research Center-Louisiana State University, Baton Rouge, LA (G.A.B.); Georgetown University, Washington, DC (S.C.C.); San Diego VA Health Care System and University of San Diego, San Diego, CA (R.R.H., S.M.); University of Tennessee, Memphis, TN (A.E.K., F.B.S.); Medstar Research Institute, Hyattsville, MD (R.E.R.); University of Texas Health Science Center, San Antonio, TX (N.M., D.T., R.A.D.); and South Texas Veterans Healthcare System, San Antonio, TX (N.M.).
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Abstract

Objective—To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes.

Methods and Results—CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10–3 mm/year; 95% CI: 2.39×10–3–7.14×10–3 mm/year) compared with placebo (9.69×10–3 mm/year; 95% CI: 7.24×10–3–12.15×10–3 mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA1c, fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment.

Conclusion—Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.

  • carotid atherosclerosis progression
  • impaired glucose tolerance
  • insulin resistance
  • inflammation
  • pioglitazone
  • Received June 8, 2012.
  • Accepted November 3, 2012.
  • © 2013 American Heart Association, Inc.
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    Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors
    Aramesh Saremi, Dawn C. Schwenke, Thomas A. Buchanan, Howard N. Hodis, Wendy J. Mack, MaryAnn Banerji, George A. Bray, Stephen C. Clement, Robert R. Henry, Abbas E. Kitabchi, Sunder Mudaliar, Robert E. Ratner, Frankie B. Stentz, Nicolas Musi, Devjit Tripathy, Ralph A. DeFronzo and Peter D. Reaven
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:393-399, originally published January 16, 2013
    https://doi.org/10.1161/ATVBAHA.112.300346

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    Pioglitazone Slows Progression of Atherosclerosis in Prediabetes Independent of Changes in Cardiovascular Risk Factors
    Aramesh Saremi, Dawn C. Schwenke, Thomas A. Buchanan, Howard N. Hodis, Wendy J. Mack, MaryAnn Banerji, George A. Bray, Stephen C. Clement, Robert R. Henry, Abbas E. Kitabchi, Sunder Mudaliar, Robert E. Ratner, Frankie B. Stentz, Nicolas Musi, Devjit Tripathy, Ralph A. DeFronzo and Peter D. Reaven
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33:393-399, originally published January 16, 2013
    https://doi.org/10.1161/ATVBAHA.112.300346
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