Skip to main content

Treatment with pioglitazone induced significant, reversible mitral regurgitation


There has in recent years been great concern about possible cardiac side effects of thiazolidinediones (TZDs). We present a case-report of a 60 year-old male who developed significant mitral regurgitation during six months treatment with pioglitazone in parallel with laboratory indications of fluid retention. Echocardiography six months after discontinuation of medication showed regression of mitral regurgitation and the laboratory parameters were also normalized. It is noteworthy that six months treatment with pioglitazone could induce significant valve dysfunction, which was reversible, and this underlines the importance of carefully monitoring patients when placing them on treatment with TZDs.


There is an ongoing discussion concerning the possible effects of thiazolidinediones (TZDs) on the heart. In a recent meta/teleo-analysis Singh et al concluded that heart failure might occur at both high and low doses, usually weeks to months after initiating TZDs and in patients without a history of heart failure [1].

Case presentation

The patient is a sixty-year-old man with type 2 diabetes known since 15 years. He has proliferative retinopathy and microalbuminuria, no history or clinical signs of cardiovascular disease, stopped smoking 30 years ago. Failure to achieve optimal glycaemic control on treatment with 850 mg metformin/day (reduced dose because of elevated creatinine) and glimepiride 6 mg/day was evident with HbA1c >10%. The patient entered an ongoing study. He received add-on treatment with pioglitazone 30 mg/day that was increased after 16 weeks to 45 mg/day since HbA1c was 8.3% and no side effects were recorded. Standard transthoracic echocardiography examinations were performed with Sonos 5500 (Philips Medical, Best, the Netherlands) at baseline (15/12 2006), after six months pioglitazone therapy (25/6 2007), and six months after discontinuation of pioglitazone (20/12 2007). Cardiac size and volumes were quantified according to current guidelines [2] and echocardiography estimate of left ventricular filling pressure were calculated as previously described [3]. Valvular regurgitation was graded visually (0.5/1/2/3-trivial, mild, moderate, and severe) [4]. Brain BNP and haemoglobin were also measured at start and after six months treatment. After 26 weeks of treatment the HbA1c decreased to 7.4% in parallel with a decrease in haemoglobin from 113 at start to 100 g/l, a weight gain of 3 kg and an increase in brain BNP from 5 to 22 pmol/l. The patient did not show any clinical signs or symptoms of cardiopulmonary affection or peripheral oedema. Echocardiography examination at baseline and at the two subsequent examinations showed a mitral valve with normal morphology, no prolaps or thickened leaflets could be observed. The baseline echocardiography examination showed trivial mitral regurgitation, whereas the echocardiography examination after six months of pioglitazone therapy showed newly developed moderate mitral regurgitation, with a predominantly central jet. Furthermore, ejection fraction was increased and left ventricular- and atrial dimensions were also increased, compared to baseline values. In addition, estimate of left ventricular filling pressure (E/Em) was slightly increased. All the echocardiography alterations and laboratory indications of fluid retention (BNP and haemoglobin) were back to baseline values six months after discontinuation of pioglitazone therapy. Figure 1, 2, 3 display echocardiography images from apical 4-chamber view at baseline, after six month pioglitazone therapy and six months after discontinuation of pioglitazone therapy, respectively. Summary of anthropometrical, echocardiography and laboratory data are displayed in Table 1.

Table 1 Descriptive statistics of anthropometrical, echocardiography and laboratory data.
Figure 1
figure 1

Display of end-systolic image from apical 4-chamber view before treatment with pioglitazone.

Figure 2
figure 2

Display of end-systolic image from apical 4-chamber view after six month of treatment with pioglitazone. The white, thicker, arrow indicates the newly developed moderate mitral regurgitation.

Figure 3
figure 3

Display of end-systolic image from apical 4-chamber view six months after discontinuation of pioglitazone. The yellow, thinner, arrow indicates the remaining mild mitral regurgitation.


This case-report highlights the importance of careful monitoring of patients under treatment with TZDs. In this case, changes in haemoglobin and BNP indicated fluid retention in the absence of clinical signs or symptoms of cardiopulmonary stress or oedema. What caused the mitral regurgitation? One plausible hypothesis is that the fluid retention caused left ventricular dilatation which in turn resulted in mitral annular dilatation and to altered papillary muscle orientation, which then leads to inadequate mitral leaflet coaptation. Mitral regurgitations that are caused by left ventricular dilatation tend to have a central jet, as in our patient. It is, however, possible that there was some structural weakness in the mitral valve apparatus that was not detected on the transthoracic echocardiography examinations and that this could in part be contributing to the regurgitation. There is a need for tools to help clinicians to identify subsets of patients for whom this kind of therapy is likely to have particularly favourable/unfavourable effect, using readily identifiable clinical and laboratory factors. BNP, being a peptide hormone released from the cardiac ventricles in response to myocyte stretch have generated a lot of attention in recent years and have been proposed as potential diagnostic and prognostic marker for cardiac disease but currently there are no clear algorithms on how this should be implemented into clinical practice. However, the knowledge is increasing in this field and hopefully the results will enable clinicians to select proper therapy for individual patients in future.



Brain natriuretic peptide


Left ventricular end-diastolic diameter


Left ventricular end-systolic diameter


End-diastolic inter-ventricular septum


End-diastolic posterior wall


Left atrial end-systolic diameter

LV diastolic:

Left ventricular end-diastolic volume

LV systolic vol:

Left ventricular end-systolic volume


Ejection fraction

LA vol:

Left atrial volume


Indices of left ventricular diastolic function


estimation of left ventricular filling pressure.


  1. Singh S, Loke YK, Furberg CD: Thiazolidinediones and heart failure: a teleo-analysis. Diabetes Care. 2007, 30: 2148-53. 10.2337/dc07-0141.

    Article  CAS  PubMed  Google Scholar 

  2. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ: Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005, 18: 1440-63. 10.1016/j.echo.2005.10.005.

    Article  PubMed  Google Scholar 

  3. Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation. 2000, 102: 1788-94.

    Article  CAS  PubMed  Google Scholar 

  4. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ: Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr. 2003, 16: 777-802. 10.1016/S0894-7317(03)00335-3.

    Article  PubMed  Google Scholar 

Download references


The patient described in this case report has given permission to publish this case report.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Magnus Dencker.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

MDo and AF conceived the idea to write this manuscript. MDe performed the echocardiography examinations. All authors wrote, and edited this manuscript together.

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 1

Authors’ original file for figure 2

Authors’ original file for figure 3

Rights and permissions

Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and permissions

About this article

Cite this article

Dorkhan, M., Dencker, M. & Frid, A. Treatment with pioglitazone induced significant, reversible mitral regurgitation. Cardiovasc Diabetol 7, 12 (2008).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: