Chest
Volume 147, Issue 1, January 2015, Pages 180-187
Journal home page for Chest

Original Research: Diffuse Lung Disease
Retrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis

https://doi.org/10.1378/chest.14-0758Get rights and content

BACKGROUND

Combined simvastatin and sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM.

METHODS

To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus sirolimus (n = 14), sirolimus alone (n = 44), or simvastatin alone (n = 20).

RESULTS

Sirolimus-related adverse events in the simvastatin plus sirolimus and sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, −1.4 ± 0.2 and −1.8 ± 0.2% predicted. After simvastatin plus sirolimus therapy, these rates changed to +1.2 ± 0.5 (P = .635) and +0.3 ± 0.4% predicted (P = .412), respectively. In 44 patients treated with sirolimus alone, FEV1 and Dlco rates of change were −1.7 ± 0.1 and −2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment (P < .001).

CONCLUSIONS

Therapy with sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of sirolimus.

Section snippets

Patient Population

Patients were referred to the National Institutes of Health for participation in an LAM natural history and pathogenesis protocol, which was approved by the National Heart, Lung, and Blood Institute Institutional Review Board (NHLBI Protocol 95-H-0186). In addition to self-referral and referral by individual physicians, patients were informed of the studies by the LAM Foundation and the Tuberous Sclerosis Alliance. All patients gave written informed consent before enrollment. Clinical,

Patients Characteristics

Fourteen patients were treated with sirolimus (mean dose, 2.7 ± 0.9 mg/d) and simvastatin (mean dose, 23.3 ± 11.6 mg/d), 20 received simvastatin alone (mean dose, 32.0 ± 16.1 mg/d), and 44 were treated with sirolimus alone (mean dose, 2.4 ± 0.8 mg/d). The initial prevalence of hypercholesterolemia in the simvastatin plus sirolimus group was 64%. Simvastatin was prescribed for the treatment of preexisting hypercholesterolemia or hypercholesterolemia that worsened or developed after beginning

Discussion

Because mTORC1, mTORC2, and RhoGTPase activity are all required for cell proliferation and survival,25 inhibition of mTORC1, mTORC2, and RhoGTPase may be more effective in abrogating LAM cell growth and proliferation than mTORC1 blockade with mTOR inhibitors alone.25, 30 In the only human study evaluating changes in lung function in patients with LAM treated with statins, the rate of decline in lung diffusion capacity was found to be greater than that of matched off-statin-therapy control

Conclusions

Combined therapy with sirolimus plus simvastatin does not result in a greater prevalence of adverse events beyond those expected from the use of each drug alone. Within the limitations of this study and because of the small numbers of patients treated with sirolimus plus simvastatin, we found no evidence that simvastatin enhances or diminishes the beneficial effects of sirolimus therapy in LAM. Because there is good evidence that simvastatin and sirolimus act synergically to abrogate the

Acknowledgments

Authors contributions: A. M. T.-D. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. A. M. T.-D. and J. M. contributed to the study design, data analysis, and writing of the manuscript; A. M. J. and P. A. J.-W. contributed to the data collection and review; M. S. contributed to the statistical analysis; and A. M. T.-D., A. M. J., P. A. J.-W., M. S., and J. M. reviewed and approved the manuscript.

References (32)

  • DD Sarbassov et al.

    Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB

    Mol Cell

    (2006)
  • AM Taveira-DaSilva et al.

    Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone

    Chest

    (2004)
  • JH Ryu et al.

    NHLBI LAM Registry Group The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment

    Am J Respir Crit Care Med

    (2006)
  • R Meraj et al.

    Lymphangioleiomyomatosis: new concepts in pathogenesis, diagnosis, and treatment

    Semin Respir Crit Care Med

    (2012)
  • VJ Ferrans et al.

    Lymphangioleiomyomatosis (LAM): a review of clinical and morphological features

    J Nippon Med Sch

    (2000)
  • J Yu et al.

    Chromosome 16 loss of heterozygosity in tuberous sclerosis and sporadic lymphangiomyomatosis

    Am J Respir Crit Care Med

    (2001)
  • Cited by (25)

    • A phase II clinical trial of the Safety Of Simvastatin (SOS) in patients with pulmonary lymphangioleiomyomatosis and with tuberous sclerosis complex

      2020, Respiratory Medicine
      Citation Excerpt :

      In addition, although the mean FEV1 (68.7% predicted) at baseline was consistent with a moderate degree of obstruction in enrolled subjects, there was a significant dichotomy in lung function impairment with 5 patients having an FEV1>80% predicted and 4 patients with an FEV1<55% predicted. Consistent with a prior retrospective review of LAM patients treated with sirolimus with the subsequent addition of simvastatin for hypercholesterolemia, both drugs were tolerated well in combination [24]. Because only one subject had TSC-LAM and only one was on everolimus, our direct conclusions about adverse events in these populations are limited.

    • Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2<sup>−</sup> Tumor Related to Lymphangioleiomyomatosis

      2016, American Journal of Pathology
      Citation Excerpt :

      We found that transfection of hyperactive mTOR down-regulated LEC markers in TSC2+ cells, suggesting that TSC2 correction promotes LEC differentiation through the inactivation of mTOR rather than through a noncanonical mechanism. Clinical trials with the mTORC1 inhibitor rapamycin, the only US Food and Drug Administration–approved drug for the treatment of LAM and AML, have revealed only partial efficacy in the treatment of both conditions22,37,81,82; therefore, combined therapies with rapamycin followed by surgery,83 in the case of AML, or including an adjuvant drug in addition to rapamycin, particularly in the case of LAM, are currently the focus of much attention.25,84,85 On the basis of the results obtained with NCTD in the treatment of TSC2− cells, we treated these cells with a combination of rapamycin and NCTD and observed additive benefit.

    • Lymphangioleiomyomatosis (LAM): Molecular Insights into mTOR Regulation Lead to Targeted Therapies

      2016, Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic Strategies
    View all citing articles on Scopus

    FUNDING/SUPPORT: This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    View full text