Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency

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Abstract

BACKGROUND. Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase–deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study.

METHODS. Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34⁺ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m²) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution.

RESULTS. With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1–2.6) and granulocytes (VCN = 0.01–0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant.

CONCLUSION. These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00794508.

FUNDING. Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.

Authors

Kit L. Shaw, Elizabeth Garabedian, Suparna Mishra, Provaboti Barman, Alejandra Davila, Denise Carbonaro, Sally Shupien, Christopher Silvin, Sabine Geiger, Barbara Nowicki, E. Monika Smogorzewska, Berkley Brown, Xiaoyan Wang, Satiro de Oliveira, Yeong Choi, Alan Ikeda, Dayna Terrazas, Pei-Yu Fu, Allen Yu, Beatriz Campo Fernandez, Aaron R. Cooper, Barbara Engel, Greg Podsakoff, Arumugam Balamurugan, Stacie Anderson, Linda Muul, G. Jayashree Jagadeesh, Neena Kapoor, John Tse, Theodore B. Moore, Ken Purdy, Radha Rishi, Kathey Mohan, Suzanne Skoda-Smith, David Buchbinder, Roshini S. Abraham, Andrew Scharenberg, Otto O. Yang, Kenneth Cornetta, David Gjertson, Michael Hershfield, Rob Sokolic, Fabio Candotti, Donald B. Kohn

Prolonged red cell storage before transfusion increases extravascular hemolysis

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Abstract

BACKGROUND. Some countries have limited the maximum allowable storage duration for red cells to 5 weeks before transfusion. In the US, red blood cells can be stored for up to 6 weeks, but randomized trials have not assessed the effects of this final week of storage on clinical outcomes.

METHODS. Sixty healthy adult volunteers were randomized to a single standard, autologous, leukoreduced, packed red cell transfusion after 1, 2, 3, 4, 5, or 6 weeks of storage (n = 10 per group). 51-Chromium posttransfusion red cell recovery studies were performed and laboratory parameters measured before and at defined times after transfusion.

RESULTS. Extravascular hemolysis after transfusion progressively increased with increasing storage time (P < 0.001 for linear trend in the AUC of serum indirect bilirubin and iron levels). Longer storage duration was associated with decreasing posttransfusion red cell recovery (P = 0.002), decreasing elevations in hematocrit (P = 0.02), and increasing serum ferritin (P < 0.0001). After 6 weeks of refrigerated storage, transfusion was followed by increases in AUC for serum iron (P < 0.01), transferrin saturation (P < 0.001), and nontransferrin-bound iron (P < 0.001) as compared with transfusion after 1 to 5 weeks of storage.

CONCLUSIONS. After 6 weeks of refrigerated storage, transfusion of autologous red cells to healthy human volunteers increased extravascular hemolysis, saturated serum transferrin, and produced circulating nontransferrin-bound iron. These outcomes, associated with increased risks of harm, provide evidence that the maximal allowable red cell storage duration should be reduced to the minimum sustainable by the blood supply, with 35 days as an attainable goal.

REGISTRATION. ClinicalTrials.gov NCT02087514.

FUNDING. NIH grant HL115557 and UL1 TR000040.

Authors

Francesca Rapido, Gary M. Brittenham, Sheila Bandyopadhyay, Francesca La Carpia, Camilla L’Acqua, Donald J. McMahon, Abdelhadi Rebbaa, Boguslaw S. Wojczyk, Jane Netterwald, Hangli Wang, Joseph Schwartz, Andrew Eisenberger, Mark Soffing, Randy Yeh, Chaitanya Divgi, Yelena Z. Ginzburg, Beth H. Shaz, Sujit Sheth, Richard O. Francis, Steven L. Spitalnik, Eldad A. Hod

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

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Abstract

BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis.

METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed.

RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4⁺ T cell infiltration, which peaked on days 10–11 after treatment, without pain, crusting, or ulceration.

CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4⁺ T cell–mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs.

TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355.

FUNDING. Not applicable (investigator-initiated clinical trial).

Authors

Trevor J. Cunningham, Mary Tabacchi, Jean-Pierre Eliane, Sara Moradi Tuchayi, Sindhu Manivasagam, Hengameh Mirzaalian, Ahu Turkoz, Raphael Kopan, Andras Schaffer, Arturo P. Saavedra, Michael Wallendorf, Lynn A. Cornelius, Shadmehr Demehri

Early pregnancy vitamin D status and risk of preeclampsia

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Abstract

BACKGROUND. Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia.

METHODS. We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10–18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32–38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D–associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia.

RESULTS. Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61–1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10–0.96). Differential expression of 348 vitamin D–associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D–associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity.

CONCLUSIONS. Vitamin D supplementation initiated in weeks 10–18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D–associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00920621.

FUNDING. Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Authors

Hooman Mirzakhani, Augusto A. Litonjua, Thomas F. McElrath, George O’Connor, Aviva Lee-Parritz, Ronald Iverson, George Macones, Robert C. Strunk, Leonard B. Bacharier, Robert Zeiger, Bruce W. Hollis, Diane E. Handy, Amitabh Sharma, Nancy Laranjo, Vincent Carey, Weilliang Qiu, Marc Santolini, Shikang Liu, Divya Chhabra, Daniel A. Enquobahrie, Michelle A. Williams, Joseph Loscalzo, Scott T. Weiss

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

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Abstract

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D.

METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses.

RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4⁺ and CD8⁺ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1⁺CD4⁺ Tem and Tcm (P < 0.01).

CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy.

TRIAL REGISTRATION.https://clinicaltrials.gov/ NCT00965458.

FUNDING. NIH and Astellas.

Authors

Mark R. Rigby, Kristina M. Harris, Ashley Pinckney, Linda A. DiMeglio, Marc S. Rendell, Eric I. Felner, Jean M. Dostou, Stephen E. Gitelman, Kurt J. Griffin, Eva Tsalikian, Peter A. Gottlieb, Carla J. Greenbaum, Nicole A. Sherry, Wayne V. Moore, Roshanak Monzavi, Steven M. Willi, Philip Raskin, Lynette Keyes-Elstein, S. Alice Long, Sai Kanaparthi, Noha Lim, Deborah Phippard, Carol L. Soppe, Margret L. Fitzgibbon, James McNamara, Gerald T. Nepom, Mario R. Ehlers, the Immune Tolerance Network (ITN) T1DAL Study Group

Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients

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Abstract

BACKGROUND. TGF-β has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-β–regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-β may benefit these patients.

METHODS. Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-β isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-β–regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS).

RESULTS. In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-β–regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment.

CONCLUSION. The rapid inhibition of TGF-β–regulated gene expression in response to fresolimumab strongly implicates TGF-β in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01284322.

FUNDING. This study was supported by the Boston University Clinical and Translational Science Institute, the NIH’s National Center for Advancing Translational Sciences Clinical and Translational Sciences, the National Institute of Arthritis Musculoskeletal and Skin Disease: Scleroderma Core Centers and Scleroderma Center of Research Translation, the Boston University Medical Campus Microarray Core, the Kellen Foundation at Hospital for Special Surgery, the Scleroderma Research Foundation, the Dr. Ralph and Marian Falk Medical Research Trust, and Novartis.

Authors

Lisa M. Rice, Cristina M. Padilla, Sarah R. McLaughlin, Allison Mathes, Jessica Ziemek, Salma Goummih, Sashidhar Nakerakanti, Michael York, Giuseppina Farina, Michael L. Whitfield, Robert F. Spiera, Romy B. Christmann, Jessica K. Gordon, Janice Weinberg, Robert W. Simms, Robert Lafyatis

β Cell death and dysfunction during type 1 diabetes development in at-risk individuals

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Abstract

Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data.

BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured.

METHODS. Here, we measured β cell death with an assay that detects β cell–derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants.

RESULTS. In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not.

CONCLUSION. We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.

TRIAL REGISTRATION. Clinical Trials.gov NCT00097292.

FUNDING. Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association.

Authors

Kevan C. Herold, Sahar Usmani-Brown, Tara Ghazi, Jasmin Lebastchi, Craig A. Beam, Melena D. Bellin, Michel Ledizet, Jay M. Sosenko, Jeffrey P. Krischer, Jerry P. Palmer

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

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Abstract

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.

METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m²/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.

RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.

CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.

TRIAL REGISTRATION. Clinicaltrials.gov NCT01165996.

FUNDING. NIH (R01CA138858, CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).

Authors

Yogen Saunthararajah, Mikkael Sekeres, Anjali Advani, Reda Mahfouz, Lisa Durkin, Tomas Radivoyevitch, Ricki Englehaupt, Joy Juersivich, Kathleen Cooper, Holleh Husseinzadeh, Bartlomiej Przychodzen, Matthew Rump, Sean Hobson, Marc Earl, Ronald Sobecks, Robert Dean, Frederic Reu, Ramon Tiu, Betty Hamilton, Edward Copelan, Alan Lichtin, Eric Hsi, Matt Kalaycio, Jaroslaw Maciejewski

Metabolically normal obese people are protected from adverse effects following weight gain

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Abstract

BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as “metabolically normal obese” (MNO), but not those defined as “metabolically abnormal obese” (MAO), are protected from the adverse metabolic effects of weight gain.

METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m² who were matched for BMI and fat mass.

RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects.

CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain–induced metabolic dysfunction.

TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170.

FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.

Authors

Elisa Fabbrini, Jun Yoshino, Mihoko Yoshino, Faidon Magkos, Courtney Tiemann Luecking, Dmitri Samovski, Gemma Fraterrigo, Adewole L. Okunade, Bruce W. Patterson, Samuel Klein

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

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Abstract

BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (S_I) in obese patients. Regular exercise can also improve S_I in obese individuals; however, it is unknown whether exercise and RYGB surgery–induced weight loss would additively improve S_I and other cardiometabolic factors.

METHODS. We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1–3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included S_I and glucose effectiveness (S_G), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO₂ peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week).

RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). S_I improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min^–1/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive S_I improvement (PP: CON vs. EX; +1.57 vs. +2.69 min^–1/μU/ml, P = 0.019) above that of surgery. Exercise also improved S_G (ITT: CON vs. EX; +0.0023 vs. +0.0063 min^–1, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO₂ peak) compared with the CON group.

CONCLUSION. Moderate exercise following RYGB surgery provides additional improvements in S_I, S_G, and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss.

TRIAL REGISTRATION. clinicaltrials.gov identifier: NCT00692367.

FUNDING. This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153.

Authors

Paul M. Coen, Charles J. Tanner, Nicole L. Helbling, Gabriel S. Dubis, Kazanna C. Hames, Hui Xie, George M. Eid, Maja Stefanovic-Racic, Frederico G.S. Toledo, John M. Jakicic, Joseph A. Houmard, Bret H. Goodpaster