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Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study.
Diabetes Metab Syndr Obes 2019; 12:743-759DM

Abstract

Purpose

Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity.

Patients and methods

Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp.

Results

This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject's age (P-value range= <0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast.

Conclusion

We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast's early effects on insulin sensitivity is indirect and likely mediated through roflumilast's prioritization of lipid over glucose handling.

Clinical trials registration

NCT01862029.

Authors+Show Affiliations

Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA, chungj@nhlbi.nih.gov, ijeoma.muo@nih.gov.NHLBI Pulmonary Branch, Laboratory of Chronic Airway Infections, National Institutes of Health, Bethesda, MD 20892, USA.Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA, chungj@nhlbi.nih.gov, ijeoma.muo@nih.gov.Biomedical and Metabolic Imaging Branch NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Section on Behavioral Endocrinology, NIMH, National Institutes of Health, Bethesda, MD 20892, USA.Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD 20892, USA.Laboratory of Inflammation and Cardiometabolic Diseases, NHLBI, National Institutes of Health, Bethesda, MD 20892, USA.Clinical Center Nutrition Department, National Institutes of Health, Bethesda, MD 20892, USA.Mass Spectrometry Clinical Core, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Mass Spectrometry Clinical Core, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Diabetes Endocrinology and Obesity Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Section on Behavioral Endocrinology, NIMH, National Institutes of Health, Bethesda, MD 20892, USA.NIMH, National Institutes of Health, Bethesda, MD 20892, USA.Biomedical and Metabolic Imaging Branch NIDDK, National Institutes of Health, Bethesda, MD 20892, USA.Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA, chungj@nhlbi.nih.gov, ijeoma.muo@nih.gov.Laboratory of Obesity and Aging Research NHLBI, National Institutes of Health, Bethesda, MD 20892, USA, chungj@nhlbi.nih.gov, ijeoma.muo@nih.gov.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31213865

Citation

Muo, Ijeoma M., et al. "Early Effects of Roflumilast On Insulin Sensitivity in Adults With Prediabetes and Overweight/obesity Involve Age-associated Fat Mass Loss - Results of an Exploratory Study." Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, vol. 12, 2019, pp. 743-759.
Muo IM, MacDonald SD, Madan R, et al. Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study. Diabetes Metab Syndr Obes. 2019;12:743-759.
Muo, I. M., MacDonald, S. D., Madan, R., Park, S. J., Gharib, A. M., Martinez, P. E., ... Chung, J. H. (2019). Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study. Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, 12, pp. 743-759. doi:10.2147/DMSO.S182953.
Muo IM, et al. Early Effects of Roflumilast On Insulin Sensitivity in Adults With Prediabetes and Overweight/obesity Involve Age-associated Fat Mass Loss - Results of an Exploratory Study. Diabetes Metab Syndr Obes. 2019;12:743-759. PubMed PMID: 31213865.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study. AU - Muo,Ijeoma M, AU - MacDonald,Sandra D, AU - Madan,Ritu, AU - Park,Sung-Jun, AU - Gharib,Ahmed M, AU - Martinez,Pedro E, AU - Walter,Mary F, AU - Yang,Shanna B, AU - Rodante,Justin A, AU - Courville,Amber B, AU - Walter,Peter J, AU - Cai,Hongyi, AU - Glicksman,Michael, AU - Guerrieri,Gioia M, AU - Ben-Dor,Rivka R, AU - Ouwerkerk,Ronald, AU - Mao,Stephanie, AU - Chung,Jay H, Y1 - 2019/05/27/ PY - 2019/6/20/entrez PY - 2019/6/20/pubmed PY - 2019/6/20/medline KW - aging KW - diabetes KW - incretins KW - inflammation KW - obesity KW - phosphodiesterase 4 SP - 743 EP - 759 JF - Diabetes, metabolic syndrome and obesity : targets and therapy JO - Diabetes Metab Syndr Obes VL - 12 N2 - Purpose: Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. Patients and methods: Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. Results: This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, (P-value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant (P=0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P=0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P=0.06), 3) decreased total and LDL cholesterol (P=0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P=0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject's age (P-value range= <0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. Conclusion: We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast's early effects on insulin sensitivity is indirect and likely mediated through roflumilast's prioritization of lipid over glucose handling. Clinical trials registration: NCT01862029. SN - 1178-7007 UR - https://www.unboundmedicine.com/medline/citation/31213865/Early_effects_of_roflumilast_on_insulin_sensitivity_in_adults_with_prediabetes_and_overweight/obesity_involve_age-associated_fat_mass_loss_-_results_of_an_exploratory_study L2 - https://dx.doi.org/10.2147/DMSO.S182953 DB - PRIME DP - Unbound Medicine ER -