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

Ijeoma M Muo, Sandra D MacDonald, Ritu Madan, Sung-Jun Park, Ahmed M Gharib, Pedro E Martinez, Mary F Walter, Shanna B Yang, Justin A Rodante, Amber B Courville, Peter J Walter, Hongyi Cai, Michael Glicksman, Gioia M Guerrieri, Rivka R Ben-Dor, Ronald Ouwerkerk, Stephanie Mao, Jay H Chung, Ijeoma M Muo, Sandra D MacDonald, Ritu Madan, Sung-Jun Park, Ahmed M Gharib, Pedro E Martinez, Mary F Walter, Shanna B Yang, Justin A Rodante, Amber B Courville, Peter J Walter, Hongyi Cai, Michael Glicksman, Gioia M Guerrieri, Rivka R Ben-Dor, Ronald Ouwerkerk, Stephanie Mao, Jay H Chung

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.

Keywords: aging; diabetes; incretins; inflammation; obesity; phosphodiesterase 4.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Spearman correlation demonstrating the significant associations among percentage changes in GLP-1 hormone and visceral adiposity in the leg skeletal muscle and in the abdomen, peripheral insulin sensitivity and leptin (A–F). Roflumilast induced alteration of insulin sensitivity is associated with changes in leptin (F) and in visceral adiposity (E). Notes: In this small study, the association of changes in GLP-1 AUC with changes in adiposity (A–C) suggests that roflumilast’s early effects on insulin sensitivity may be through reduction in adiposity and/or through incretin effect. Roflumilast-induced association between changes in soleus EMCL and L2-L3 visceral fat (D) highlights possible linkage between these two anatomically separate, visceral fat depot. Abbreviations: AUC, area under the curve; EMCL, extramyocellular lipid; GLP, glucagon-like peptide.
Figure 2
Figure 2
Spearman correlation demonstrating the age-associated effects of roflumilast on plasma free fatty acids and on fat mass loss. (A–D). The observed significant correlations (E and F) suggest that a majority of the changes in total body fat appears to stem from relative changes in fat mass in the leg and trunk regions.
Figure 3
Figure 3
Roflumilast induced changes among incretin hormones, inflammatory, and adhesion markers with statistical significance fall within a constellation. Both interval changes in ICAM and E-selectin were associated (A). After roflumilast but not before roflumilast, ICAM and GLP-1 (B) and E-selectin and GIP (C) were significantly associated. After roflumilast but not before roflumilast, ICAM is also significantly associated with MCP and TNF-α (D and E). Abbreviations: AUC, area under the curve; GIP, glucose-dependent insulinotropic polypeptide or gastric inhibitory peptide; GLP, glucagon-like peptide; ICAM, intracellular adhesion molecule; MCP, monocyte chemoattractant protein; TNF, tumor necrosis factor.
Figure 4
Figure 4
Spearman correlation demonstrating the significant associations among percentage changes in GIP hormone, adiponectin, and lumbar subcutaneous adiposity (A–D). Roflumilast induced change in lumbar subcutaneous adiposity is much more significantly associated with roflumilast-induced changes in the leptin and adiponectin ratio (D) than in interval changes in adiponectin ratio alone (C). Abbreviations: AUC, area under the curve; GIP, glucose-dependent insulinotropic polypeptide or gastric inhibitory peptide.
Figure 5
Figure 5
Working hypothesis for roflumilast’s age-associated beneficial changes in body composition. Abbreviation: cAMP, cyclic AMP.

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