Editorial
Current Knowledge and Perspectives for Pharmacological Treatment in OSA
Sébastien Baillieula, Renaud Tamisiera, Danny J. Eckertb,1, Jean-Louis Pépina,1,
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a Grenoble Alpes University, HP2 Laboratory, INSERM U1300 and Grenoble Alpes University Hospital, Grenoble, France
b Flinders Health and Medical Research Institute and Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia
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Eckert, Jean-Louis Pépin" "autores" => array:4 [ 0 => array:3 [ "nombre" => "Sébastien" "apellidos" => "Baillieul" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Renaud" "apellidos" => "Tamisier" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Danny J." "apellidos" => "Eckert" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] ] ] 3 => array:4 [ "nombre" => "Jean-Louis" "apellidos" => "Pépin" "email" => array:1 [ 0 => "JPepin@chu-grenoble.fr" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">1</span>" "identificador" => "fn0005" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Grenoble Alpes University, HP2 Laboratory, INSERM U1300 and Grenoble Alpes University Hospital, Grenoble, France" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Flinders Health and Medical Research Institute and Adelaide Institute for Sleep Health, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, Australia" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1354 "Ancho" => 2500 "Tamanyo" => 261884 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">From conventional continuous positive airway pressure therapy to emerging targeted pharmacological approaches for OSA. Abbreviations: PAP: positive airway pressure; OSA: obstructive sleep apnoea.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Obstructive sleep apnoea (OSA) impacts approximatively one billion people globally,<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">1,2</span></a> and is associated with detrimental cardiovascular, metabolic, and neurocognitive consequences, as well as bothersome diurnal symptoms that adversely impact daytime function and work productivity.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">3</span></a> It is now acknowledged that OSA is a highly heterogeneous condition encompassing various endophenotypes, defined as the association of clinical manifestations of OSA (phenotypes) and their underlying pathophysiological traits (endotypes).<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">4</span></a> Identification of these endophenotypes is a prerequisite for risk stratification and prognosis anticipation.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Continuous positive airway pressure (CPAP) is the first line treatment for severe OSA.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">3</span></a> CPAP primarily targets the anatomical endotype which is characterised by impaired upper airway (UA) anatomy and increased UA collapsibility.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">6</span></a> However, CPAP therapy termination rates remain high in unselected OSA populations, reaching 47.7% at three years after treatment initiation.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">7</span></a> At the era of precision medicine in OSA,<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">8</span></a> identification of the specific endophenotypes of OSA provides the foundation for research and development of tailored alternatives to the current “one size fits all” CPAP treatment approach.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">6</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Over the last two decades, the development of pharmacological therapies for the treatment of OSA and its associated symptoms have accelerated.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">6</span></a> These pharmacological therapies mainly target non anatomical endophenotypic traits or “treatable traits” (<span class="elsevierStyleItalic">i.e.</span>, reduced pharyngeal dilator function, high loop gain, low arousal threshold) existing in approximatively 70% of OSA patients (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">6,8–10</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Pharmaceutical approaches used as primary OSA therapies and dedicated to specific endophenotypic traits</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Reduced pharyngeal dilator function</span><p id="par0020" class="elsevierStylePara elsevierViewall">The loss of UA dilator muscle activity at sleep onset and the lack of muscle compensation during sleep in response to UA obstruction is one of the key pathophysiological mechanisms of OSA.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">6,11</span></a> Current pharmacological approaches targeting UA dilator muscle activity have largely focused on combinations of noradrenergic (to compensate the lack of noradrenergic activity in non-rapid eye movement sleep participating to sleep-related hypotonia of UA muscles) and antimuscarinic (to counteract the persistent muscarinic activity involved in muscle atonia in rapid eye movement sleep) agents. Four randomised, placebo-controlled, double-blind, crossover trials to date have investigated the effects of different combinations of noradrenergic and antimuscarinic agents on OSA severity. In two short term studies conducted over a single night, the combination of Atomoxetine (Ato, a norepinephrine reuptake inhibitor, 80<span class="elsevierStyleHsp" style=""></span>mg) plus Oxybutynin (antimuscarinic, broad M-subtype receptor selectivity, 5<span class="elsevierStyleHsp" style=""></span>mg) or Reboxetine (4<span class="elsevierStyleHsp" style=""></span>mg) plus hyoscine butylbromide (20<span class="elsevierStyleHsp" style=""></span>mg) reduced the apnoea-hypopnoea index (AHI) by 63%<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">12</span></a> or by 17<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>events/h,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">13</span></a> respectively. Perger et al.,<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">14</span></a> using a combination of Reboxetine (4<span class="elsevierStyleHsp" style=""></span>mg) and Oxybutynin (5<span class="elsevierStyleHsp" style=""></span>mg) over a one-week treatment period in 16 OSA subjects, showed a 59% median reduction in AHI, compared to a 6% median reduction under placebo. Interestingly, this reduction in OSA severity was paralleled by a significant improvement in reaction time on psychomotor vigilance test whereas no reduction in the score on the Epworth Sleepiness Scale was observed. The question of the optimal pharmacological combination and the underlying mechanism is still debated.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> The combination of Ato (80<span class="elsevierStyleHsp" style=""></span>mg) plus biperiden hydrochloride (2<span class="elsevierStyleHsp" style=""></span>mg, M1 muscarinic receptor selectivity) reduced perceived sleepiness whereas Ato (80<span class="elsevierStyleHsp" style=""></span>mg) plus solifenacin succinate (5<span class="elsevierStyleHsp" style=""></span>mg, M2 and M3 muscarinic receptor selectivity) modestly improves UA function with only a shift from obstructive apnoeas towards hypopnoeas during nonrapid eye movement sleep.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> Initial investigation of intranasal application of BAY2253651 in people with OSA, a potassium channel blocker targeting genioglossus muscle activation via pharyngeal mucosal receptor stimulation, yielded no significant therapeutic effect.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Low arousal threshold</span><p id="par0025" class="elsevierStylePara elsevierViewall">Low arousal threshold corresponds to the propensity to wake up too easily in response to respiratory events. This endotype may be important for 30–50% of OSA patients.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">17</span></a> Increasing the arousal threshold by using hypnotics can reduce OSA severity [see for review: Carter and Eckert<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">17</span></a>], challenging the common belief of the negative effects of hypnotics on UA physiology and breathing during sleep in OSA. One night of Zolpidem (10<span class="elsevierStyleHsp" style=""></span>mg) increased the arousal threshold without any change in pharyngeal muscle responsiveness nor OSA severity.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a> However, it increases sleep efficiency by approximately 10%, which may be beneficial in people with OSA and insomnia, the so called COMISA.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">19,20</span></a> The effect of adding Zolpidem (10<span class="elsevierStyleHsp" style=""></span>mg) to the Ato<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>Oxybutynin combination (80<span class="elsevierStyleHsp" style=""></span>mg and 5<span class="elsevierStyleHsp" style=""></span>mg, respectively) to counteract the modest, but present, wake-promoting properties of Ato has recently been investigated.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a> Zolpidem improved sleep efficiency without altering OSA severity. However, next-morning objective alertness was altered, warranting caution on the use of this combination.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">High loop gain</span><p id="par0030" class="elsevierStylePara elsevierViewall">The unstable or excessive ventilatory responses to carbon dioxide changes during sleep is associated with an increased risk of OSA and may concern up to one-third of OSA patients.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">6,10</span></a> Two carbonic anhydrase inhibitors, Acetazolamide and Zonisamide, are efficacious in reducing loop gain and subsequently AHI.<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">22,23</span></a> Interestingly, both Ato and Reboxetine may reduce ventilatory instability further reinforcing their effect on OSA severity.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">12,13,15</span></a> However, all these therapeutic approaches induced heterogeneous responses in terms of OSA severity reduction in unselected population. A prerequisite to their prescription would be the identification of the underlying endophenotypic traits at an individual level, which is accessible in clinical research but not disseminated in routine practice.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">6</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Pharmacological approaches as adjunct or combined therapies</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">OSA risk factors</span><p id="par0035" class="elsevierStylePara elsevierViewall">The American Thoracic Society consensus guidelines support the deployment of add-on therapies for body weight reduction in overweight or obese CPAP-treated OSA patients,<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a> essentially to reduce the burden of related comorbidities. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist is approved both for the treatment of type 2 diabetes and for weight management. After 32 weeks of treatment (3<span class="elsevierStyleHsp" style=""></span>mg daily) in obese patients with moderate/severe OSA, and as an adjunct to diet and exercise, significantly greater reductions in AHI, body weight, systolic blood pressure, and HbA1c were observed in comparison to placebo.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">25</span></a> A randomised, controlled multicentre trial (ROMANCE Study, EUDRACT No. 2014-000988-41) conducted in obese patients with comorbid type 2 diabetes and OSA, treated or not with CPAP, is investigating the effects of 26 weeks of subcutaneous liraglutide on OSA severity.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">26</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Nocturnal rostral fluid shift is another mechanism involved in the exacerbation of OSA severity [see for review: White et al.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">27</span></a>]. Different classes of diuretics, by targeting body fluid accumulation and fluid shift, may ameliorate OSA severity in selected patients.<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">28</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The effects of these medications targeting weight loss and fluid overload cannot be dissociated from lifestyle interventions and changes, including diet and exercise.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Residual diurnal symptoms</span><p id="par0050" class="elsevierStylePara elsevierViewall">Up to 10–15% of patients continue to experience excessive daytime sleepiness (EDS), one of the cardinal symptoms of OSA, despite appropriate management of OSA with CPAP or other primary therapies.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">29</span></a> Large multicentre randomised controlled trials have recently established the efficacy of solriamfetol (dopamine/norepinephrine reuptake inhibitor)<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">30,31</span></a> and pitolisant (selective histamine receptor-3 antagonist)<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">32,33</span></a> in reducing subjective and objective residual sleepiness. If these therapies are approved for clinical use, their long-term benefits and safety need to be established, specifically in OSA patients with cardiovascular comorbidities.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Perspectives in the next five years</span><p id="par0055" class="elsevierStylePara elsevierViewall">Pharmacological approaches may represent an effective alternative to CPAP treatment in selected patients presenting with specific endophenotypes. However, different pharmacotherapy approaches for OSA are at different stages of maturity. No pharmacological treatment has been approved for the primary treatment of OSA so far. Long-term efficacy and safety in comorbid populations remain to be established. The large-scale deployment of pharmacological therapy requires the following issues to be addressed:<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0060" class="elsevierStylePara elsevierViewall">Repositioning of already available drugs should be considered.</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0065" class="elsevierStylePara elsevierViewall">In a personalised approach to treat OSA, the therapeutic strategy of choice (device- or pharmacotherapy-based) should be related to the individual specific endophenotype and risk profile. Further investigations are required to standardise OSA clusters of phenotypes for their reproducible use in future clinical trials. An automation of the identification of endophenotypes of OSA is required, for their direct clinical use, by optimising already available tools such as gold-standard polysomnography.<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">34,35</span></a></p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">All patients may not benefit from pharmacological treatment. If these approaches may be beneficial in some, they may be ineffective or detrimental in others, especially in the long term. Cardiovascular, metabolic, and sleep-related comorbidities should be considered in the evaluation of pharmacological therapies. These steps may serve as accompanying the evolution of OSA treatment, combining precision and innovation, with the aim of delivering personalised therapies.</p></li></ul></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Competing interests statement</span><p id="par0075" class="elsevierStylePara elsevierViewall">Sébastien Baillieul, Renaud Tamisier and Jean-Louis Pépin are supported by the French National Research Agency in the framework of the “Investissements d’avenir” program (ANR-15-IDEX-02) and the “e-health and integrated care and trajectories medicine and MIAI artificial intelligence” Chairs of excellence from the Grenoble Alpes University Foundation (MIAI @ Grenoble Alpes, [ANR-19-P3IA-0003]).</p><p id="par0080" class="elsevierStylePara elsevierViewall">Danny J. Eckert is supported by a National Health and Medical Research Council (NHMRC) of Australia Senior Research (1116942) and Leadership Fellowships (1196261). He receives Cooperative Research Centre Project Grant Funding, a research collaboration between the Australian Government, Academia and Industry (Industry partner: Oventus Medical) and has research grants supported by Bayer, Takeda, Apnimed and Invicta Medical. He serves as a consultant for Bayer and Takeda and on the scientific advisory boards for Apnimed and Invicta Medical.</p><p id="par0085" class="elsevierStylePara elsevierViewall">These sponsors had no role in the writing of this editorial.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:5 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Pharmaceutical approaches used as primary OSA therapies and dedicated to specific endophenotypic traits" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Reduced pharyngeal dilator function" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Low arousal threshold" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "High loop gain" ] ] ] 1 => array:3 [ "identificador" => "sec0025" "titulo" => "Pharmacological approaches as adjunct or combined therapies" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "OSA risk factors" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Residual diurnal symptoms" ] ] ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Perspectives in the next five years" ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Competing interests statement" ] 4 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Co-senior authors.</p>" "identificador" => "fn0005" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1354 "Ancho" => 2500 "Tamanyo" => 261884 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">From conventional continuous positive airway pressure therapy to emerging targeted pharmacological approaches for OSA. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 44 | 30 | 74 |
| 2024 September | 61 | 19 | 80 |
| 2024 August | 83 | 47 | 130 |
| 2024 July | 54 | 34 | 88 |
| 2024 June | 64 | 39 | 103 |
| 2024 May | 98 | 32 | 130 |
| 2024 April | 46 | 37 | 83 |
| 2024 March | 67 | 37 | 104 |
| 2024 February | 55 | 40 | 95 |
| 2024 January | 45 | 36 | 81 |
| 2023 December | 102 | 26 | 128 |
| 2023 November | 99 | 45 | 144 |
| 2023 October | 109 | 32 | 141 |
| 2023 September | 90 | 51 | 141 |
| 2023 August | 52 | 34 | 86 |
| 2023 July | 64 | 28 | 92 |
| 2023 June | 77 | 41 | 118 |
| 2023 May | 81 | 42 | 123 |
| 2023 April | 88 | 61 | 149 |
| 2023 March | 114 | 78 | 192 |
| 2023 February | 101 | 38 | 139 |
| 2023 January | 83 | 83 | 166 |
| 2022 December | 109 | 74 | 183 |
| 2022 November | 177 | 221 | 398 |
| 2022 October | 855 | 373 | 1228 |
| 2022 September | 4 | 3 | 7 |
| 2022 August | 1 | 2 | 3 |
| 2022 July | 2 | 4 | 6 |
| 2022 June | 1 | 2 | 3 |
| 2022 May | 12 | 6 | 18 |
| 2022 March | 1 | 2 | 3 |
| 2022 February | 3 | 6 | 9 |
| 2022 January | 0 | 2 | 2 |
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