Title:An association between liraglutide treatment and reduction in excessive daytime sleepiness in obese subjects with type 2 diabetes

Transcription

1 Author's response to reviews Title:An association between liraglutide treatment and reduction in excessive daytime sleepiness in obese subjects with type 2 diabetes Authors: Fernando Gomez-Peralta (fgomezperalta@gmail.com) Cristina Abreu (cabreupadin@gmail.com) Jose Carlos Castro (jcastro@saludcastillayleon.es) Elvira Alcarria (elvira_alcarria@yahoo.es) Margarita Cruz-Bravo (margacruzbra@gmail.com) Maria Jesus Garcia-LLorente (mjgarciall@hotmail.es) Cristina Albornos (crisalbornos@hotmail.com) Concepcion Moreno (morenoconcha@hotmail.com) María Cepeda (mariacepe@hotmail.com) Francisca Almodovar (falmodovar@fhalcorcon.es) Version:2Date:1 November 2015 Author's response to reviews: see over

2 Fernando Gomez-Peralta, MD, PhD Endocrinology and Nutrition Unit Segovia General Hospital C/ Miguel Servet s/n, Segovia (Spain) Mobile: Segovia, October 29 th, 2015 Dear Arlene Pura, Thank you for sending your dated September 30 th We think that the comments and suggestions of change made by the reviewers on our original report: Influence of liraglutide on excessive daytime sleepiness in obese subjects with type-2 diabetes (Ref. No. MS: ) by Gomez-Peralta, et al. are appropriate and we have taken them into account in order to improve our present version. These changes in the revised paper have been highlighted using the Microsoft Word s Track Changes tool to easily identify them. We also believe that the criticisms made by the referees deserve further comments. These are enclosed in the present document and, following your suggestion, we submit them to review so that you may consider our paper for publication as an original manuscript in BMC Endocrine Disorders. All authors have critically revised the manuscript and approved this revision for its submission. The manuscript has not been submitted to another journal and is not being considered for publication elsewhere as a whole or in part in any language. We thank you so much for your kind consideration and stay looking forward to hearing from you. Yours sincerely, Fernando Gomez-Peralta, MD, PhD 1

3 Editor s comment Comment 1: My main concern is the conclusion that liraglutide improved EDS because it could be that just the weight loss that improved EDS. Hence the lack of a control arm is a major limitation for this study. The authors could attempt linear regression that will include final ESS or change in ESS as the outcome measure and variables such as age, gender, baseline weight, change in weight, change in A1c and baseline ESS etc. as predictors. And they can compare the change in ESS between patients who lost weight and those who did not. Response: We acknowledge that the lack of a control group may be a limitation that has already been taken into consideration when interpreting our study results, and so is commented in the Discussion section of the original manuscript. Nevertheless, this study was not conceived to compare treatment strategies in obese subjects with a diagnosis of type-2 diabetes, but to evaluate whether treatment with liraglutide was associated with an improvement of excessive daytime sleepiness (EDS), in order to learn about the conditions derived from routine clinical practice. Indeed, we did attempt linear regressions that included final Epworth Sleepiness Scale (ESS) and change in ESS as the outcome measures and variables, such as age, gender, baseline weight, change in weight, change in HbA1c, and baseline ESS, as predictors, leading to a non-significant association between these variables, except for baseline ESS. Furthermore, as requested, we did compare the change in ESS between patients who lost weight and those who did not, including those patients who either gained weight or stayed the same. Even though the comparison showed statistically significant differences in the change in ESS score between these two groups (- 1.6±2.9 vs 1.0±2.0; p<0.05), this comparison lacks of significance as the number of patients in each group was unbalanced as the vast majority of the patients had lost weight. 2

4 Comment 2: Another important point which is difficult for me to interpret is the negative correlations between ESS and weight...etc. This means that high ESS (i.e. patients with more EDS) had lower BMI and lower weight, why? You would expect OSA to be more common with higher BMI's especially that OSA is very common in patients with T2D. The authors need to discuss these correlations in more details. Response: Following to previous reviewer s comment regarding the negative correlation found between baseline ESS and baseline body weight, we rephrased the Discussion section, including specific comments on this issue. Briefly, obstructive sleep apnea (related to obesity) could be one of the causes of EDS, but there is increased daytime sleepiness without obstructive sleep apnea or obesity. In this context, previous studies have described that being overweight was not an independent risk factor for increased daytime sleepiness. a,b In fact, Dixon JB, et al. explained that not only the anthropometric measures, but also the general demographic, and biochemical parameters accounted for the ESS score variance. In fact, anthropometric parameters explained only 3% of ESS score variance. Comment 3: As many of the patients had normal ESS, have the authors analysed the data in those with only evidence of EDS or ESS > 10?" Response: We already analyzed the data (i.e. age, gender, duration of type-2 diabetes and the clinical and metabolic parameters) in those patients with an ESS score 10 or ESS score> 10, showing no statistically significant differences between these two groups. Reviewer 1: Nicolai Jacob Wewer Albrechtsen Major Compulsory Revisions Comment 1: Could the authors please explain why they chosen not to include a control group without liraglutide? Response: As explained previously (please, refer to Comment 1 of Editor), this study was designed to evaluate whether treatment with liraglutide was associated with an improvement of EDS in obese subjects with a diagnosis of type-2 diabetes in order to learn about the conditions derived from routine clinical practice. a Dixon JB, et al. Obesity (Silver Spring) 2007;15(10): b Vgontzas AN, et al. J Clin Endocrinol Metab 2000;85(3):

5 Comment 2: Could the authors describe if and how the ESS scores has been validated? Response: The ESS is a self-administered questionnaire that asks the patients the chances of their dozing in eight situations often encountered in daily life. It was firstly described in 1991 (ref. No. 12 in the manuscript). c The ESS was initially validated in English in the original version, d and subsequently in other languages, such as Spanish. e It has been used in clinical trials and meta-analysis and it is broadly recommended as a diagnostic tool of EDS in evidence-based clinical guidelines as validated subjective sleepiness/somnolence measure. f Comment 3: In RESULTS section under subsection CHANGES at ESS SCORE,,, "Pairwise comparisons showed that the ESS score significantly decreased from baseline to month 1 (6.3 ± 4.6 vs 4.9 ± 3.9; p<0.001) and from baseline to month 3 (5.7 ± 4.4 vs 4.2 ± 3.6; p<0.001" why is the baseline different? Response: Following reviewer s comment, we have thoroughly reviewed this aspect and confirm that only subjects with both baseline and endpoint data were included in the comparisons analyses in order to provide the best statistical rigor. That is the reason for different baseline values for each parameter when two different time points are analyzed. Comment 4: Why did the authors not used a one way ANOVA since they compared many variables and in addition baseline to 1 month and to 3 month Response: We did not use a one way ANOVA, as this tests the significance of group differences between more than groups, in order to determine that there is a difference between groups, but it does not tell which one is different. However, the t- test looks at differences between two groups on some variables of interest. c Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14: d Johns MW. Daytime sleepiness, snoring, and obstructive sleep apnea. The Epworth Sleepiness Scale. Chest. 1993;103(1):30-6. e Chiner E, et al. Validation of the Spanish version of the Epworth Sleepiness Scale in patients with a sleep apnea syndrome. Arch Bronconeumol. 1999;35(9): f Balk EM, et al. Diagnosis and Treatment of Obstructive Sleep Apnea in Adults. Comparative Effectiveness Review No. 32. (Prepared by Tufts Evidence-based Practice Center under Contract No ). AHRQ Publication No. 11-EHC052-EF. Rockville, MD: Agency for Healthcare Research and Quality. July Available at: 4

6 Minor Essential Revisions Comment 1: OSA - please spell out the first time used Response: Following reviewer s suggestion, we have carefully reviewed the text and besides the appearance in the Abstract and Keywords sections (not abbreviated as this term does not appear again in these sections, p. 2 of the original manuscript), we confirm that we have spelled out the term OSA the first time it has been used in the text, please refer to p. 3 (Introduction section) of the original manuscript. Comment 2: "After three months of treatment with liraglutide, significant reductions were achieved in the means of body weight (102.8 ± 17.9 kg vs 98.4 ± 16.9 kg, p<0.001), BMI (39.6 ± 6.8 kg/m 2 vs 37.9 ± 6.4 kg/m 2 ; p<0.001), waist circumference (122.1 ± 14.0 cm vs ± 13.3 cm; p<0.001) and neck circumference (42.2 ± 3.3 cm vs 40.8 ± 3.3 cm; p<0.005), while the body fat percentage hardly changed from baseline to month 3 (42.1 ± 7.6 % vs 41.2 ± 8.1 %; p= 0.173)." Results section. This is rather unclear if these values are from baseline to 3 month or? please change accordingly. Response: Following reviewer s suggestion, we have carefully reviewed the data presented in this section and we do confirm that the values presented are from baseline to 3 month. Therefore, we have modified the text accordingly to avoid confusion. The text now appears as follows: After three months of treatment with liraglutide, significant reductions were achieved in the means of body weight (102.8 ± 17.9 kg vs 98.4 ± 16.9 kg, p<0.001), BMI (39.6 ± 6.8 kg/m2 vs 37.9 ± 6.4 kg/m2; p<0.001), waist circumference (122.1 ± 14.0 cm vs ± 13.3 cm; p<0.001) and neck circumference (42.2 ± 3.3 cm vs 40.8 ± 3.3 cm; p<0.005), while the body fat percentage hardly changed from baseline to month 3 (42.1 ± 7.6 % vs 41.2 ± 8.1 %; p= 0.173). 5

7 Reviewer 2: Jacqueline Cleator Major Compulsory Revisions Comment 1: Title: Consider an alternative title. An influence suggests causality and this has not currently been demonstrated. An association between liraglutide treatment and reduction in EDS may be a better approach. Response: Following reviewer s request, we decided to change the title of the original manuscript in order to avoid confusion, as follows: An association between liraglutide treatment and reduction in EDS in obese subjects with type 2 diabetes Comment 2: Background: There is an established relationship between OSA and EDS and as OSA is common in this clinical group it would be helpful to include discussion of this in this section. Response: Following reviewer s suggestion, we have introduced this relationship in the Background section, as well as new references (page 3 of the original manuscript). Therefore, the reference numbers have updated accordingly. The text of the first paragraph now appears as follows: Abnormal sleep patterns (ASPs), characterized by short or long durations of sleep and excessive daytime sleepiness (EDS), have a considerable impact on an individual s health [1]. Obstructive sleep apnea (OSA) is the most common form of ASP, characterized by the repetitive complete or partial collapse of the upper airway during sleep [2]. There is a growing body of literature describing the association between ASPs and the subsequent development of type-2 diabetes, even in nonobese individuals [3-7]. EDS is more prevalent in subjects with diabetes and in subjects with insulin resistance, a well-known prediabetic condition [7,8]. Additionally, OSA has also been shown to impact on glycemic control among diabetic patients, independently of obesity [8]. Comment 3: Methods: Study subjects: A pre-existing - The study numbers with OSA need to be identified. Response: We used the ESS as a measure for EDS, as in our study we addressed to evaluate the effect of liraglutide treatment on EDS in obese subjects with type-2 diabetes. Indeed, we agree that EDS is part of the constellation of the OSA syndrome and that the ESS is commonly used to screen for OSA. Despite all these, 6

8 we were not looking for changes in OSA measurements (e.g. apnoea hypopnoea index in polysomnography). The study numbers of patients with a diagnosis of OSA was not registered, as a pre-existing clinical diagnosis of OSA was not deemed necessary for study inclusion. Nevertheless, as detailed in the Results section (p. 6 of the original manuscript), 26 (17.4%) patients presented an ESS score > 10 at baseline. Statistical considerations: means were compared with Was an attempt made to control for confounding factors in the analysis? Response: We do confirm that at the time of study analyses, we did not control for confounding factors. Comment 4: Results: Subject characteristics: Between March justification for the sample size needed Response: Following reviewer s comment, the justification of the sample size for the study was: Based on the results of the study conducted by Russell-Jones, et al g, the present study was designed to detect a decrease in HbA1c of 1±2% after 12 weeks of treatment with liraglutide. Statistical analysis was performed at twosided with an alpha-error of 0.05 and a risk beta of Based on these parameters, a sample size of at least 50 patients was therefore necessary. Nevertheless, we decided not to justify the sample size in the original manuscript, as there is no sound basis for this requirement in observational studies, which not only does not promote the transparency of research reports but rather contributes to undermining it h. g Reference: Russell-Jones, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+su): a randomized controlled trial. Diabetologia 2009;52(10): h Silva Ayçaguer LC(1), Alonso Galbán P. [Explanation of samples sizes in current biomedical journals: an irrational requirement]. Gac Sanit. 2013; 27(1):53-7 7

9 Correlation of ESS score : I find the reporting of the correlations confusing and in need of more clarification. The baseline correlations are actually quite weak, as is the changes in ESS score and reductions in weight correlation (presumably at 3 months). Were any attempts made to perform partial correlations and control for weight in changes in ESS score? This would determine if the relationship was independent of weight loss. Response: Following reviewer s comment, we performed partial correlations and controlling for weight in changes of ESS score, showing no significant relation between these variables, although we could suggest that there is a tendency, as the p-value was We agree that the main determinant of ESS improvement in this population could be the weight reduction. In fact, weight reduction is a leading effect of liraglutide treatment. However, due to the absence of a unique statistical correlation between both variables changes and the previous scientific evidence published, we discussed about other possible additional effects of liraglutide mechanistically involved in ESS reduction. Comment 5: Discussion Para 1. Again, I m not sure an effect has been demonstrated it is more an association, as reflected in the hypothesis at the end of the background section. Please consider altering the wording to reflect this. Response: We have thoroughly considered the reviewer s comment and completely agree. Therefore, following the reviewer s comment we have changed it in the Discussion section of the original manuscript (page 7), as follows: To the best of our knowledge, this is the first study demonstrating the effect association of liraglutide treatment on the management of EDS over a short period of time in obese subjects with type 2 diabetes in routine clinical practice. 8

10 Para 3. This sentence is unclear. if you are saying ASPs ( which includes EDS) and OSA are different entities then this is all the more reason to account for the OSA status of your sample. Also, you have used the ESS as a measure of EDS and acknowledged its usefulness in predicting OSA, so I m unclear how these arguments follow. Please clarify this discussion. Response: We rephrased this part of the discussion, according to your suggestion. Please, refer to lines of the Discussion section. Para 4 Therefore, long acting. Please revise - I think more work is needed to establish the exact nature of the direct and indirect effects of liraglutide on EDS before claiming this. Response: We agree that the main determinant of ESS improvement in this population could be the weight reduction, a leading effect of liraglutide. However, due to the absence of a unique statistical correlation between both variables changes and the previous scientific evidence published and commented on the text, we discussed other possible additional effects of liraglutide mechanistically involved in ESS reduction. We believe that there is a place for speculation on additional effects of GLP1 receptors agonists on EDS because there is not a definitive explanation for that effect. We think that this part of the discussion enriches the manuscript and could be appreciated by the interested audience. Para 5. The limitations also need to consider other factors in a free living environment that might impact on the results such as diet and exercise. Eg. Weight loss may increase activity, which may improve EDS. Response: Following reviewer s suggestion, we have included this limitation in the Discussion section (page 9). The text appears as follows: (...) Furthermore, other factors in a free living environment might impact on the results, such as diet or exercise. Finally, it It can be ascertained from the lack of a comparator group and the retrospective nature of the study design that biases could have been introduced when collecting data. Discretionary Revisions Results -Subject characteristics Para 1. If the data are available it would be useful to see how the score of 17.4% correlates with those with or without a diagnosis of OSA. 9

11 Response: We do agree with the reviewer s comment: it would have been very useful to see how those 26 (17.4%) patients with an ESS score > 10 correlated with or without a diagnosis of OSA. However, the diagnosis of OSA was not collected at the time of data retrieval. Discussion Para 3 Although GLP-1 action so to strengthen this argument, was a relationship demonstrated between reduction in waist and EDS? this does not appear to be reported Response: We do agree with the reviewer s comment: we found a demonstrated correlation between waist circumference and EDS. Accordingly, we rephrased this discussion section and added this information in order to clarify the manuscript. Minor issues not for publication Discussion: Para 3.The word data is plural. Response: We have eliminated this word, as well as the sentence, as we have attempted to correct the Discussion section. 10