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  244  Journal of Clinical Sleep Medicine, Vol.6, No. 3, 2010 D iabetes mellitus (DM) has been regarded as a major public health concern and one of the main causes of morbidity and mortality. The potential effect of gender on DM develop-ment has been extensively addressed in the literature. A clear male predominance of type 1 DM is seen across the age range. However, type 2 DM, which accounts for almost 90% of all DM cases, particularly in association with the increasing obe-sity rate, occurs more frequently in women. 1  Moreover, many of the complications such as diabetic ketoacidosis, dyslipidemia,  peripheral vascular disease, and lipodystropathy, as well as hy- pertension, coronary artery disease (CAD), and sudden death are more common in diabetic women compared to men with DM. 1,2  Obstructive sleep apnea (OSA) is characterized by repeti-tive collapse of the upper airway during sleep, which leads to  progressive hypoxia and hypercapnia. The prevalence of OSA  before the age of 60 is known to be two or three times as high in men as in women. 3  Hormonal changes during menopause may  be the cause of a change in this proportion at higher age. In sleep clinic cohorts, female OSA patients are usually older and more obese than male subjects with OSA at the time of the diagnosis. 4  The risk factors age and central abdominal obesity are com-mon both in OSA and DM. Several cross-sectional studies have identied a higher prevalence of OSA among adults with in-sulin resistance or DM. 5,6  Likewise, there are data suggesting a higher prevalence of DM in subjects with OSA independent of age, gender, and obesity. 7  In a recent report from Australia, moderate to severe OSA was suggested to be a signicant risk factor for incident DM in a population-based cohort. 8  More-over, OSA and DM may constitute additional or synergistic risk factors for cardiovascular morbidity and mortality. 9  Hence, the International Diabetes Federation Taskforce on Epidemiology and Prevention has recently recommended that health profes-sionals working in both DM and OSA should ensure that a pa-tient presenting with one condition is considered for the other. 10 In general, several reports have displayed a link between sleep duration and impaired insulin metabolism suggesting that sleep loss could also contribute to development of DM. 11  In one study, a relationship between short (≤ 6 h) or long (≥ 8 h) sleep duration and increased risk of DM was found in middle-aged women but not in men. 12  Conversely, another study demonstrat-ed a higher incidence of DM in men with short or long sleep du-ration. 13  However, less is known regarding the impact of gender in the development of DM in OSA patients. Habitual snoring, a surrogate marker of OSA, was found to be a risk factor for the development of DM over 10 years, independent of confounding Impact of Gender on Incident Diabetes Mellitus in Obstructive Sleep Apnea: A 16-Year Follow-Up Yelda Turgut Celen, M.D. 1 ; Jan Hedner, M.D., Ph.D. 2 ;   Jan Carlson, M.D. Ph.D. 2 ; Yüksel Peker, MD., Ph.D. 1,2 1 Sleep Medicine Unit, Department of Neurology and Rehabilitation Medicine, Skaraborg Hospital, Skövde, Sweden; 2 Sleep Laboratory, Department of Pulmonary Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden     S    C    I    E    N    T    I    F    I    C     I    N    V    E    S    T    I    G    A    T    I    O    N    S Study Objective:  To address the inuence of gender and ob-structive sleep apnea (OSA) on development of diabetes mel-litus (DM) in a sleep clinic cohort. Design:  A longitudinal observational study. Participants:  A consecutive middle-aged (30-69 years) sleep clinic cohort from 1991 (n = 318; 254 men, 64 women) with eli-gible baseline characteristics, clinical charts, and information from the Swedish Hospital Discharge Registry were identied. Ten individuals with DM at baseline and 47 patients who died during the follow-up period were excluded. Measurements:  The remaining 261 subjects were asked to complete a postal questionnaire regarding concomitant dis-eases including DM, diagnosed by a physician. Results:  In total, 168 patients (64.4%) replied. The incidence of DM was 24.9% in patients with OSA (overnight oxygen de-saturations ≥ 30 in 1991) compared with 10.8% in subjects without OSA (p = 0.020). New-onset DM in men was 19.1% in OSA vs  11.1% in non-OSA (n.s.), while the corresponding values in women were 50.0% in OSA and 9.5% in non-OSA (p = 0.022). In a multivariate analysis, DM was predicted by OSA in women with an odds ratio (OR) of 11.8, but not by age, body mass index (BMI) at baseline, or weight change at follow-up. In men, only BMI (OR 1.16) predicted DM. Conclusion:  The contribution of OSA to DM development seems to be gender-dependent and higher in women than in men. Keywords:  Diabetes mellitus, gender, sleep apnea Citation:  Celen YT; Hedner J; Carlson J; Peker Y. Impact of gender on incident diabetes mellitus in obstructive sleep ap-nea: a 16-year follow-up. J Clin Sleep Med   2010;6(3):244-250. BRIEF SUMMARY Current Knowledge/Study Rationale: Cross-sectional studies sug-gest an independent association between obstructive sleep apnea and diabetes mellitus. Few data exist regarding the incident diabetes in sleep-clinic cohorts at long-term and impact of gender in this context. Study Impact:  This 16-year follow-up study demonstrates an increased incidence of physician diagnosed diabetes mellitus among patients with obstructive sleep apnea with signicant oxygen desaturations. The con-tribution of intermittent hypoxemia to diabetes development seems to be gender dependent and higher in women than in men.  245  Journal of Clinical Sleep Medicine, Vol.6, No. 3, 2010 Incident Diabetes in Sleep Apnea and Gender  factors in a community-based male population. 14  A more recent  prospective study associated snoring and sleepiness with an el-evated risk of DM in the female population, 15  and this gender difference was also demonstrated for the relationship between DM and snoring/witnessed apnea. 16  Thus, the existing evidence regarding the inuence of gender on the development of DM in OSA patients is mostly based on the self-reported question-naires rather than the objective measures of OSA. In the current study, we addressed the impact of gender on development of DM in a consecutive sleep clinic cohort with OSA diagnosed by overnight polygraphy. METHODSStudy Population The study population has been described in detail elsewhere. 17  In brief, 370 consecutive cases referred to the sleep laboratory with a history of snoring and/or witnessed apnea underwent an overnight polygraphic recording in the sleep laboratory. The pa-tients were enrolled regardless of a history of excessive daytime sleepiness (EDS). By review of baseline data of this cohort, 20 young (age < 30 y) and 17 elderly (age > 69 y) subjects were ex-cluded. Likewise, 15 individuals who had moved abroad or could not be identied and/or localized by the Population Register of the National Tax Board of Sweden were excluded ( Figure 1 ). For the remaining 318 middle-aged (30-69 y) subjects, complemen-tary information on health status was obtained from the Swedish Hospital Discharge Register (SHDR) via the Center for Epidemi-ology, National Board of Health and Welfare (see below) as well as from clinic charts from the event of the baseline recording. Ten  patients who had DM at baseline were excluded. Each subject was followed up for 16 years from January 1, 1991, to December 31, 2007. Forty-seven patients died during the follow-up period. The remaining 261 subjects were asked to complete a question-naire (see below). After one reminder by post, 168 (64.4%) re- plied by December 31, 2007, and were identied for the present study ( Figure 1 ). The Ethics Committee of the Medical Faculty of the University of Gothenburg approved the study protocol. Baseline Investigations All overnight sleep studies were assessed in the sleep laborato-ry. Investigations were initiated at approximately 23:00 and nal-ized at 06:00. Lights out and lights on were recorded along with the subjective sleep quality and subjective sleep duration. The mean estimated sleep time was empirically chosen to be 6 h. The investigation included a continuous recording of transcutaneous arterial oxygen saturation (SpO 2 ) via a nger probe (BIOX 3700; Ohmeda, Louisville, CO), nasal and oral airow recorded via a thermistor, and respiration and body movement monitored via a static charge sensitive bed (SCSB [Bio-matt; Biorec Inc., Raisio, Finland]). Signals were amplied and recorded on a lter pen recorder (Kipp & Zonen, Delft, Holland). An apnea was scored when SpO 2  dropped by at least 4% from the immediately preced-ing baseline simultaneously with absence of nasal and oral air-ow as well as presence of chest movements for > 10 s. Scoring was made manually from each recording strip by trained techni-cians unrelated to the study itself. The total number of signicant oxygen desaturations (OD) as well as the minimal SpO 2 reached during the overnight recording (SpO 2 min) was determined. An overnight OD ≥ 30 was dened as OSA. This value was based on  previously established diagnostic criteria 18  of an apnea index ≥ 5 for the sleep apnea syndrome, which was accepted at the time of the baseline investigations. The oxygen desaturation index (ODI) was dened as the average number of OD per hour. Body weight and height was measured at the time of sleep investigation. Body mass index (BMI) was calculated according to the formula body weight divided by height squared. Swedish Hospital Discharge Register The Swedish Hospital Discharge Register (SHDR) covers all public inpatient care since 1987. In the SHDR, there are 4 different types of information: patient related data (personal identication number, sex, age, place of residence); hospital related data (county council, hospital, department); administra-tion related data (date of admission, discharge, length of stay, acute or planned admission, admitted from, discharged to); and medical data (main diagnosis, secondary diagnoses, external cause of injury and poisoning, surgical procedures). The classi-cation of diseases was implemented according to ICD-9 codes until 1997 and ICD-10 codes thereafter. Data from the SHDR was obtained for a 3-year extension period prior to as well as a 7-year period following the baseline investigation. Questionnaires The postal questionnaires, sent to 261 survivors in the begin-ning of 2007, included questions regarding current height and weight, history of smoking, concomitant diseases (including DM) diagnosed by a physician, as well as hospital admissions, ongoing medication, and treatment for snoring or OSA during the follow-up period. Information regarding self-reports of physician diagnosed DM was checked with the SHDR reports. Drugs that were registered include those listed within the anatomical thera- peutic chemical classication system codes C01–C08. 19  BMI gain was dened as a change in BMI values from 1991 to 2007. Treatment of OSA OSA treatment was initiated by different physicians ac-cording to the clinical routines depending on severity of the sleep related breathing disorder, the extent of EDS, and social Figure 1 —Patient log demonstrating the study cohort and the different subgroups  246  Journal of Clinical Sleep Medicine, Vol.6, No. 3, 2010 YT Celen, J Hedner, J Carlson et al aspects of loud snoring. Treatment with continuous positive airway pressure (CPAP), surgery (uvulopalatopharyngoplasty [UPPP]), oral device, or weight counseling was offered to the  patients in accordance with the prevailing contemporary rou-tines. All patients undergoing surgery were invited for postop-erative sleep study to evaluate the effectiveness of treatment. In the event of therapeutic failure, patients were offered CPAP or oral device. Therapeutic CPAP titration was performed ac-cording to the prevailing manual standardized procedure, us-ing CPAP nasal pressure monitoring in an overnight laboratory setting. The therapeutic effect of CPAP was routinely reinves-tigated 3 and 12 months after the initiation of treatment. Ob- jective evaluation of CPAP use was obtained from the device time-counter (hours divided by days since last recording). In-completely treated cases were regarded as OSA patients with-out treatment or with remaining OSA in spite of treatment with UPPP, oral device, or daily CPAP run-time < 50% of estimated sleep time at the rst year follow-up. OSA patients who had stopped using CPAP devices according to the 2007 follow-up questionnaire were also regarded as incompletely treated. Ef-ciently treated OSA patients were dened as patients with OD < 30 at the renewed sleep study following UPPP, on treatment with oral device, or on CPAP with an objective daily CPAP run-time ≥ 50% of estimated sleep hours. Subjects regarded as inefciently treated at 1 year were included in the efciently treated group at 16-year follow-up if they were on CPAP ther-apy according to the questionnaires. Statistics Statistical analysis was performed using the statistical analysis program SPSS 15.0 for Windows (SPSS, Chicago, IL). Continuous values are given as means ± SD. A p val-ue (2-sided) ≤ 0.05 was regarded as statistically signicant. The χ  2  test and Fisher exact test were used for comparison  between categorical variables; when the comparison involved continuous variables, the t test was used. The nonparametric test (Mann-Whitney) was used when the normal distribution criteria was not the case. The inuence of multiple variables was analyzed using multiple logistic regression analysis. All signicant variables that correlated with the outcome mea-sures in the univariate analyses were subsequently included in a multiple logistic regression model, and adjusted odds ratios (OR) were calculated from the regression coefcients in men and women, respectively. All ORs are presented with their 95% condence intervals (CI). RESULTS A total number of 168 participants without DM in 1991 (137 men, 31 women; mean age 48.2 ± 9.0 years, mean BMI 26.6 ± 3.8 kg/m 2  at baseline) replied to the questionnaires in 2007 ( Figure 1 ). The response rate did not differ signicantly  between men (64.3%) and women (64.5%). No signicant dif-ference was found between responders and nonresponders with regard to age (48.2 vs  46.8 y), BMI (26.6 vs  26.7 kg/m 2 ), current smoking (38.1% vs  39.3%), OSA diagnosis (33.9% vs 29.9%), or severity of OSA in terms of ODI (6.3 vs  7.4 /h) and SpO 2 min (85.8% vs  86.4%) at baseline.OSA was present at baseline in almost a third of the nal male and female cohorts ( Figure 1 ). Patients with OSA were older and had a higher BMI than the subjects without OSA at  baseline, but the proportion of current smokers did not differ signicantly between the groups ( Table 1 ). As shown in Table 2 , both male and female OSA patients had a higher BMI at baseline than the respective non-OSA groups. OSA in women was also associated with a higher age. In sub- jects without OSA, there was no gender difference regardng age or BMI at baseline; whereas in the OSA group, women were signicantly more obese and older than men ( Table 2 ). Table 2 —Demographic and clinical characteristics of males and females in 1991 and 2007 stratied by OSA VariableOSAnon-OSAp valueMales N4790 Age at baseline, years49.4 ± 7.8 a 47.0 ± 9.30.147BMI in 1991, kg/m 2 27.6 ± 3.5 b 25.8 ± 3.50.002BMI in 2007, kg/m 2 28.8 ± 4.3 c 27.4 ± 5.00.103Current smokers in 1991, n (%)15 (31.9)34 (37.8)0.497Current smokers in 2007, n (%)8 (17.0)15 (16.7)0.958ODI, n/h19.1 ± 17.21.8 ± 1.8< 0.001SpO 2 min, %81.0 ± 7.688.5 ± 3.8< 0.001 Females N1021 Age at baseline, years54.3 ± 6.8 a 47.8 ± 10.30.047BMI in 1991, kg/m 2 30.5 ± 5.0 b 26.0 ± 4.90.028BMI in 2007, kg/m 2 33.1 ± 6.0 c 28.1 ± 5.90.044Current smokers in 1991, n (%)4 (40.0)11 (52.4)0.704Current smokers in 2007, n (%)2 (20.0)7 (33.3)0.677ODI, n/h15.3 ± 11.01.4 ± 2.0< 0.001SpO 2 min, %77.0 ± 6.488.6 ± 6.0< 0.001Continuous variables are expressed as mean ± SD, statistics by unpaired Student’s t   test. Comparison of groups by χ 2 test or Fisher exact test (two-sided). OSA refers to obstructive sleep apnea; BMI, body mass index; ODI, oxygen desaturation index; SpO 2 min, minimum oxygen saturation; a p = 0.070; b p = 0.033; c p = 0.010. Table 1 —Demographic and clinical characteristics of the nal study population in 1991 and 2007 VariableOSAnon-OSAp value(n = 57)(n = 111)Age at baseline, years 50.2 ± 7.847.2 ± 9.460.030 Male gender, n (%) 47 (82.5)90 (81.1)0.828 BMI in 1991, kg/m 2 28.2 ± 3.925.8 ± 3.5 < 0.001 BMI in 2007, kg/m 2 29.6 ± 4.927.5 ± 5.10.015 Current smokers in 1991, n (%) 19 (33.3)45 (40.5)0.362 Current smokers in 2007, n (%) 10 (17.5)22 (19.8)0.722 ODI in 1991, n/h 18.4 ± 16.71.7 ± 1.8 < 0.001 SpO 2 min in 1991, % 80.3 ± 7.588.6 ± 4.3 < 0.001Continuous variables are expressed as mean ± SD, statistics by unpaired Student t   test. Comparison of groups by χ 2 test. OSA refers to obstructive sleep apnea; BMI, body mass index; ODI, oxygen desaturation index; SpO 2 min, minimum oxygen saturation  247  Journal of Clinical Sleep Medicine, Vol.6, No. 3, 2010 Incident Diabetes in Sleep Apnea and Gender  When addressing the signicant predictors in men and wom-en, respectively, incident DM was associated with BMI and ODI in men and with OSA and SpO 2 min in women in univari-ate analysis ( Table 4 ). In a multivariate model, ODI was no lon-ger signicant after adjustment for age and BMI in men ( Table 5 ). In women, both OSA and SpO 2 min remained as signicant  predictors. Including weight gain into the multivariate analysis did not change the outcome of the study. As the distribution of incident DM did not differ signicantly between efciently treated vs  inefciently treated OSA patients in men (5 vs  4) or women (2 vs  3), the treatment factor was not included in the multivariate analysis. DISCUSSION This sleep clinic study has demonstrated a markedly in-creased incidence of DM in patients with OSA during a follow-up period of 16 years. Moreover, our results suggest that the contribution of OSA to DM development seems to be gender-dependent and higher in women than in men. To our knowledge, this is the rst long-term, observation-al study of incident DM with regard to gender difference in a sleep-clinic cohort. The strength of this study is the construc-tion of an inception cohort with known OSA status, free of out-come measures at baseline as well as the use of SHDR from a well-organized public epidemiologic center providing reliable After the baseline investigations, treatment of OSA was initi-ated with CPAP (n = 20) and/or UPPP (n = 26) and/or an oral device (n = 7), whereas no active treatment was considered in 14 (24.6%) patients with either mild OSA and/or absence of EDS. Among the CPAP-treated OSA patients, 6 (30.0%) cases returned the device or had low compliance with treatment at follow-up. Two of these received sucessful treatment with an oral device. Of the subjects undergoing UPPP, 15 (57.7%) still exhibited OSA at the follow-up recording. Three of these pa-tients were given CPAP and 2 received oral devices. Among 7 subjects receiving an oral device, 4 were considered inefcient-ly treated, and 2 of these were allocated to CPAP therapy. Thus, in the whole cohort, 31 (54.4%) OSA patients were regarded as efciently treated by CPAP and/or UPPP and/or oral device.  No difference was observed with regard to gender in treatment effectiveness (55.3% in men vs 50.0% in women). Based on questionnaires, incident DM, diagnosed by a phy-sician, was reported in 26 cases (15.5%). Of these, 14 had OSA (24.6%) and 12 did not (10.8%; p = 0.020). In the whole cohort, regardless of OSA diagnosis at baseline, 19 men (13.9%) and 7 women (22.6%; n.s) reported DM at follow-up. As illustrated in Figure 1 , DM was reported by 9 OSA patients and by 10 non-OSA subjects in men (n.s) and by 5 OSA patients and 2 non-OSA subjects (p = 0.022) in women. When comparing the subgroups of OSA patients with incident DM with regard to gender, the women were older (mean age 56.0 ± 6.1 vs  48.0 ± 4.7 y; p = 0.018) and slightly more obese (mean BMI 30.1 ± 6.6 vs  29.0 ± 3.9 kg/m 2 ; n.s), but had a markedly lower severity of OSA (mean ODI 8.4 ± 1.5 vs 30.8 ± 29.0/h; p = 0.050). When analyzing the baseline non-OSA group, 9 men but none of the women reported new-onset OSA during the follow-up period, according to information obtained from question-naires. Three of these 9 cases (33.3%) with new-onset OSA reported incident DM at the same time. Among the remaining 81 men without new-onset OSA, the incidence of DM was re- ported in 7 (8.6%; p = 0.059). Compared with the baseline val-ues, there was a marked increase in BMI at follow-up (27.6 ± 4.9 vs  31.3 ± 10.8 kg/m 2 ; p = 0.041) in the incident DM cases in the non-OSA group. In a subanalysis, when the efciently treated OSA patients (15 males and 4 females) were switched to the non-OSA group, there was a slight increase in incident DM among the OSA pa-tients in both genders. As shown in Table 3 , males with incident DM had higher BMI than the subjects without DM and demonstrated higher ODI. In the female group, the incident DM patients were older than the non-DM cases. OSA was more prevalent and more se-vere in the incident DM cases compared to the subjects without DM ( Table 3 ). When including a gender term and testing for interactions, there was a tendency for interaction between gender and OSA with regard to incident DM. Within the non-OSA group, dif-ference between DM incidence among men and women was very small (11% vs  9%) while this difference was considerably greater within the OSA group (19% vs 50%). However, this tendency did not reach statistical signicance when interaction term “gender x OSA” was tested in a multiple regression model (p = 0.172), probably because of the small number of women in the OSA group. Table 3 —Demographic and clinical characteristics of males and females stratied by incident DM Variableincident DMno DMp valueMales N19118 Age at baseline, years45.6 ± 6.2 a 48.2 ± 9.20.129BMI in 1991, kg/m 2 28.1 ± 4.026.1 ± 3.20.016BMI in 2007, kg/m 2 30.2 ± 2.227.5 ± 3.9 b 0.024Current smokers in 1991, n (%)5 (26.3)44 (37.3)0.445Current smokers in 2007, n (%)2 (10.5)21 (17.8)0.740OSA at baseline, n (%)9 (47.4)38 (32.2)0.196ODI, n/h15.8 ± 24.36.4 ± 10.10.048SpO 2 min, %83.6 ± 9.9 c 86.4 ± 5.70.296 Females N724 Age at baseline, years55.1 ± 6.6 a 48.4 ± 10.00.054BMI in 1991, kg/m 2 28.4 ± 5.127.1 ± 5.40.583BMI in 2007, kg/m 2 30.0 ± 5.529.7 ± 6.6 b 0.899Current smokers in 1991, n (%)3 (42.9)12 (50.4)1.000Current smokers in 2007, n (%)2 (28.6)7 (29.2)1.000OSA at baseline, n (%)5 (71.4)5 (20.8)0.022ODI, n/h7.0 ± 2.85.6 ± 10.30.027SpO 2 min, %76.6 ± 8.9 c 87.3 ± 6.30.006Continuous variables are expressed as mean ± SD, statistics by unpaired Student’s t   test or Mann-Whitney test. Comparison of groups by χ 2 test or Fisher exact test (two-sided). OSA refers to obstructive sleep apnea; BMI, body mass index; ODI, oxygen desaturation index; SpO 2 min, minimum oxygen saturation; a p = 0.002; b p = 0.034; c p = 0.049.
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