Gary Zammit

Short Sleep Duration as a Risk Factor for Hypertension Analyses of the First National Health and Nutrition Examination Survey

Depriving healthy subjects of sleep has been shown to acutely increase blood pressure and sympathetic nervous system activity. Prolonged short sleep durations could lead to hypertension through extended exposure to raised 24-hour blood pressure and heart rate, elevated sympathetic nervous system activity, and increased salt retention. Such forces could lead to structural adaptations and the entrainment of the cardiovascular system to operate at an elevated pressure equilibrium. Sleep disorders are associated with cardiovascular disease, but we are not aware of any published prospective population studies that have shown a link between short sleep duration and the incidence of hypertension in subjects without apparent sleep disorders. We assessed whether short sleep duration would increase the risk for hypertension incidence by conducting longitudinal analyses of the first National Health and Nutrition Examination Survey (n=4810) using Cox proportional hazards models and controlling for covariates. Hypertension incidence (n=647) was determined by physician diagnosis, hospital record, or cause of death over the 8- to 10-year follow-up period between 1982 and 1992. Sleep durations of ≤5 hours per night were associated with a significantly increased risk of hypertension (hazard ratio, 2.10; 95% CI, 1.58 to 2.79) in subjects between the ages of 32 and 59 years, and controlling for the potential confounding variables only partially attenuated this relationship. The increased risk continued to be significant after controlling for obesity and diabetes, which was consistent with the hypothesis that these variables would act as partial mediators. Short sleep duration could, therefore, be a significant risk factor for hypertension.

Obstructive Sleep Apnea Among Obese Patients With Type 2 Diabetes

OBJECTIVE To assess the risk factors for the presence and severity of obstructive sleep apnea (OSA) among obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Unattended polysomnography was performed in 306 participants. RESULTS Over 86% of participants had OSA with an apnea-hypopnea index (AHI) ≥5 events/h. The mean AHI was 20.5 ± 16.8 events/h. A total of 30.5% of the participants had moderate OSA (15 ≤ AHI <30), and 22.6% had severe OSA (AHI ≥30). Waist circumference (odds ratio 1.1; 95% CI 1.0–1.1; P = 0.03) was significantly related to the presence of OSA. Severe OSA was most likely in individuals with a higher BMI (odds ratio 1.1; 95% CI 1.0–1.2; P = 0.03). CONCLUSIONS Physicians should be particularly cognizant of the likelihood of OSA in obese patients with type 2 diabetes, especially among individuals with higher waist circumference and BMI.

A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD Study.

BACKGROUND The belief that weight loss improves obstructive sleep apnea (OSA) has limited empirical support. The purpose of this 4-center study was to assess the effects of weight loss on OSA over a 1-year period. METHODS The study included 264 participants with type 2 diabetes and a mean (SD) age of 61.2 (6.5) years, weight of 102.4 (18.3) kg, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 36.7 (5.7), and an apnea-hypopnea index (AHI) of 23.2 (16.5) events per hour. The participants were randomly assigned to either a behavioral weight loss program developed specifically for obese patients with type 2 diabetes (intensive lifestyle intervention [ILI]) or 3 group sessions related to effective diabetes management (diabetes support and education [DSE]). RESULTS The ILI participants lost more weight at 1 year than did DSE participants (10.8 kg vs 0.6 kg; P < .001). Relative to the DSE group, the ILI intervention was associated with an adjusted (SE) decrease in AHI of 9.7 (2.0) events per hour (P < .001). At 1 year, more than 3 times as many participants in the ILI group than in the DSE group had total remission of their OSA, and the prevalence of severe OSA among ILI participants was half that of the DSE group. Initial AHI and weight loss were the strongest predictors of changes in AHI at 1 year (P < .01). Participants with a weight loss of 10 kg or more had the greatest reductions in AHI. CONCLUSIONS Physicians and their patients can expect that weight loss will result in significant and clinically relevant improvements in OSA among obese patients with type 2 diabetes. Trial Registration clinicaltrials.gov Identifier: NCT00194259.

Work-shift period and weight change ☆

The present study was done to determine whether weight gain was more prevalent in workers on late shifts than in those on day shifts. A questionnaire about changes in weight, food intake, exercise, and sleep since starting the job on the current shift was given to day-shift and late-shift (evening and night) hospital workers. Data were analyzed for 85 subjects, 36 of whom worked during the day shift and 49 the late shift. The late-shift group reported a mean weight gain of 4.3 kg, which was greater than the mean weight gain of 0.9 kg for the day-shift group (P = 0.02). There were, however, no significant differences in current body mass index (26.7 +/- 5.4 SD) between groups. There was a trend for late-shift workers to report eating more since beginning the later shift (P = 0.06). When combined with those reporting exercising less (P = NS), this trend became significant (P = 0.04). Late-shift workers reported eating fewer meals (1.9 +/- 0.9 SD) than the day-shift workers (2.5 +/- 0.9; P = 0.002). In addition, late-shift workers reported eating the last daily meal later (mean = 22:27, or 10:27 PM) than day-shift workers (17:52 or 5:52 PM; P < 0.00005). Late-shift workers also reported more naps (P = 0.01) and longer naps (P = 0.05) during the work week than did day-shift workers. The reported changes in eating, exercise, and sleep may contribute to the increased weight gain of late-shift workers.

Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia

SUMMARY Objective: Eszopiclone is a new, single-isomer, non-benzodiazepine, cyclopyrrolone agent under investigation for the treatment of insomnia. The present study was a randomized, double-blind, multicenter, placebo-controlled trial conducted to assess the efficacy and safety of eszopiclone in adults with chronic primary insomnia. Research design and methods: Patients (n = 308) were randomized to receive placebo or eszopiclone (2 mg or 3 mg) for 44 consecutive nights, followed by 2 nights of single-blind placebo. Efficacy was evaluated with polysomnography (Nights 1, 15 and 29) and patient-reports (Nights 1, 15, 29 and 43/44). Next-day residual effects were evaluated using the Digit-Symbol Substitution Test (DSST). Results: Eszopiclone 3 mg had significantly less time to sleep onset ( p ≤ 0.0001), more total sleep time and sleep efficiency ( p ≤ 0.0001), better sleep maintenance (p ≤ 0.01), and enhanced quality and depth of sleep ( p < 0.05) across the double-blind period compared with placebo. Eszopiclone 2 mg had significantly less time to sleep onset ( p ≤ 0.001), more total sleep time ( p ≤ 0.01) and sleep efficiency ( p ≤ 0.001), and enhanced quality and depth of sleep ( p < 0.05) compared with placebo, but did not significantly improve sleep maintenance. There was no evidence of tolerance or rebound insomnia after therapy discontinuation. Median DSST scores showed no decrement in psychomotor performance relative to baseline and did not differ from placebo in either eszopiclone group. Treatment was well tolerated; the most common adverse event related to eszopiclone was unpleasant taste. Conclusions: Patients treated with nightly eszopiclone 3 mg had better polysomnographic (through Night 29) and patient-reported measures (through Night 44) of sleep over the 6-week trial. There was no evidence of tolerance or rebound insomnia and no detrimental effects on next-day psychomotor performance using the DSST.

Long-term effect of weight loss on obstructive sleep apnea severity in obese patients with type 2 diabetes.

STUDY OBJECTIVES To examine whether the initial benefit of weight loss on obstructive sleep apnea (OSA) severity at 1 year is maintained at 4 years. DESIGN Randomized controlled trial with follow-up at 1, 2, and 4 years. SETTING 4 Look AHEAD clinical centers. PARTICIPANTS Two hundred sixty-four obese adults with type 2 diabetes and OSA. INTERVENTIONS Intensive lifestyle intervention with a behavioral weight loss program or diabetes support and education. MEASUREMENTS Change in apnea-hypopnea index on polysomnogram. RESULTS The intensive lifestyle intervention groups mean weight loss was 10.7 ± 0.7 (standard error), 7.4 ± 0.7, and 5.2 ± 0.7 kg at 1, 2, and 4 years respectively, compared to a less than 1-kg weight loss for the control group at each time (P < 0.001). Apnea-hypopnea index difference between groups was 9.7 ± 2.0, 8.0 ± 2.0, and 7.7 ± 2.3 events/h at 1, 2 and 4 years respectively (P < 0.001). Change in apnea-hypopnea index over time was related to the amount of weight loss (P < 0.0001) and intervention, independent of weight loss (P = 0.001). Remission of OSA at 4 years was 5 times more common with intensive lifestyle intervention (20.7%) than diabetes support and education (3.6%). CONCLUSIONS Among obese adults with type 2 diabetes and OSA, intensive lifestyle intervention produced greater reductions in weight and apnea-hypopnea index over a 4 year period than did diabetes support and education. Beneficial effects of intensive lifestyle intervention on apneahypopnea index at 1 year persisted at 4 years, despite an almost 50% weight regain. Effect of intensive lifestyle intervention on apnea-hypopnea index was largely, but not entirely, due to weight loss.

A new questionnaire to detect sleep disorders

OBJECTIVES Sleep disorders remain largely undiagnosed in the general population. The current study assessed whether the Global Sleep Assessment Questionnaire (GSAQ) could: (1), distinguish between sleep disorders (including no sleep disorder); (2), be a reliable and valid sleep disorder screener; and (3), serve as a practical, user-friendly screening tool for primary care and sleep centers. METHODS Two hundred and twelve adults from five sleep centers and two primary care clinics completed the GSAQ and received confirmed diagnoses from a sleep specialist. Of the 212 patients, 139 (65.6%) had at least one sleep disorder, 60 (28.3%) had two or more sleep disorders, and 13 (6.1%) had no confirmed sleep disorder. Ninety-one (43%) individuals completed the GSAQ a second time for reliability testing. Scores for each sleep disorder including, but not limited to, primary insomnia (I), insomnia associated with a mental disorder (IME), obstructive sleep apnea (OSA), periodic limb movement (PLM), and parasomnia (P) were computed. The sensitivity and specificity were estimated using comprehensive clinical diagnosis as the gold standard and mean domain scores as a cutpoint. RESULTS The mean participant age was 45 years, 52% were female. Observed frequencies were: 36 (I), 14 (IME), 31 (OSA), 7 (PLM) and 4% (P). Test-retest reliability ranged from 0.51 to 0.92. Pearson correlation coefficients suggested that the GSAQ discriminated between diagnoses. The sensitivities and specificities were 79/57, 83/51, 93/58, 93/52, and 100/49 for I, IME, OSA, PLM, and P, respectively. CONCLUSIONS Our findings suggest that the GSAQ can aid in recognizing sleep disorders. Future studies should focus on characterizing its predictive values in primary care settings.

Insomnia and Sleep Duration as Mediators of the Relationship Between Depression and Hypertension Incidence

BACKGROUND Depression has been found to predict the incidence of hypertension and other adverse cardiovascular events in prospective studies. Insomnia and short sleep duration, which are typical symptoms of depression, have also been shown to increase the risk for hypertension incidence. Insomnia is associated with increased activation of the hypothalamic-pituitary-adrenal axis, and short sleep duration raises average 24-h blood pressure, which over time could lead to structural adaptations that gradually reset the entire cardiovascular system to operate at an elevated pressure equilibrium. No previous published population studies have examined whether insomnia and sleep duration mediate the relationship between depression and hypertension incidence. METHODS We conducted multivariate longitudinal (1982-1992) analyses stratified by age of the First National Health and Nutrition Examination Survey (NHANES I) (n = 4,913) using Cox proportional hazards models. RESULTS Middle-aged subjects who suffered from depression at baseline were 44% more likely to be diagnosed with hypertension over the follow-up period after controlling for covariates (hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.15-1.80). Both short sleep duration and insomnia were also significantly associated with hypertension incidence. Consistent with insomnia and sleep duration acting as mediators of the relationship between depression and hypertension incidence, the inclusion of these variables in the multivariate models appreciably attenuated the association (HR = 1.27, 95% CI 1.00-1.61). Depression, sleep duration, and insomnia were not significantly associated with hypertension incidence in elderly subjects. CONCLUSIONS These results suggest the hypothesis that treatment of sleep problems in middle-aged individuals suffering from depression could reduce their risk for developing hypertension, and its vascular and cardiac complications.

Zolpidem reduces the sleep disturbance of jet lag.

OBJECTIVE To determine the degree to which zolpidem 10 mg would reduce the sleep disruption associated with rapid, eastward transatlantic travel. BACKGROUND Subsequent to rapid transmeridian travel, individuals often complain of jet lag which includes transient disturbances in sleep patterns, alertness, appetite and mood. Disturbed sleep and impaired alertness appear to be the most debilitating symptoms of jet lag. METHODS This multi-center, double-blind randomized, placebo-controlled, parallel-groups study involved 138 adult (mean age 44.9 years) experienced travelers while on their regular eastward transatlantic assignments originating in the US and crossing 5-9 time zones. Subjects were normal sleepers when not traveling and had to have traveled overseas at least twice during the last 24 months. Subjects were randomized to zolpidem 10 mg or placebo for three (optionally four) consecutive nights starting with the first nighttime sleep after travel. Sleep was assessed with daily questionnaires. RESULTS A total of 130 subjects completed the study. Compared to placebo, zolpidem was associated with significantly improved sleep (statistically significant differences at nights indicated) longer total sleep time (night 1), reduced number of awakenings (nights 1 and 2), and improved sleep quality (nights 1, 2 and 3). Zolpidem was not associated with improvement in sleep latency. No unexpected or serious adverse events were reported and the most common adverse event was headache in both groups (9.2 and 17.6% for placebo and zolpidem, respectively). CONCLUSION In seasoned travelers, zolpidem 10 mg produced significant improvement in sleep following rapid transmeridian travel.

Comparative Tolerability of Newer Agents for Insomnia

Newer treatment options for insomnia include the non-benzodiazepine hypnotics zolpidem, zolpidem-controlled release, zaleplon, zopiclone, eszopiclone and the melatonin receptor agonist, ramelteon. These compounds are generally well tolerated and present favourable safety profiles in comparison with the older benzodiazepines and barbiturates. Commonly cited impairments of memory formation and decrements in psychomotor performance are related to the mechanism of action of hypnotics, and are both dose- and time-dependent. These effects typically are minimal on the morning following night-time administration. The non-benzodiazepines are associated with some risk for dependence and abuse. However, concerns regarding such risks appear to be greater than warranted by empirical evidence. The appropriate therapeutic use of hypnotics is generally not associated with physiological responses that are commonly thought to lead to dependence, such as tolerance or discontinuation effects. Former substance abusers and psychiatric patients appear to be at greatest risk. The labelling of hypnotics was recently updated to incorporate warnings about very rare, but serious adverse events that have been identified in postmarketing surveillance. These events include anaphylaxis (severe allergic reaction); angio-oedema (severe facial swelling); and complex sleep-related behaviours, which may include sleep-driving, making phone calls and preparing and eating food. This article will review the adverse event profiles of these newer sedative hypnotics, their effects on memory and psychomotor performance, abuse liability concerns and the most recent information about the rare adverse effects that prompted the recent revision to the labelling of drugs in the hypnotic class.