Yeah, But How Are They Doing 6 Months from Now?

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a retained consultant for Cephalon and Ventus, and serves on the speakers bureaus for Cephalon and Boehringer Ingelheim.

Synopsis: Treatment with a low-calorie diet resulted in substantial weight loss, and improved obstructive sleep apnea in obese men, with the greatest improvement in patients who had severe sleep apnea.

Source: Johansson K, et al. Effect of a very low energy diet on moderate and severe obstructive sleep apnea in obese men: A randomised controlled trial. BMJ 2009;339:b4609.

These investigators wanted to assess the effect of a very low-calorie diet on weight loss and obstructive sleep apnea (OSA). They sent a written invitation and screening questionnaire to patients who met entry criteria into the study. Patients who were interested in participating and who met the inclusion criteria had to attend an information meeting, and were screened by a physician to evaluate contraindications. Exclusions to participation were diabetes, current use of a weight-loss drug, previous bariatric surgery, or recent angina pectoris or atrial fibrillation. Of 291 patients invited to be in the study, the investigators were able to recruit 63, all men. These patients had a mean age of 49 years, a mean body mass index (BMI) of 34 kg/m2, and a mean Apnea plus Hypopnea Index (AHI) of 37 events/hour. Of these, 30 were randomized to the very low-calorie intervention, and 33 were randomized to the control group. The intervention group received a liquid very low-energy diet (2.3 MJ, or about 549 calories per day) for 7 weeks, followed by 2 weeks of gradual introduction to normal food, reaching 6.3 MJ (about 1505 calories) per day at week 9. The actual protocol used was the Cambridge diet. Clinical examinations that included weight, waist circumference, neck circumference, and percentage body fat were done every other week. Urinary ketosis was also tested at each visit. In addition, each visit included a 1-hour group session supervised by a research nurse and two study dietitians.

The patients in the control group were told to stick to their usual diet during the 9 weeks of the study, but they also attended clinical examinations at weeks 1, 3, 5, 7, and 9 that were identical to those of the intervention group. The controls did not have group sessions, but they were offered the same weight-loss program as the intervention group, once the 9-week follow-up was completed.

At the end of the study (week 9), the intervention group's mean body weight was 20 kg (44 pounds) lower than that of the control group. In the intervention group, the mean change in weight was -18.7 kg and mean change in BMI was -5.7 kg/m2, compared with a weight gain of 1.1 kg and increase in BMI of 0.3 kg/m2 in the control group. Twenty-two of 30 of the very low-calorie diet patients were no longer obese, but all of the control patients still were.

At the end of the study, the mean AHI in the intervention group was 12 events/hour, compared with 35 events in the control group. For the intervention group, there was a dose-response relationship between weight loss and change in AHI. In other words, the more weight they lost, the more their AHI improved. Five of 30 in the intervention group had an AHI < 5 events/hour, which is considered normal. On the other hand, only one of the patients in the control group had an AHI < 15 events/hour at the end of the study. There was a greater improvement in AHI in patients who had severe obstructive sleep apnea (AHI > 30 events/hour) at baseline compared to those with moderate (AHI 15-30 events/hour) sleep apnea, although the amount of weight they lost was similar. All patients in the intervention group had urinary ketosis at each visit, indicating adherence to the diet. Reductions in self-reported daytime sleepiness score at week 9 were greater in the intervention group than in the control group.

There were 8 adverse events in the intervention group that were believed to be due to the study diet. These included constipation (n = 3), elevated alanine aminotransferase concentrations (n = 2), dizziness (n = 1), gout (n = 1), and dry lips (n = 1). These adverse events were transient and resolved, without intervention, by the end of the study.

Commentary

Obstructive sleep apnea is a prevalent and largely under-diagnosed condition, affecting, as a conservative estimate, at least 5% of North Americans.1,2 Untreated obstructive sleep apnea is a multi-organ system disease, and is associated with increased risk of moving vehicle crash,3 cardiovascular disease,4,5 impaired glucose tolerance,6 and cognitive impairment.7 Indeed, obstructive sleep apnea is now first on the list of the causes of secondary hypertension promulgated by the Joint National Council on Hypertension (JNC 7).8

Most importantly, moderate-to-severe OSA is associated with increased all-cause mortality.9

The treatment of choice for obstructive sleep apnea is continuous positive airway pressure (CPAP), which is effective in relieving sleepiness and has been shown to improve or reverse many of the sequelae of sleep-disordered breathing. However, CPAP is burdensome treatment, and alternative treatments are eagerly sought by patients with OSA and their treating physicians. Although weight loss has been advocated as a primary treatment strategy for OSA, it is difficult to accomplish, and even more difficult to maintain.

This study is one of the first randomized controlled trials assessing weight loss as a treatment for sleep apnea, and the results are encouraging. In this paper, a very low-calorie diet resulted in a clinically important improvement of moderate-to-severe obstructive sleep apnea in obese men. AHI was cut by two-thirds in the intervention group compared with no change in the control group, and 17% of the intervention group patients had resolution of their disease.

Because weight loss is so difficult to accomplish, much of what is known about the effects of weight loss on OSA has resulted from bariatric surgery studies,10 and randomized controlled trials in this area are exceedingly rare. A recent randomized trial of weight loss in patients with mild sleep apnea resulted in a 40% reduction in AHI from a weight loss of 10.7 kg after a year in patients with mild disease.11 Another recent study of intensive lifestyle intervention vs group sessions about diabetes management resulted in a 10.8 kg weight loss in the intervention group, and a three-fold increase in resolution of OSA.12

So it can be done. The question is how best to do it. The authors of the current report note that "provision of bariatric surgery to all patients with this problem is not realistic." No kidding. They also argue that a systematic review of randomized weight-loss trials with a minimum follow-up of a year showed that very low-energy diets resulted in a greater (10%) weight reduction from baseline weight than drug treatment (8%). While that may be true, it implies a significant regain of weight after the termination of the very low-calorie diet. Indeed, a recent meta-analysis of very low-calorie diets, compared with low-calorie diets, concluded that very low-calorie diets produced greater short-term, but similar long-term weight loss.13 What remains to be seen is the evolution of the sleep apnea in the patients in this study over time.

For now, maybe the message for our patients should be: Losing weight will help your sleep apnea, and you don't have to get thin again to get significant improvement. Every little bit helps.

References

1. Tishler PV, et al. Incidence of sleep-disordered breathing in an urban adult population. JAMA 2003;289:2230-2237.

2. Young T, et al. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:1217-1239.

3. Ellen RL, et al. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med 2006;2:193-200.

4. Shahar E, et al. Sleep-disordered breathing and cardiovascular disease. Am J Respir Crit Care Med 2001;163:19-25.

5. Peker Y, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:159-165.

6. Shaw JE, et al. Sleep-disordered breathing and type 2 diabetes. Diabetes Res Clin Pract 2008;81:2-12.

7. Kim H, et al. Sleep-disordered breathing and neuropsychological deficits. Am J Respir Crit Care Med 1997;156:1813-1819.

8. Chobanian AV, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003;289:2560-2572.

9. Young T, et al. Sleep disordered breathing and mortality. Sleep 2008;31:1071-1078.

10. Buchwald H, et al. Bariatric surgery: A systematic review and meta-analysis. JAMA 2004;292:1724-1737.

11. Tuomilehto HP, et al. Lifestyle intervention with weight reduction. Am J Respir Crit Care Med 2009;179:320-327.

12. Foster GD, et al. A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes. Arch Intern Med 2009;169:1619-1626.

13. Franz MJ, et al. Weight-loss outcomes: A systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 2007;107:1755-1767.

14. Tsai AG, Wadden TA. The evolution of very-low-calorie diets. Obesity (Silver Spring) 2006;14:1283-1293.