Reply to MH Davidson, JW Anderson, EC Konz, and GL Blackburn

The American Journal of Clinical Nutrition, University of California, One Shields Avenue, Davis, CA 95616–8790, E-mail: ajcn{at}ucdavis.edu

Davidson points out that the achievements of the orlistat trials must be weighed within the context of each experiment. I agree. Yet in the JAMA trial in which he is lead author, only a 3% difference in percentage of initial weight lost over 1 y separated the orlistat group (10%) and the placebo group (7%). This difference was produced under experimental conditions of high-intensity (monthly or less) dietary education and surveillance of all subjects, a procedure that goes beyond the typical standard of care for obesity management in most medical practices (1). In the trial published in the Journal (2), the bias was in selection of subjects who already had proven their ability to lose weight with diet restriction; diets were then prescribed for the 1-y drug trial that met the realistic conditions required to maintain metabolic balance according to each subject's individual needs.

In response to Davidson as well as to Anderson and Konz, the central point of my editorial remains (3). Specifically, if 24% of subjects in the trial published in this journal either stabilized or continued to lose weight while receiving 120 mg orlistat 3 times daily, the overwhelming majority, 76%, regained weight despite this—hardly a ringing endorsement of the drug (2). Whether long-term use of orlistat will have a salutary effect on lifestyle is purely conjectural.

Blackburn objects to my notes of caution on the long-term safety of orlistat, yet many of his arguments reinforce my points. First, the available drug trials are of relatively short duration compared with the long-term use that doubtless will be made of orlistat by a target population of predominantly pre- and postmenopausal obese women already at risk for bone depletion. It is hardly likely that orlistat will be "used as directed," because a cursory Internet search identifies >4000 web sites from which orlistat can be purchased without a physician evaluation, personal prescription, or physician surveillance. Albeit an imperfect simile, the cited study on bone disease associated with long-term steatorrhea in chronic pancreatitis provides a cautionary model for the potential risks of iatrogenic orlistat-induced pancreatic insufficiency and steatorrhea (4). Second, nonsteroidal antiinflammatory drugs for arthritis treatment provide an excellent example of a class of drugs for which a very common side effect—unexpected and potentially life-threatening gastrointestinal bleeding—only became apparent after millions of prescriptions were filled and patients took the medication for many years (5). Third, I would be remiss in my editorial responsibilities if I failed to question the opinions of my colleagues, whether or not they carry the same specialty card. Finally, my editorial's conclusion should reinforce the fact that I am as profoundly concerned as any other clinical nutrition specialist over the very real health consequences of obesity. All of these concerns reinforce the continued and frustrating problem of finding a reliable, safe, and effective means for prevention and treatment of obesity (3).

REFERENCES

1. Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999;281:235–42.
2. Hill JO, Hauptman J, Anderson JW, et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am J Clin Nutr 1999;69:1108–16.
3. Halsted CH. Is blockade of pancreatic lipase the answer? Am J Clin Nutr 1999;69:1059–60 (editorial).
4. Moran CE, Sosa EG, Martinez SM, et al. Bone mineral density in patients with pancreatic insufficiency and steatorrhea. Am J Gastroenterol 1997;92:867–71.
5. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340:1888–99.