Orlistat

Digit preference lays conclusions about orlistat open to doubt

EDITOR--The drug point by Persson et al provides an excellent example of the common and widely criticised practice of digit preference when recording blood pressure.[1] The British Hypertension Society guidelines recommend measuring blood pressure to the nearest 2 mm Hg.[2] Persson et al did not adopt this method of measurement because the chances of recording 12 zeros are several million to one.

Bias of this kind could have a profound effect on the study's conclusions. For example, Persson et al concluded that 170/100 mm Hg (when taking orlistat) was greater than 160/90 mm Hg (when not taking the drug). If a blood pressure of 166/96 mm Hg was rounded up to 170/100 nun Hg and 164/94 mm Hg was rounded down to 160/90 mm Hg, then the true difference would be 2/2 mm Hg rather than the 10/10 mm Hg as recorded by the observer. Given the open nature of the investigation, the considerable day to day variation that can occur in measuring blood pressure, and the strong digit preference observed in this study, the conclusions must be open to considerable doubt.

G D Johnston professor of clinical pharmacology Department of Therapeutics and Pharmacology, Queen's University, Belfast, Belfast BT9 7BL

[1] Persson M, Vitols S, Yue QY. Orlistat associated with hypertension. BMJ 2000;321:87. (8 July.)

[2] Ramsey LE, Williams B, Johnston GD, MacGregor GA, Poston L, Potter JF, et al. Guidelines for management of hypertension: report of the third working party of the British Hypertension Society. J Hum Hypertens 1999;13:569-92.

Roche concludes that there is no evidence of a causal association

EDITOR--In their drug point Persson et al report that hypertension occurred in a woman when she took orlistat.[1] Further information indicates that the hypertensive events are not related to treatment with orlistat.

After finally stopping orlistat in August 1999 the patient was reported to have developed fever, headache, oedema, and joint pains in mid-November 1999. Diuretic treatment was restarted, and fever and oedema resolved/ blood pressure was reported as normal during this period. In March 2000 the oedema and headache recurred and her blood pressure was 170/100 mm Hg; the patient had not taken diuretic treatment while on holiday for a week. Frusemide was resumed, and after a few days the oedema resolved and her blood pressure was 140/90 mm Hg. Information recently received indicates that investigations performed by a specialist internist concluded that the patient has idiopathic oedema.

Orlistat has been studied in over 20 000 patients, and since it was first launched in 1998 there have been more than 8.2 million patient treatments. It is well documented that weight loss due to diet alone is associated with a reduction in blood pressure. The Cochrane Collaboration recently completed a review indicating that a weight loss of 4-8% was associated with a decrease in blood pressure of about 3 mm Hg.[2]

In clinical studies, patients treated with orlistat lost significantly more weight than control patients (placebo plus diet)[3 4] and thus showed correspondingly greater reductions in blood pressure than control patients. A meta-analysis of five randomised, double blind, placebo controlled studies

(3132 patients) showed that patients who had raised diastolic blood pressure at baseline ([is greater than or equal to] 90 mm Hg) showed a 7.9 mm Hg reduction in diastolic blood pressure when treated with orlistat compared with a 5.5 mm Hg reduction in the control group.[5]

Finally, of the 1466 patients treated with placebo plus diet in the clinical trial database, 1.3% had hypertension of new onset or worsening hypertension and 0.1% had a hypertensive crisis. Of the 1913 patients treated with orlistat on that same database, 1.2% had new or worsening hypertension and none had a hypertensive crisis as an adverse event.

After a review of these and the cumulative data in the Roche safety database we have concluded that there is no evidence of a causal association between orlistat and hypertension. We trust that the information provided puts the drug point into perspective.

Martin H Huber global head safety risk management Pharmaceuticals Division Clinical Science, Safety Risk Management, F Hoffman-La Roche, CH-4070 Basle, Switzerland

Martin_harold.huber@roche.com

[1] Persson M, Vitols S, Yue Q-Y. Orlistat associated with hypertenskm. BMJ 2000;321:87. (8 July.)

[2] Mulrow CD Chittuette E, Angel L, Cornell 1, Summerbell C, Anagnostelis B, et al. Dieting to reduce body weight for controlling hypertension in adults. Cochrane Database Syst Rev 2000;(2):CD000484.

[3] Sjostrom L, Rissanen A, Andersen T, Boldrin M, Golay A, Koppeschaar HI), et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998;352:167-72.

[4] Davidson MH, HauptmanJ, DiGirahno M, Foreyt JP, Halsted CH, Heber D, et al. Weight control and risk factor reduction of ofiislat in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999;281:235-42.

[5] Zavoral JH. Treatment with orlistat reduces cardiovascular risk in obese patients. J Hypertem 1998; 16:2013-7.

Authors' reply

EDITOR--Johnston has pointed out the importance of following recommended guidelines when measuring blood pressure. We agree that this is necessary when performing a study to measure blood pressure. The difference is that we presented a case report of increased blood pressure associated with a drug newly approved in Sweden, the first in our pharmacovigilance spontaneous reporting system. The patient was never admitted, but when she consulted her doctor about her headache and oedema she was found to have raised blood pressure. With confirmatory results on stopping treatment and rechallenging with the drug we could not disregard the doctor's observation.

Huber found no evidence of a causal relation between orlistat treatment and hypertensive reaction in the reported case on the basis of the follow up information provided by us. We thought that other factors such as an infection may have played a part in the episode of fever, headache, oedema, and joint pains three months after stopping orlistat. We concluded that orlistat was associated with hypertension because the patient was healthy before orlistat was started, and her first episodes and the confirmatory results on dechallenging and rechallenging with orlistat showed a close temporal relation. Orlistat and the later infection seem likely to have provoked the episodes of oedema and increased blood pressure. Moreover, we have received four additional case reports of orlistat associated with increased blood pressure (table).

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

Rare undesirable reactions are often detected after a drug has been in widespread use. It is not surprising that a reaction with an incidence of less than 1/1000 exposed patients is not discovered in a clinical trial of 2000 patients. Average decreases in blood pressure will not exclude the possibility that individual patients may react differently. Although we do not know the plausible mechanisms, the signal of increased blood pressure during orlistat treatment should be further evaluated.[1]

Matty Persson research nurse

Sigurd Vitols associate professor in clinical pharmacology Regional Centre for Pharmacovigilance, Karolinska University Hospital, S-171 76, Stockholm, Sweden

Qun-Ying Yue associate professor in clinical pharmacology Pharmacovigilance Unit, Medical Products Agency, S-751 03, Uppsala, Sweden

[1] Delamothe T Reporting adverse drug reactions. BMJ 1992;304:465.

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