Study Uncovers Serious Underreporting of Harms in Orlistat’s Trials

Public Citizen’s Health Research Group initially petitioned the Food and Drug Administration (FDA) in 2006 to ban the prescription weight-loss drug orlistat (XENICAL) because it exposes patients to serious risks that greatly outweigh its minimal benefits.[1],[2],[3] A second 2011 petition sought to ban a less potent over-the-counter version, ALLI, as well as XENICAL. Both times, the agency denied our petition.

A recent Danish study brought to light new evidence that supports our position.[4] The study showed that orlistat’s side effects were seriously underreported in published medical journal articles for the trials that the drugmaker conducted to support the drug’s approval. The study was published in PLOS Medicine in August 2016.

About orlistat

The FDA approved XENICAL, the prescription form of orlistat, in 1999 for inducing and maintaining weight loss in obese individuals with a body mass index (BMI; a measure of body fat based on an adult’s height and weight) of 30 or higher and in those with a BMI of 27 or higher if they also have certain risk factors, such as hypertension, diabetes or high fat levels in the blood.[5] (A normal BMI is 18.5 to 24.9.)[6]

In 2007, the agency approved orlistat’s over-the-counter form (ALLI), which contains half the dose of XENICAL, for “overweight” individuals.[7] Both forms are specifically approved to be taken only in combination with a low-calorie diet. Orlistat reduces the absorption of fats from ingested foods; it is, therefore, intended to be taken with every meal that contains fat.

Our 2011 petition stated that the weight loss that orlistat users experienced in clinical trials was minimal:[8]

One trial showed that obese subjects taking the half dose and the full dose of XENICAL for one year lost only 5.6 and 7.1 pounds (respectively) more than the subjects who took a placebo. Similarly, the FDA statistician who reviewed the trials on ALLI concluded that overweight users can expect to lose only two to four more pounds than those who rely solely on diet and exercise routines to lose weight.

A 2016 review of orlistat studies found that only 44 percent of patients taking orlistat lost at least 5 percent of their baseline body weight.[9] A population-based study that followed nearly 17,000 orlistat users showed that 94 percent discontinued the drug within the first year of use, a much higher discontinuation rate than was reported in clinical trials used to support FDA approval of the drug[10].

Orlistat’s modest benefits are outweighed by its serious potential adverse effects — caused by the drug’s high capability to penetrate various tissues — including severe liver injury or failure resulting in liver transplantation or death, kidney stones, kidney failure and inflammation of the pancreas.[11],[12] Less serious but common side effects include abdominal pain, gas, fecal urgency and oily stools. Orlistat interferes with the absorption of fat-soluble vitamins (A, D, E and K) and certain drugs. It also interacts with common medications. For example, orlistat can decrease the effect of the oral blood thinner warfarin (COUMADIN, JANTOVEN) and the thyroid replacement drug levothyroxine (LEVO-T, LEVOXYL, SYNTHROID, TIROSINT, UNITHROID).[13]

The PLOS Medicine study

The Danish researchers compared details of all reported side effects among subjects enrolled in randomized clinical trials for orlistat from two sources: medical journal articles that presented the results of the trials and corresponding reports of these trials that had been submitted to the European Medicines Agency (EMA) for drug approval.[14] Their study summarized findings from seven such trials. Altogether, more than 4,200 subjects were included in these trials, which were conducted in the mid-1990s.

The researchers found that between only three percent to 33 percent of the total number of side effects included in four of the seven EMA clinical study reports had actually been reported in the corresponding medical journal publications, even where the publications explicitly stated that all adverse events were recorded. The researchers could not calculate the percentage of underreporting for the remaining three publications because the number of side effects was not reported for all subjects in these publications.

In one trial, the researchers identified more than 1,300 side effects that were not mentioned in the main text of the EMA clinical study report itself but were noted in an appendix that they found in the clinical study report. It turned out that many patients had experienced multiple separate episodes of the same side effects, yet the drugmaker counted these side effects only once per patient. Additionally, the orlistat users in this trial had experienced nearly twice as many days with side effects as those in the placebo control group. Furthermore, the side effects that occurred among orlistat’s users were more severe than those that occurred in the control group. The researchers noted that none of this information was stated in either the main text of the EMA clinical study report or the journal publication concerning this trial.

The researchers also found various ways in which protocol instructions to trial investigators played a role in minimizing the appearance of side effects associated with orlistat.

By significantly underreporting side effects of orlistat in published journal articles of clinical trials and not clearly summarizing side effect data in EMA clinical study reports, the makers of orlistat downplayed the drug’s risks and thus distorted its risk-benefit profile for physicians and others reading these articles.

What You Can Do

If you are one of the millions of Americans who are overweight or obese, you should never take orlistat to lose weight. Likewise, do not fall victim to any other weight-loss drugs on the market. Instead, follow the only effective and safe long-term solution for shedding any unwanted pounds: regular exercise and a lower-calorie diet.

References

[1] Public Citizen’s Health Research Group. Petition to ban diet drug orlistat (XENICAL). April 10, 2006. http://citizen.org/Page.aspx?pid=667. Accessed April 3, 2017.
[2] Public Citizen’s Health Research Group. Supplement to petition to ban diet drug orlistat (XENICAL). June 5, 2006. http://citizen.org/Page.aspx?pid=2732. Accessed April 3, 2017.
[3] Public Citizen’s Health Research Group. Petition to ban orlistat (ALLI, XENICAL). April 14, 2011. https://www.citizen.org/our-work/health-and-safety/petition-fda-ban-orlistat-alli-xenical. Accessed April 3, 2017.
[4] Schroll JB, Penninga EI, Gøtzsche PC. Assessment of adverse events in protocols, clinical study reports, and published papers of trials of orlistat: A document analysis. PLOS Med. 2016;13(8):e1002101.
[5] Genentech, Inc. Label: orlistat (XENICAL). October 17, 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bbdc95b-82a1-4ba5-8185-6504ff68cc06&audience=consumer. Accessed April 3, 2017.
[6] National Heart, Lung, and Blood Institute. Calculate your body mass index. https://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm. Accessed April 10, 2017.
[7] GlaxoSmithKline Consumer Healthcare Holdings (US) LLC. Label: orlistat (ALLI). June 6, 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a2d3bd73-f3af-4ea5-a57c-66b0004cfe4f&audience=consumer. Accessed April 3, 2017.
[8] FDA should remove weight-loss drugs ALLI and XENICAL from the market. Worst Pills, Best Pills News. October 2011. /newsletters/view/768. Accessed April 3, 2017.
[9] Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and adverse events. JAMA. 2016;315(22):2424-2434.
[10] Padwal R, Kezouh A, Levine M, Etminan M. Long-term persistence with orlistat and sibutramine in a population-based cohort. Int J Obes. 2007;31(10):1567-1570.
[11] Public Citizen’s Health Research Group. Petition to ban orlistat (ALLI, XENICAL). April 14, 2011. https://www.citizen.org/our-work/health-and-safety/petition-fda-ban-orlistat-alli-xenical. Accessed April 3, 2017.
[12] Genentech, Inc. Label: orlistat (XENICAL). October 17, 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bbdc95b-82a1-4ba5-8185-6504ff68cc06&audience=consumer. Accessed April 3, 2017.
[13] Genentech, Inc. Label: orlistat (XENICAL). October 17, 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5bbdc95b-82a1-4ba5-8185-6504ff68cc06&audience=consumer. Accessed April 3, 2017.
[14] Schroll JB, Penninga EI, Gøtzsche PC. Assessment of adverse events in protocols, clinical study reports, and published papers of trials of orlistat: A document analysis. PLOS Med. 2016;13(8):e1002101.