Lorcaserin (BELVIQ): Another Do Not Use Diet Drug

In 2012, the Food and Drug Administration (FDA) approved lorcaserin (BELVIQ) for weight loss in obese adults or overweight adults who also have at least one weight-related health condition (such as diabetes or high blood pressure).[1] Lorcaserin increases the level of serotonin, a chemical in the brain that regulates mood, memory and appetite.[2] Serotonin is also released in the heart to help regulate cardiovascular function.[3]

In clinical trials, subjects taking lorcaserin lost only 3 percent more weight than those taking a placebo.[4] We recommend that you do not use this drug because it leads to only minimal weight loss, causes heart valve damage and has other serious side effects (see box, below).

Risks to the heart

Lorcaserin is chemically similar to the weight loss drugs fenfluramine and dexfenfluramine, which were withdrawn from the market by the FDA in 1997 due to evidence of heart valve damage.[5] Not surprisingly, pre-approval clinical trials indicated that lorcaserin may also be associated with this same risk. In fact, the trials showed that lorcaserin might increase the risk of heart valve damage by as much as 67 percent, a level that exceeds FDA approval guidelines regarding the risk of drug-related valvular heart disease.[6] Therefore, by FDA’s own standards, this drug should not have been approved.

In a clinical trial enrolling overweight patients with diabetes, the risk for valvular heart disease was even worse: The incidence was almost six times higher in lorcaserin-treated patients (2.9 percent) than in those treated with a placebo (0.5 percent).[7] Product labeling also acknowledges that in trials involving overweight diabetic patients, lorcaserin increased the risks for high blood pressure and peripheral edema (swelling in legs), as well as for hypoglycemia (low blood sugar) and worsening diabetes.[8] This poses a very serious safety concern, since most overweight diabetic patients are already at risk for serious heart problems, and a key goal of diabetes management should be preventing, not causing, cardiovascular disease.

Pre-approval clinical trials also suggest lorcaserin may increase risk for heart attacks; during clinical testing, four patients using lorcaserin had a heart attack compared to none who took a placebo.[9]

The chairman of the FDA advisory committee that evaluated lorcaserin concluded, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.”[10]

A cardiologist on the committee who voted against approval stated, “Given the totality of evidence, the potential benefits of lorcaserin do not, in my opinion, outweigh the potential risks when used long-term in a population of overweight and obese individuals.”[11]

The European Medicines Agency rejected approval for lorcaserin due to its adverse effects, particularly on the heart.[12] Even though it approved lorcaserin, the FDA had similar safety concerns and required post-approval clinical trials to better evaluate cardiovascular risks, including the risk of heart valve damage.[13]

Psychological and other effects

Adverse psychiatric effects—specifically depression, anxiety and insomnia—leading to withdrawal or hospitalization occurred more frequently in patients treated with lorcaserin (2.2 percent) than in those taking a placebo (1.1 percent).[14] Considering the increased incidence of depression symptoms with lorcaserin (4.9 percent, compared to 3.6 percent in patients taking a placebo),[15] it is not surprising that the FDA has also identified suicide risk as a serious safety concern. During clinical testing, 1.3 percent of patients taking lorcaserin discontinued treatment due to suicidal thinking, depression or mood-related problems, compared to only 0.6 percent taking a placebo.[16]

Lorcaserin is chemically similar to LSD (lysergic acid diethylamide), a hallucinogen with a high potential for abuse. Thus, similar to LSD,[17] lorcaserin is associated with abuse-related adverse psychiatric effects, including euphoria, and is classified as a controlled substance (schedule IV) due to its potential for abuse, particularly at higher doses.[18] In fact, evidence from clinical trials indicated more than a twofold greater incidence of euphoria in patients treated with lorcaserin twice daily at FDA-approved doses (8.9 percent) compared to those taking a placebo (4 percent).[19]

Lorcaserin is also associated with increased seizure risk and cognitive impairment. During clinical trials, four patients treated with lorcaserin (versus none treated with a placebo) discontinued treatment due to seizures.[20] Patients using lorcaserin were also more likely to report difficulty concentrating, reduced attention, or memory problems (2.3 percent) compared to those taking placebos (0.7 percent).[21]

Lorcaserin product labeling warns about the increased risk for serious eye disorders, including cataracts, which impair vision and could lead to permanent blindness. Overweight diabetic patients, already at risk for eye problems, were particularly vulnerable. During clinical trials, the incidence of eye disorders among overweight diabetics was four times higher in patients treated with lorcaserin (6.3 percent) than in those taking a placebo (1.6 percent).[22]

In clinical trials reviewed by the FDA, abnormally high levels of prolactin—a hormone released by the pituitary gland in the brain—were more common in patients using lorcaserin than in those using a placebo (1.7 percent versus 0.8 percent).[23] This is a serious safety concern because mounting evidence links elevated prolactin to increased risk of breast cancer.[24] In fact, the FDA rejected lorcaserin’s initial application because studies in mice showed an increased incidence of breast cancer following administration of the drug.[25] An increase in breast cancer cases was not seen in patients treated with lorcaserin in clinical trials,[26] but these trials were too short to rule out an increased risk.

Due to lorcaserin’s effects on serotonin, which are similar to those of some commonly used antidrepressants, it is also associated with the serious, sometimes fatal, conditions known as serotonin syndrome and neuroleptic malignant syndrome (see box for more details). In fact, during clinical testing there were two cases of serotonin syndrome among patients treated with lorcaserin and none in those taking a placebo.[27]

What You Can Do

We recommend that you do not use lorcaserin or any other weight loss drug because of these serious risks. Instead, talk with your doctor about lifestyle changes, diet and exercise to help you lose weight safely and effectively.

References

[1] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[2] Frazer A, Hensler JG. Serotonin Involvement in Physiological Function and Behavior. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999. https://www.ncbi.nlm.nih.gov/books/NBK27940/. Accessed January 17, 2017.

[3] Frishman WH, Grewall P. Serotonin and the heart. Ann Med. 2000;32(3):195-209.

[4] Wharton S, Serodio KJ. Next generation of weight management medications: implications for diabetes and CVD risk. Curr Cardiol Rep. 2015;17(5):35.

[5] Food and Drug Administration. FDA announces withdrawal of fenfluramine and dexfenfluramine (fen-phen). July 7, 2005. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm179871.htm. Accessed January 26, 2017.

[6] Food and Drug Administration. Summary Review: Lorcaserin (Belviq) tablets. NDA#: 22529. June 24, 2012. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000SumR.pdf. Accessed January 26, 2017.

[7] Ibid.

[8] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[9] Food and Drug Administration. FDA briefing document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting. September 16, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM225631.pdf. Accessed January 26, 2017. Page 231.

[10] Food and Drug Administration, Center for Drug Evaluation and Research. Transcript of Endocrinologic and Metabolic Drugs Advisory Committee Meeting. May 10, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM309522.pdf. Accessed January 26, 2017. Page 328.

[11] Ibid. Page 354.

[12] Wolfe SM. When EMA and FDA decisions conflict: Differences in patients or in regulation? BMJ. 2013 Aug 21;347:f5140.

[13] FDA Center for Drug Evaluation and Research. NDA number 022529: approval letter. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012/022529Orig1s000ltr.pdf. Accessed January 26, 2017.

[14] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[15] Food and Drug Administration. FDA briefing document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting. September 16, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM225631.pdf. Accessed January 26, 2017. Page 193.

[16] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[17] Food and Drug Administration. FDA briefing document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting. September 16, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM225631.pdf. Accessed January 26, 2017. Page 12.

[18] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[19] Food and Drug Administration. FDA briefing document for the Endocrinologic and Metabolic Drugs Advisory Committee Meeting. September 16, 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM225631.pdf. Accessed January 26, 2017. Page 185.

[20] Ibid. Page 156.

[21] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.

[22] Ibid.

[23] Ibid.

[24] Tikk K, Sookthai D, Fortner RT, et al. Circulating prolactin and in situ breast cancer risk in the European EPIC cohort: A case-control study. Breast Cancer Res. 2015 Mar 31;17:49.

[25] Food and Drug Administration. Complete response letter to Arena Pharmaceuticals regarding NDA# 22529 for Lorqess (lorcaserin). October 22, 2010. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000OtherActionLtrs.pdf. Accessed January 26, 2017.

[26] Food and Drug Administration, Center for Drug Evaluation and Research. Transcript of Endocrinologic and Metabolic Drugs Advisory Committee Meeting. May 10, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeeting Materials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM309522.pdf. Accessed January 26, 2017.

[27] Eisai Inc. Label: lorcaserin hydrochloride (BELVIQ). November 2016. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f&type=pdf&name=7cbbb12f-760d-487d-b789-ae2d52a3e01f. Accessed January 26, 2017.