False-Hope Alzheimer’s Disease Drugs

As of August 1, the French national insurance system no longer reimburses the costs of Alzheimer’s disease (AD) drugs.[1] Instead, the funds saved from this decision will be used to provide care services for AD patients.[2]

The French decision aligns with Public Citizen’s Health Research Group’s conclusion that all of the currently approved AD drugs offer very minimal symptomatic benefits for only some patients and do not alter the underlying disease. As a result, we have long classified these drugs as Do Not Use.[3]

Alzheimer’s disease and drugs used to treat it

AD is a brain disorder that slowly destroys memory; cognitive skills; the ability to perform activities of daily living (including dressing and bathing); and the ability to recognize familiar objects, people and places. It affects nearly 6 million Americans,[4] most of whom are elderly.

In addition to being a leading cause of disability and poor health, the disease is the sixth-leading cause of overall deaths and is the fifth-leading cause of death among people aged 65 or older in the U.S.[5]

Because AD progresses silently for years, significant structural brain damage often exists by the time clinical symptoms appear.[6] This makes it challenging for scientists to develop effective treatments for the disease.

Four drugs have been approved by the Food and Drug Administration (FDA) to treat AD.[7] However, these drugs are symptomatic therapies: They neither cure the disease nor stop its progression.

Three of these drugs, known as acetylcholinesterase inhibitors, initially were approved by the FDA from 1996 to 2001 for mild-to-moderate dementia of the Alzheimer’s type: donepezil (ARICEPT), galantamine (RAZADYNE) and rivastigmine (EXELON).[8],[9],[10] Donepezil also is now approved for severe AD. These drugs increase the level of acetylcholine, a neurotransmitter that is low in the brains of affected individuals, with the assumption that this might improve the symptoms of AD-associated dementia.

The fourth drug, memantine (NAMENDA), was approved by the FDA in 2003 for the treatment of moderate-to-severe dementia of the Alzheimer’s type.[11] It works by blocking a receptor called the N-methyl-D-aspartate receptor, which is postulated to improve the symptoms of AD.

Scant, questionable benefits

The approval of these four AD drugs brought genuine hope. However, the benefit of these drugs is limited to small improvements in cognitive function and activities of daily living. For example, a 2006 meta-analysis (analysis of data from multiple clinical trials) estimated that treatment with an acetylcholinesterase inhibitor, compared with a placebo, results in a 2.4-point improvement on a 70-point cognition scale in patients with mild-to-moderate stages of the disease.[12]

A 2018 meta-analysis of studies on donepezil linked the drug to only about a three-point improvement in cognitive function on a 70-point scale.[13] Notably, this meta-analysis showed that the costs of health care use were similar between patients who received donepezil and those who received a placebo. A 2015 meta-analysis of studies on rivastigmine found similar minimal benefits and pointed out the uncertain clinical importance of these effects.[14]

A meta-analysis of studies on memantine in patients with moderate-to-severe AD also showed that the drug had meager benefits: a three-point improvement in cognitive function (on a 100-point scale), a one-point improvement in activities of daily living (on a 54-point scale) and a three-point improvement in behavior (on a 144-point scale).[15]

Given that these drugs do not alter the underlying course of the disease, it is unclear how these very small increases in the number of points scored on cognitive or functional exams translate to improving the lives of AD patients in the real world.

Adverse effects and interactions with other drugs

Although earlier data suggested an acceptable safety profile for AD drugs, data that documented their numerous, sometimes fatal, adverse effects emerged over time.[16] As early as 2003, a meta-analysis showed that for every 12 patients treated with a cholinesterase inhibitor, one patient would benefit by achieving minimal improvement or better and another patient would experience adverse effects.[17]

The most serious adverse effects of cholinesterase inhibitors are slow heart rate, heart block and syncope (sudden loss of consciousness).[18] Common adverse events of these drugs are nausea, diarrhea and vomiting. Loss of appetite and weight loss also occur with the use of these drugs.

The most common adverse effects of memantine include dizziness, headache, confusion and constipation.[19] Inflammation of the pancreas and kidney failure also have been reported with use of this drug.

Importantly, use of AD drugs exposes patients to the risk of dangerous interactions with numerous drugs including beta blockers, antipsychotic drugs (including chlorpromazine [generic only]) and anticholinergic drugs (such as oxybutynin [DITROPAN XL, GELNIQUE, OXYTROL, OXYTROL FOR WOMEN]).[20]

What You Can Do

If you (or a loved one) has Alzheimer’s disease, avoid use of the four aforementioned drugs because their benefits do not outweigh their risks. Instead, as the French are now doing, use social and behavioral approaches for adapting to the limitations of the disease and improving quality of life.

References

[1]Prescrire Int. Drugs for Alzheimer’s disease: finally delisted in France! June 15, 2018. http://english.prescrire.org/en/81/168/55126/0/NewsDetails.aspx. Accessed August 2, 2018. .

[2]Alzheimer drugs halted. The Connexion. June 27, 2018. https://www.connexionfrance.com/French-news/Alzheimer-drugs-Aricept-Ebixa-Exelon-Reminyl-will-no-longer-be-reimbursed-in-France. Accessed August 3, 2018.

[3]Drugs for Alzheimer's disease. Worst Pills, Best Pills News. July 2004. /newsletters/view/289. Accessed August 2, 2018.

[4]Alzheimer’s Association. Alzheimer’s disease facts and figures. 2018. https://www.alz.org/alzheimers-dementia/facts-figures. Accessed August 2, 2018.

[5]Ibid.

[6]Food and Drug Administration. Statement from FDA Commissioner Scott Gottlieb, M.D. on advancing the development of novel treatments for neurological conditions; part of broader effort on modernizing FDA’s new drug review programs. February 15, 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596897.htm. Accessed August 2, 2018.

[7]Drugs for Alzheimer's disease. Worst Pills, Best Pills News. July 2004. /newsletters/view/289. Accessed August 2, 2018.

[8]Eisai Inc. Label: Donepezil (ARICEPT). July 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020690s039,021720s012,022568s008lbl.pdf. Accessed August 2, 2018.

[9]Janssen Pharmaceuticals, Inc. Label: Galantamine (RAZADYNE). September 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021169Orig1s032,021224Orig1s030,021615Orig1s023lbl.pdf. Accessed August 2, 2018.

[10]Novartis Pharmaceuticals Corporation. Label: Rivastigmine (EXELON). November 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020823s035,021025s023lbl.pdf. Accessed August 2 2018.

[11]Allergan, Inc. Label: memantine (NAMENDA). August 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba. Accessed August 2, 2018.

[12]Birks JS. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;Jan 25(1):CD005593.

[13]Birks JS, Harvey RJ. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev. 2018;Jun 18(6):CD001190.

[14]Birks JS, Grimley Evans J. Rivastigmine for Alzheimer’s disease. Cochrane Database Syst Rev. 2015;Apr 10(4):CD001191.

[15]McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;Apr 19(2):CD003154.

[16]Prescrire Int. Drugs for Alzheimer’s disease: finally delisted in France! June 15, 2018. http://english.prescrire.org/en/81/168/55126/0/NewsDetails.aspx. Accessed August 2, 2018.

[17]Lanctôt KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ. 2003;169(6):557-564.

[18]Press D, Alexander M. Cholinesterase inhibitors in the treatment of dementia. UpToDate. June 2018. https://www.uptodate.com/contents/cholinesterase-inhibitors-in-the-treatment-of-dementia. Accessed August 2,2018.

[19]Allergan, Inc. Label: memantine (NAMENDA). August 2016. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba. Accessed August 2, 2018.

[20]Alzheimer’s disease in France: Too many patients exposed to drug interactions involving cholinesterase inhibitors. Prescrire Int. 2014;23(150):156.