Drug therapies for Alzheimer Disease

Drug therapies for Alzheimer Disease

First, Do No Pharm Tom Finucane January 2014 31 No conflict of interest

Objective I would like to persuade you that we are in general enslaved in a plausible pseudoscience. Are these distinctive disease entities?

Heartburn Upset stomach

Stomachache GERD Pyrosis Dyspepsia Indigestion The besetting malady of this country is dyspepsia. From it about half of the income

of doctors is derived, and at least two-thirds of that of the patent medicine vendors. Osler 1900 Bellyache v.i. to grumble or complain, esp in a whining manner. Merriam Webster

Merriam Webster 2020 GERD v.i. (see bellyache) CANCER? GERD, Barretts, Cancer?

For patients with Barretts esophagus, the goal of pharmacologic acid suppression with agents such as the proton pump inhibitors is to control reflux symptoms. ACG Guidelines on Barretts 2008 The incidence of esophageal adenocarcinoma has been increasing steadily since 1980.

(Squamous CA has been falling.) Pennathur Lancet 2013 Gastric secretion of hydrochloric acid appears to be unique to vertebrates and is almost ubiquitous in all fishes, amphibians, reptiles, birds and

mammals. Koelz HR. Scand J Gastroenterol 1992. Comparative anatomy and physiology suggest that gastric acid has evolved approx 350 million years ago. The similarity of the acid-secreting

mechanism implies a major advantage for selection Proton pump inhibitors Relative risk of Pneumonia 1.9

Laheij JAMA 2004 1.5 Eurich Am J Med 2010, etc c. diff diarrhea 2.9 Dial JAMA 2005, etc hip fracture 2.7 Yang JAMA 2006

FDA Drug Safety Comm, 2010 Hospital-acquired pneumonia Cohort study 64,000 admissions. 27,000 got PPIs. 8,000 got H2 blkrs. Some got both Taking a PPI is associated with a 30% increase in

HAP. Herzig JAMA 2009 What do we want from drug treatment for Alzheimer Disease? What is Alzheimer Disease? Have you ever heard a clinician apply the

diagnosis dementia of unknown cause? That is actually called Alzheimers Highly variable clinical expression and clinical course. Worldwide shifts in incidence over the recent decades. Major effect of age.

Risk factors for AD? Aging Vascular risk factors Educational level Down syndrome Head circumference

Apolipoprotein pattern Family history Head trauma Vascular risk factors

What is the biological plausibility that modifying a neurotransmitter using a systemic medication will produce meaningful benefit in a patient with Alzheimer Disease? What do we want? Changes in mental status testing?

Changes that patient or companions can notice? Changes that improve the life of patient or companion? Stabilization of disease? Changes in mental status testing? A consistently positive finding.

On MMSE and ADAS-cog, donepezil produced statistically significant benefit. MMSE: improved in 7 of 9 studies. No study showed a 2-point improvement ADAS cog. No study showed a 4-point improvement. (Scale is 70 points.) This is proof of principle.

Changes that patient or companions can notice? The average difference on the CIBIC-plus was about 0.33 points. A score of Minimally improved was 1.0. This point is not airtight because we are using ordinal categorical data. It may be that a few people do better than

placebo. Changes that improve the life of patient or companion? Quality of life of (mild-moderate) patients is measured in 2 trials. There is no consistent difference.

A third trial used the Patient Global Assessment Scale where patients rate their impression of change. No significant differences were observed. No significant differences were seen between donepezil and placebo in behavioural and psychological symptoms,

carer psychopathology, formal care costs, unpaid caregiver time, adverse events or deaths, or between 5mg and 10 mg donepezil. Courtney Lancet 2004

Stabilization? No significant benefits were seen with donepezil compared with placebo in institutionalisations (42% vs. 44% at 3 years; p=0.4) or progression of disability (58% vs. 59% at 3 years; p=0.4). Courtney

Lancet 2004 Evidence is insufficient to support the use of pharmaceutical agents or dietary supplements to prevent cognitive decline or Alzheimers disease. Preventing AD and cognitive decline http://consensus.nih.gov/2010/docs/alz/

ALZ_Final_Statement.pdf Despite intensive laboratory and clinical research over three decades, an effective treatment to delay the onset and progression of Alzheimer's disease is not at hand. Selkoe, DJ

Preventing AD Science; Sept 2012 The Package Insert. Cholinesterase inhibitors Changes in mental status testing? Changes that patient or companions

can notice? Changes that improve the life of patient or companion? Stabilization of disease? Adverse effects Dropout rates averaged 30% in the cholinesterase groups and 18% in placebo

groups in the RCTs reviewed by Birks in Cochrane Anorexia, weight loss, nausea, vomiting, tremor in Cochrane In cohort studies, bradycardia, pacemaker placement, falls, hip fracture What is proper treatment if, after

best conservative efforts, a daughter asks for help with her Dad who has dementia, has moved in with her, and is sundowning in a way that destabilizes her family? SECOND-GENERATION OR ATYPICAL

ANTIPSYCHOTICS? 32 First, the time has come to abandon the terms first-generation and secondgeneration antipsychotics, as they do not merit this distinction. The only secondgeneration antipsychotic that is obviously better than other drugs is clozapine, and

this is a very old drug indeed. Tyrer Lancet 2009 Second-generation antipsychotics are now used more commonly than firstgeneration drugs, even though controlled trials have failed to demonstrate a clear advantage in efficacy with the newer drugs, except for clozapine and possibly

olanzapine Med Letter 6.13 Antipsychotic drugs differ in many propeties and can therefore not be categorised in first-generation and second-generation groupings. Leucht. Lancet. 2013

How about Expensive antipsychotics 36 Why choose them?

Reduction in extrapyramidal symptoms. 37 Tardive dyskinesia 5.2% with second-generation antipsychotics versus 5.2% with firstgeneration antipsychotics (P = 0.865)

in the elderly Medical Letter 6.13 (weak evidence) Safety? 39

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ZYPREXA is not approved for the treatment of patients with

dementia-related psychosis. 40 Efficacy? 41

Atypicals in Alzheimers AD plus: agitation, aggression, psychosis Randomized to: quetiapine olanzapine risperidone placebo Schneider NEJ, 2006 42

Main outcomes The main outcomes were the time from initial treatment to the discontinuation of treatment for any reason and the number of patients with at least minimal improvement on the Clinical Global Impression of Change (CGIC) scale

at 12 weeks. 43 Lilly assessed penalties totaling $1.415 billion for off-label marketing of its drug, Zyprexa. One portion of that sum is a $515 million criminal fine, the largest criminal fine

ever imposed upon an individual US corporation. usdoj.gov 1/15/09 44

Total Zyprexa Sales Since 1996: $39 billion 1st 6 months of 2008: $3.5 billion 45

Abbott to pay $1.6 billion for illegally marketing drug Abbott directed its sales force to get Depakote widely used in nursing homes, principally to neutralize older patients Abbott essentially preyed on the

most helpless patient populations. An attorney Wash Post 5.8.12 GlaxoSmith Kline July 2012 GlaxoSmith Kline agreed to pay a fine of $3 billion to resolve civil and criminal liabilities regarding

its promotion of drugs, as well as its failure to report safety data. This is the largest health care fraud settlement in the United States to date. J&J $2.2 billion

alleged kickbacks to doctors and pharmacies to promote the antipsychotic drugs Risperdal . WashPost 11/4/2013 Utilization? 49

FOR decades, antipsychotic drugs were a niche product. Today, theyre the top-selling class of pharmaceuticals in America, generating annual revenue of about $14.6 billion and surpassing sales of even blockbusters like heart-protective statins. D. Wilson NYT 10/2/10

50 Egas Moniz wins Nobel Prize in 1949 for the development of a procedure Frontal lobotomy

Chronic Sedentary Feasting, Aging, and the Tight Control of DM2 The precise drugs used and their exact sequence may not be as important as achieving and maintaining glycemic targets safely. ADA guidelines 2011

A worldwide epidemic Chronic Sedentary Feasting What drugs have been shown in RCTs to reduce the risk of micro

or macrovascular disease or death? Mean age of subjects (yrs)

ADVANCE ACCORD VADT UKPDS

UGDP Steno 2 UGDP 66 62 60 53

52 55 52 Survival as a function of HbA1C in people with Type 2 DM: a retrospective cohort study. Currie CJ Lancet 6 Feb. 10

(Mean age 64) A Professor of Medicine and diabetologist at UTHSCSA reviewed a 2007 paper for the NEJ that raised a question of cardiovascular risk from rosiglitazone. Before submitting his review, he faxed a copy of it to GSK, from whom he received

emoluments. Nature 451;2008:509. Today the A.D.A.s treasurer is the director of investor relations for Johnson and Johnson New York Times, 11/25/06

The precise drugs used and their exact sequence may not be as important as achieving and maintaining glycemic targets safely. ADA guidelines 2011 Evidence from RCTs Except for ACCORD and for metformin in UKPDS

34, no RCT of tight control in DM2 has shown a reduction in *MI * Renal failure *CVA * Blindness *Amputation * Neuropathy * Death

For GERD, AD, dementia-related behavioral disturbance, chronic sedentary feasting: First do no Pharm. Or as Olser said, .. As compared with standard

therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive

glucose lowering in high-risk patients with type 2 diabetes. ACCORD NEJM Intensive glucose control in patients with

poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications with the exception of progression of albuminuria (P = 0.01) VADT NEJM

A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and

microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy ADVANCE NEJM ADVANCE Combined endpoint; 5 yrs: 18.1 vs 20%

Microvascular: 9.4 vs 10.9 (Nephropathy: 4.1 vs 5.2) No difference in Major macrovascular events Death from cardiovascular causes Death from any cause

The main benefit conferred by the ADVANCE treatment regimen was a one-fifth reduction in renal complications. [From 5 to 4 per 100 over 5 years. Chance of not having macroalbuminuria: 95 ->96%]

The component of new or worsening nephropathy most clearly reduced through intensive glucose control was the development of macroalbuminuria.

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