MC

ED

Volume 9

December

HECK

2023

N 28
o

Editorial
Unavoidable harms of Alzheimer’s agent
Review

Lecanemab removes substitute of lost cells:
leading to brain hemorrhage and atrophy

Vaccine Information
Beware of distortion by healthy-vaccine effect
New Products

GLP-1 agonist for obesity: Semaglutide (Wegovy)

CONTENTS (December 2023, Vol. 9, No. 28)
Editorial
Unavoidable harms of Alzheimer’ s agent
Review
Lecanemab removes substitute of lost cells leading to brain
hemorrhage and atrophy
Vaccine Information
Is it true：“Several vaccines reduce Alzheimer’ s disease” ?
Beware of distortion by healthy-vaccine effect
New Products
GLP-1 agonist for obesity: Semaglutide (Wegovy)
Too many harms including suicide. Do not use ！

MED CHECK

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41

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Dec. 2023/ Vol.9 No.28 ・ Page 39

ED
HECK

Unavoidable Hams of Alzheimer’s agent
Translated and modified from MedCheck(in Japanese) Nov. 2023 (N110) and Jan 2024(N111)

Editorial

M
C

In 2007, MedCheck concluded that no drug can be recommended for dementia. It was based on
the results from a 4-year randomized controlled trial (RCT) of donepezil which showed that the agent
did not help reduce “institutionalization’’ as the index of care burden, it increased serious adverse

reactions, including death. In France, the reimbursement rate for four Alzheimer’s disease agents,
including donepezil, was lowered from 65% to 15% in 2011 due to a lack of evidence of long-term
therapeutic benefit. However, in Japan in the same year, three drugs other than donepezil wereapproved. This contrasts with France, where reimbursement for these four agents was finally delisted
in 2018.
By using the same methods (CDR-SB) as in the RCT of lecanemab, donepezil improved the scoreby 0.85 points compared with the placebo group at six months, but was not effective in reducing
institutionalization. On the other hand, lecanemab only improved the score by 0.45 points at 1.5 years,
even though the RCT was conducted in favour of lecanemab: odds of patients who discontinued due
to adverse events was 2.5 times that of the placebo group and those who discontinued were basically

Editorial

excluded from the efficacy evaluation. Institutionalization was not included as a study outcome.

As we conducted further research on lecanemab and the pathogenesis of Alzheimer’s disease, theharms of lecanemab are becoming clearer. Lecanemab induces multiple cerebral hemorrhages leading

to death and cerebral atrophy, both are closely related with the mechanism of action of lecanemab.

We also found that “the amyloid beta theory” claimed as the cause of Alzheimer’s disease is notcorrect (page41 of this issue). It can be inferred that dementia will worsen as brain atrophy progresses.

Major media uncritically report the manufacturer’s advertisement claiming that lecanemab, unlike

conventional drugs, treats the cause of Alzheimer’s disease and delays its progression. Patientsare often advised by their doctors that ‘if left untreated, the disease will continue to progress’ andare encouraged to accept the unreliable treatment. Consequently, truly effective prevention andtreatment options, such as aerobic exercise and methods for caring for Alzheimer’s patients, such as“Humanitude”, will be overlooked.

The burden on the health care economy is also enormous. In Japan, lecanemab has been used since

December 25, 2023. The annual cost of the drug is approximately $20,000 for a person weighing 50kg, and about $30,000 for 60 kg. Although a high-cost compensation system may reduce out-of-pocket
expenses, it will still be funded by taxes and insurance, and which could place a burden on the public.

In addition, PET examination requires significant out-of-pocket expenses. Do not use lecanemab, even

if it were not expensive, as the harm is clear while there is no evidence of efficacy. Please read ourseries of articles on lecanemab.

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Dec. 2023/ Vol.9 No.28

Review

Lecanemab removes substitute of lost cells leading toinevitable cerebral hemorrhage and atrophy
Translated and revised from Med Check (in Japanese) Nov. 2023 (N110) and Jan. 2024(N111)
Med Check Editorial Team

Abstract●Lecanemab is a product of monoclonal antibody that binds to and removes amyloid-β in the brain. It has beenfound that when used to treat mild cases of Alzheimer’s disease, it can cause multiple cerebral hemorrhage
leading to death and brain atrophy.
●Cerebral neuronal progenitor cells exposed to mild oxidative stress secrete a moderate amount of amyloid-βwhich improves cognitive function and stimulates to create new neurons. However, when high concentrations ofamyloid-β are produced due to excessive oxidative stress, it interferes with the formation of new nerve cells.
●Hence, the excessive amyloid-β is not the cause of Alzheimer’s disease, but is the result of excessive oxidative
stress, the real cause of the disease. Even if amyloid-β is reduced, it does not mean that the cause of the diseaseis removed.
●In the brains of Alzheimer’s disease patients, much of the vascular smooth muscle is replaced by amyloid-β.
This is the result of damaged smooth muscle cells secreting excessive amyloid-β due to excessive oxidative stressand being replaced by the amyloid-β as substitute.
●When lecanemab removes amyloid-β from blood vessel walls, edema and hemorrhage occur, injuring
surrounding brain tissue and subsequently causing brain atrophy. These are common and class adverse effects
of monoclonal antibody preparations and are consistent with the mechanisms of pathogenesis of Alzheimer’s
disease and cerebral amyloid angiopathy and the mechanisms of action of lecanemab.
●It is difficult to imagine that a substance that atrophies the whole brain could improve cognitive function.
Nothing about reducing the burden of care is taken into account in the clinical trials. It is not worth paying thehigh price. Even if it were not expensive, it should not be used because there is no evidence of benefit, but only
serious harms.
Conclusions: Reducing amyloid-β, which is not the cause of dementia, will only cause brain atrophy andmultiple cerebral hemorrhage, leading to death at the worst. Do not use lecanemab.

Keywords:
amyloid-β, oxidative stress, neuronal progenitor cells, ventricular enlargement, cerebral edema, cerebral hemorrhage, cerebral
amyloid angiopathy (CAA), cerebrovascular smooth muscle

Introductiondisease described in MedCheck in English No. 27 [1]was not sufficient. Subsequent research has revealed

Lecanemab (Lequenbi®) was launched on December

greater harms of lecanemab and the mechanisms of

20, 2023 in Japan. It is indicated for “mild cognitive

pathogenesis of Alzheimer ’s disease. Serious harms

impairment or mild Alzheimer’s disease”.

of lecanemab include multiple cerebral hemorrhages

The mechanism of pathogenesis of Alzheimer ’s

leading to death [2], brain atrophy and ventricular
MED CHECK

Dec. 2023/ Vol.9 No.28 ・ Page 41

Review
enlargement [3,4]. These are closely related tocreate new neuronal cells.

cerebrovascular amyloidosis (CAA) [5], in which

In other words, when neuronal progenitor cells are

amyloid-β (Aβ) accumulates in the walls of ar teries

damaged by moderate oxidative stress, Aβ is secreted

in the brain. Aβ is essential in the mechanism of

a p p r o p r i a t e l y, s t i m u l a t i n g s u r v i v i n g n e u r o n a lrepairing damage to neuronal cells [6] and vascularprogenitor cells and neuronal stem cells to recruit

smooth muscle cells [7] caused by mild oxidative

new neurons. This mechanism can be described as as t re s s ( N o t e ) . H owe ve r, exce s s i ve ox i d at i ve s t re s s

feedback function essential for maintaining a healthy

impairs the formation of normal neuronal cells andbrain.

vascular smooth muscle cells that are replaced by
the Aβ accumulated. Therefore, we will first explaint h e m e c h a n i s m s o f p a t h o g e n e s i s o f A l z h e i m e r ’s

Excessive oxidative stress suppresses neurogenesis

disease based on new findings. Considering theseH o w e v e r, e x c e s s i v e o x i d a t i v e s t r e s s i n j u r e smechanisms, it may be understandable thatneurons, damages neuronal progenitor cells severely,lecanemab cannot eliminate the cause of Alzheimer’s

and reduces activity of pumping functions bydisease, has no efficacy, and inevitably causes brain

p-glycoprotein in endothelial cells of cerebral blood

atrophy and multiple cerebral hemorrhage, leading tovessels [1,14-16], Aβ accumulates in the brain to highdeaths at the worst.

concentrations [1,14].

Note :Oxygen is essential for the human body, but reactive oxygencan damage the genes, proteins, and lipids of normal cells in the body,

In addition, high concentrations of Aβ inhibit thedifferentiation of neuronal stem cells into neurons

cause cell degeneration and necrosis, and cause aging and various[11, 12]. Hence the number of neurons continues todiseases. Nitric oxide (NO), which is released from tissues whendecrease.

reperfusion occurred after prolonged ischemia due to excessive stressor during infection, is a typical reactive oxygen or free radicals. Livingorganisms have a mechanism to eliminate reactive oxygen, but a statein which reactive oxygen exceeds this ability is called “oxidative stress”.

Neuronal progenitor cells secrete Aβ

Therefore, it can be concluded that the true causeof neuronal cell loss leading to dementia is exclusively
exce s s i ve ox i d at i ve s t re s s, a n d t h at A β i s m e re l y
a “r e s u l t ” o f e xc e s s i v e o x i d a t i v e s t r e s s . I n o t h e rwords, reducing Aβ does not eliminate the cause of
Alzheimer’s disease.

Even in old age, approximately 700 new neurons
are produced in the hippocampus alone per day, or
250,000 new neurons per year [8,9]. When neuronal

Cerebrovascular smooth muscle also secretes Aβ

cells are damaged by oxidative stress associated withMore importantly, in the arterioles in the brains ofprolonged ischemia and re-perfusion, the “neuronal

Alzheimer’s disease patients, Aβ replaces the smoothp r o g e n i t o r c e l l s” t h a t a r e t h e c e l l s j u s t p r i o r t omuscle cells which is essential for blood vessels toneuronal cells differentiate into new neuronal cells.

constrict and dilate as needed. In some areas, smooth

When the DNA of cultured human neuronalmuscle has been completely replaced by Aβ [5].

progenitor cells was damaged by treatment with

Cultured cerebral ar ter y smooth muscle cells

hydrogen peroxide (H2O2) , Aβ40 and Aβ42 that are

secreted Aβ40 and Aβ42 when exposed to oxidative

believed to be the cause of Alzheimer’s disease, wasstress [7]. Various changes associated with these havesecreted [6].

also occurred without contradiction. Oxidative stressinduced by other methods (iron ions) [17] also resulted

Moderate Aβ creates new nerve cells
A moderate amount of newly secreted Aβ not onlyin Aβ secretion from vascular smooth muscle cells,
and under starvation from vascular endothelial cells[18].

enhances cognitive function [1] but also stimulates

When smooth muscle cells are injured, smoothother living neuronal progenitor cells [10] and neuronalmuscle progenitor cells and smooth muscle stem

stem cells [11-13] to promote their differentiation andcells are stimulated and differentiated to produce

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Dec. 2023/ Vol.9 No.28

new smooth muscle cells [19,20]. Although the datacerebral hemorrhages and necrotizing vasculopathy

are not as complete as in the case of neuronal stema s s o c i a t e d w i t h t - PA i n f u s i o n i n a p a t i e n t w i t hcells to neuronal cells, it is likely that, similar to

cerebrovascular amyloid who had received

neuronal system, moderately secreted Aβ promotes

lecanemab” [21]. Fur thermore, magnetic resonancethe differentiation of smooth muscle stem cells andimaging (MRI) of the head performed 49 days before

creates new smooth muscle cells. However, excessive

the use of lecanemab revealed no findings such asoxidative stress increases Aβ which is hard to be

microhemorrhage or edema.

excreted from the brain, and accumulates excessively,

The authors of the phase 3 randomised control

inhibiting the differentiation of smooth muscle stemt r i a l ( R C T ) o f l e c a n e m a b co u nte r t h at t h e re h ave

cells and inhibiting the new generation of smoothbeen reports of fatal large catastrophic intracerebral

m u s c l e ce l l s. I f va s c u l a r s m o o t h m u s c l e ce l l s a rehemorrhages after t-PA treatment in persons withexcessively damaged by excessive oxidative stresscerebral amyloid angiopathy (CAA) in the absence ofa n d n e w s m o o t h m u s c l e ce l l s c a n n o t b e fo r m e d,any anti-amyloid medications [22].

blood vessels will rupture. Hence, Aβ accumulated inarteries is thought to serve as a substitute for smoothCase 2 [23]: A 79-year-old female. After using

muscle to prevent blood vessel from rupturing.

lecanemab during the extended period, she developed
significant cerebral edema, multiple cerebral

Three cases of death after multiple cerebral

hemorrhages less than 1 cm in size, and seizures, andhemorrhages

died. Several neurologists who reviewed the records

Case 1 [21]: A 65-year-old woman with early stage

noted an association with lecanemab [23].

of cognitive decline but with normal daily activities.
Fo u r d a y s a f t e r s h e r e c e i v e d t h r e e i n j e c t i o n s o f

Case 3 [24,25]: An 87-year-old male. During the use

lecanemab during the extension period after the endof a direc t oral anticoagulant (DOAC ) apixaban inof the RC T, she developed an ischemic stroke andthe ex tension period, he received lecanemab andpresented to the emergency room 30 minutes later.

fell possibly due to intracerebral hemorrhage. Both

After taking computed tomography (C T ) just before(apixaban and lecanemab) were stopped. One montht - PA ( a l t e p l a s e ) a d m i n i s t r a t i o n s h o w e d n o b r a i nlater, he had a myocardial infarction and received

hemorrhage with no contraindication to t-PA. Whenanother anticoagulant followed by a cerebral

she received 86% of the planned dose of t-PA, herhemorrhage leading to death. Eisai does not recognize

blood pressure increased to 250/111 mmHg, so thea causal relationship and claims that the cause was ainfusion was stopped (increased blood pressure may be

fall, heart disease, respiratory infection, or recurrence

due to cerebral bleeding) . A CT scan showed extensive,of a mild stroke-like attack [24,25].

m u l t i fo c a l i nt ra p a re n c hy m a l h e m o r r h a g e s. Th re edays later endotracheal intubation was per formed,

In the review repor t by the Japanese regulator y

but she died. The autopsy showed extensivea u t h o r i t i e s [ 2 6 ] , t h e s e t h re e d e at h s we re t re ate dmultifocal intraparenchymal hemorrhages, cerebral

separately from the trial as they occurred after thea m y l o i d a n g i o p a t h y, “ h i g h” A l z h e i m e r ’s d i s e a s edata collection period of the main trial, and because

neuropathologic changes, and diffuse histioc ytic

a relationship with lecanemab could not be ruled

vasculitis with necrotizing vasculopathy involving

out, it was concluded that “a cautionary statement is

amyloid deposition within (but not outside) the bloodrequired on the package inser t”. However, because

vessel walls.

it is not treated as an “Boxed Warnings” the alerting

The reporting physician pointed out “The extensive
number and variation in sizes of the cerebral
hemorrhages in this patient would be unusual as aeffect may be small.

Lecanemab causes brain atrophy: in phase 2complication of t-PA solely related to cerebrovascular

Figure 1 is a graph showing whole brain atrophy (Fig.

amyloid. The findings raise the possibility of

1 A) and enlarged ventricular volume (Fig. 1B) that were

MED CHECK

Dec. 2023/ Vol.9 No.28 ・ Page 43

Review
Figure 1: Decreased whole brain volume and increased ventricular volume

The unit is unknown as it is not mentioned in the clinical trial report paper[3].
Figures are cited and modified from ref. [3] Swanson CJ et al. Alzheimers Res Ther. 2021;13(1):80.

Figure 2: Volume change of whole brain and lateral ventricle

Reconstructed from data on ref. [4] Alves F et al. Neurology. 2023;100(20):e2114-e2124.

reported in the Phase 2b clinical trial [3].
Clinical doses of lecanemab resulted in significantly
smaller whole brain volume (Fig. 1 A) and enlarged

Other monoclonal antibodies also cause brain
atrophy

ventricular volume (Fig. 1 B) compared with the placebo

C li ni ca l t r i a ls have be e n co nduc te d o n var ious

group. The figure shows that the whole brain volume

agents for dementia targeting reduction of Aβ, suchdecreased 27% more in the clinical dose group thanas monoclonal antibodies against Aβ and inhibitors

in the placebo group. This means that the degree ofof the enzyme secretase, which converts the amyloid

brain atrophy was 27% severer than in the placebo

precursor protein (APP) into Aβ.
Am o n g t h e m , t h e re s u l t s o f a m e t a - a n a l ys i s o fgroup.
On the other hand, the volume of the ventricles,

measurements of whole brain volume and ventricularwhich contains cerebrospinal fluid, was 43% larger

volume were published in April 2023 [4]. Based on thethan in the placebo group (Fig. 1 B) . The enlargement

data extracted from the paper, we made Figure 2A toof the ventricles is thought to be due to brain atrophy,

show the relative changes (%) in whole brain volume

and the results are consistent with brain atrophy.

and ventricular volume due to monoclonal antibodies,

Although these results were reported in the phase 2b

such as lecanemab compared with the placebo group.

clinical trial, this point was not reported in the phase

Figure 2B shows mean differences.

3 trial [27].

The relative reduction in whole brain volume
was greatest with lecanemab at 28%, followed byPage 44 ・ MED CHECK

Dec. 2023/ Vol.9 No.28

Figure 3:Association of volume change with ARIA and amyloid reduction
Extracted from Figure 5 on ref.
[4] Alves F et al. Neurology.
2023;100(20):e2114-e2124.
ARIA: amyloid related imaging
abnormality (brain edema and/or
brain hemorrhage)
SUVR：standardized uptake
value ratio PET: positronemission tomography

Figure 4: Whole brain volume change from MCI to dementia level

Extracted from Figure 6 on ref.
[4] Alves F et al. Neurology.
2023;100(20):e2114-e2124.
ARIA: amyloid related imaging
abnormality (brain edema and/or
brain hemorrhage)

Figure 5: Ventricular volume change from MCI to dementia level

Extracted and modified from Figure 6
on the ref. [4])It is estimated that it takes 25 months
to reach the onset level of Alzheimer's
disease, but withmonoclonal antibody like lecanemab,
this could be shortened to 18 months(by about 7 months).

d o n a n e m a b. A d d i t i o n a l l y, a d u c a n u m a b h a d t h e

to change from non-dementia level to the dementia

largest increase in lateral ventricular volume at 57%,

level. However, with clinical doses of lecanemab andfollowed by lecanemab in third place with an increaseother m onoclonal anti body with amyloid-relatedof approximately 37%.

imaging abnormalities (ARIA: brain edema and

There was an extremely strong positive correlation

hemorrhage) , it took 3 years 3 months or 4 months(r=0.86, p=6.2×10-7) between the size of this ventricularearlier (9.3%) than the natural course (Figure 4) [4]. By

enlargement and the degree of cerebral edema andanalysing the ventricular volume change from mild

cerebral hemorrhage seen on MRI (Figure 3) [4].

cognitive impairment (MCI) to dementia level, it isI t took 3 years and 7 months under the natural
course (placebo group) for the degree of brain atrophy

shortened from 25 months to 18 months by 7 months(28%) (Figure 5).

MED CHECK

Dec. 2023/ Vol.9 No.28 ・ Page 45

Review
Figure 6: Illustrated Progression of cerebral amyloid angiopathy

Cited from the graphical abstract on the ref. [5] Kozberg MG et al. Brain Commun. 2022 Sep 26;4(5):fcac245.

Brain atrophy after edema and hemorrhage

broken.
The manufacturer blames other illnesses for the

In Alzheimer’s disease brains, neuronal progenitor

patient's death due to multiple cerebral hemorrhages

cells are destroyed by oxidative stress andafter using lecanemab [26]. It is like saying the house

excitotoxicity, and neurons cannot be replenished. In

was flooded during a rainstorm because it was very

addition, the smooth muscle cells in the arterial wall

old but not because of the removal of the plastic. A

are damaged in many places, so they are replaced andreanalysis of the results of the phase 3 trial reported

reinforced by Aβ.

that quality of life (QOL) has improved [28], but thisA s t h e d i s e a s e p r o g r e s s e s f u r t h e r, A β a l s odisappears, causing fibrinoid necrosis, and the vessel

is also unreliable as the results of those who dropped
out of the trial are not considered.

wall becomes extremely fragile (Figure 6) [5].
Monoclonal antibodies bind not only to soluble Aβ

In Practice: Do not use lecanemab

but also can bind to and remove insoluble Aβ. They

Cognitive function in people who were unable tocombine to form immune complexes, and as they

continue the study due to brain edema or hemorrhage

are removed by the immune response, inflammation

have not been properly examined, so the efficac yoccurs leading to edema. Also, if a small amounton change of cognitive function cannot be trusted.

is removed from the blood vessel wall and a small

Moreover, lecanemab induce brain atrophy definitely,

defect is created, blood components will leak out andand may induce multiple cerebral hemorrhages

edema will occur. If a large amount of Aβ is suddenly

leading to death at the worst. Therefore, lecanemab

removed, defects in the blood vessel wall will cause

may progress Alzheimer ’s disease rather than delay

bleeding and injure the surrounding brain tissue.

it. The use of lecanemab is extremely dangerous. Do

After hemorrhagic injuries have healed, the brain will

not use it even if it were not expensive.

shrink and the ventricles will enlarge.
I t i s l i k e re p l a c i n g a g l a s s d o o r t h a t h a s b e e nbroken in a rainstorm with a plastic thin sheet toprotect it from the rain and wind, but then peeling off
the plastic blaming the plastic as the cause of glass
Page 46 ・ MED CHECK

Dec. 2023/ Vol.9 No.28

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Vaccine Information
Is it true: “Several vaccines reduce Alzheimer’s disease”?
Beware of distortion by healthy-vaccine effectTranslated and revised from Med Check(in Japanese) Nov. 2023 ; 23 (110)：135-137
Med Check Editorial Team

Abstract● There are several articles titled “Several vaccines associated with reduced risk of Alzheimer’s disease”. MedCheck
editorial team examined the original articles to investigate if it really could be considered vaccine effects.
● The original paper was an observational study based on hypothesis that Alzheimer’s disease may be prevented by
reducing infection with neuroinflammation as one of the causes of Alzheimer’s disease. However, this hypothesis
itself was not reasonable, because the assumed number of vaccine-preventable Alzheimer’s disease patientsdetermined by the Number needed to treat exceed the maximum number of preventable infectious diseases by
each vaccine.
● The observational studies claiming a reduction in other diseases that vaccines did not originally target almost
always neglect healthy-vaccinee effect: vaccinated persons have better health status than unvaccinated persons.

Conclusions: Observational studies that claim vaccine effectiveness or safety need to be read criticallywith attention to distortion by healthy-vaccinee effect.

Keywords:
tetanus, diphtheria, pertussis, shingles, pneumococcus

Alzheimer’s disease”. The study was an observational

Introduction

study that followed approximately 1.65 million

Med Check Editorial Team emphasized the need topeople aged 65 years or older in the USA for 8

be aware of healthy-vaccinee effect when interpreting

years and compared the incidence of Alzheimer ’s

st u d ie s inve s t igati n g va cci n e e ffi cac y or a dve r se

disease with and without previous vaccination withreactions [1]. Some news reports have been publishedte t a n u s, d i p ht h e r i a , p e r t u s s i s, h e r p e s zo s te r a n do n t h e p o s s i b i l i t y t h at “ce r t a i n va cc i n at i o n s m ay

pneumococcal vaccines [5]. The authors of the paper

reduce risk of Alzheimer’s disease [2-4]” since August

per formed propensity score matching (Note 1) and

2023. However, after studying the original ar ticle,

repor ted that the incidence of Alzheimer ’s disease

these news reports needed to be read critically.

was approximately 30% lower in the vaccinated groupcompared with the unvaccinated group (Appendix 1)

What does the original paper claim?

.

Note 1: Propensity score matching is a method to adjust for baseline

The original article was based on the hypothesis

characteristics which could affect outcome. For tetanus, diphtheria andthat “various infections induce neuroinflammation,

pertussis vaccines, analyses have been conducted with approximately

which in turn causes Alzheimer ’s disease, and that

120, 000 people in the vaccinated group and 1.53 million people in

suppressing infections with vaccines would reduce
A l z h e i m e r ’s d i s e a s e , o r t h a t v a c c i n e s a c t i v a t e
t h e i m m u n e s ys te m , w h i c h i n t u r n wo u l d re d u ce
Page 48 ・ MED CHECK

Dec. 2023/ Vol.9 No.28

the unvaccinated group, adjusted for age, sex, race, smoking history
and prevalence of hypertension, diabetes, asthma, atrial fibrillation,congestive heart failure patients, etc.

Table: Maximum number of vaccine-preventable infection case (U.S. age ≧ 65)

Vaccine Information*a: Details were shown in Appendix 1. on this slides*b: Details were shown in Appendix 2. on this slides*c: To simplify the calculation, vaccine efficacy is assumed to be 100% (Assuming that “vaccinated persons are not infected”.)
If infectious diseases cause Alzheimer’s disease (AD), the upper limit of “vaccine-preventable AD patients” is maximum number of vaccine-preventable infectious disease(column D).
However, for diphtheria, pertussis, tetanus, and pneumococcus, “Number of vaccine-preventable AD patients assumed by calculation using NNT (column E)” is much larger
than “maximum number of vaccine-preventable infectious disease cases (column D)”.
Therefore, it is not reasonable to claim that vaccines can prevent Alzheimer’s disease based on the hypothesis “Alzheimer’s disease is prevented by reducing infection withneuroinflammation as one of the causes of Alzheimer’s disease”.

The number of vaccine-preventable Alzheimer’s
patients outweighs the number of vaccinepreventable infected patients!?
Suppose the hypothesis that “vaccines prevent each
infection and prevent Alzheimer’s disease following

disease is much higher than the number of vaccinepreventable infections (Table).
Note 2: NNT is indicator of how many people need to be vaccinated toprevent one target disease, i.e., if NNT = 33, thirty-three people need
to be vaccinated to prevent one person from contracting the target
disease.

those infec tions” is correc t, based on the Number
needed to treat: NNT (Note 2) described in the paper,

Any vaccine is 30% effective in reducing

the number of people aged 65 years and older in the

Alzheimer’s disease!?

US (about 40 million) [6], and the vaccination rate

It is strange that any vaccine is effective in reducing

for each vaccine vaccination rates [7], the following

Alzheimer disease by 25 to 30 % and the NNT is incalculations can be made. Over the eight-year period

the 30 to 40 range ( Appendix 1 ) [5]. If these vaccinesfrom September 2011 to August 2019, the tetanus,

reduced infection rates and subsequent Alzheimer’s

diphtheria and pertussis vaccines should havedisease, there should be over order of magnitude

prevented about 720,000 people from Alzheimer ’s

difference in NNT for each vaccine type. Because thedisease, the shingles vaccine about 430,000 people,

estimated incidence of shingles is approximately 800

and the pneumococcal vaccine about 820, 000 people

times higher than diphtheria, pertussis and tetanus(Appendix 2).

combined, and approximately 40 times higher thanpneumococcus.

O n t h e o t h e r h a n d, a cco rd i n g to U S i n fe c t i o u s

The discussion in the paper [5] argues that thedisease statistics [8-12], it could be calculated that

reduc tion in infec tion rates and ac tivation of thein the eight-year period from S eptember 2011 toimmune system by the vaccine may have contributed

August 2019, approximately 4,100 Americans agedt o t h e re d u c t i o n i n A l z h e i m e r ’s d i s e a s e, b u t t h e

65 years and older overall had either tetanus,

claim that “the reduction in infection rates reduced

diphtheria, pertussis, 3.28 million had shingles andsubsequent Alzheimer’s disease” is not appropriate.

approximately 82,000 had pneumococcus (details wereshown in Appendix 3)

If so, the calculation is that for tetanus, diphtheria,

Propensity score matching is not perfect foradjusting bias

pertussis and pneumococcal infections, the number ofJackson et al. have published a study comparing all-cases of (supposedly) vaccine-preventable Alzheimer’scause mortality risk between the influenza vaccinated
MED CHECK

Dec. 2023/ Vol.9 No.28 ・ Page 49

Vaccine Information
Figure：How healthy-vaccinee effect distort the vaccine study

for vaccination [14-16], and these individuals may
also have originally an increased risk of Alzheimer’s
disease [17,18].

Conclusion:
Beware of distortion by healthy-vaccine effectAlthough there was an observational study
showing that BCG vaccination was associated witha reduction in COVID-19 infections (about 40%) [19],a later published paper on a randomised controlled
trial showed that BCG vaccination does not reduce
COVID-19 infections [20]. Another paper stated thatand the non-vaccinated [13]. They showed that thethe results of a seemingly 30% reduction in COVID-19

total mortality risk was lower in vaccinated persons

h o s p i t a l a d m i s s i o n s a n d d e at h s d u e to i n f l u e n z a

not only in the influenza epidemic season but also invaccination was in fac t because of health-vaccine

the pre -epidemic season. This was due to healthy-

effect [21].

vaccinee effect (bias) , which could not be adjusted bypropensity score matching [13].

There are several other obser vational studies inwhich diseases that vaccines are not supposed to

In the original paper [5], the differences inprevent appear to be reduced in the vaccinated groupproportions, such as diabetes and atrial fibrillation[22-24]. However, when reading these papers, it issufferers, have been adjusted, but not for theimportant to have a critical eye and take into accountseverity of these diseases. For example, patients with

the impact of distortion by healthy-vaccinee effectmoderate or severe disease are considered ineligible(Figure).

Appendix 1:Reported proportion of petients with Alzheimer’s disease among vaccinated and unvaccinated, and NNT

Compiled from paper Table 2 in Harris et al. [5] J Alzheimers Dis 2023;95(2):703-18
Tdap: tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Td: tetanus toxoid and reduced diphtheria toxoid,
HZ: herpes zoster, N: number of propensity score matched population, AD: Alzheimer's disease, RR: relative risk,
RRR: relative risk reduction, VE: vaccine effectiveness, ARR: absolute risk reduction, NNT: number needed to treat.

Appendix 2: Number of vaccinated and Alzheimer’s disease to be reduced by each vaccine (U.S. ≧ 65）*a: https://www2.census.gov/programs-surveys/popest/tables/2010-2019/national/asrh/*b: https://www.cdc.gov/mmwr/volumes/70/ss/ss7003a1.htm
AD: Alzheimer’s disease
If “vaccines reduce the number of infected persons and thereby prevents Alzheimer’s disease (AD)”, then “the number of AD patients that would be reduced by the vaccine”
will always be less than the number of persons suffering from infectious diseases. This is because the assumption is made that this AD develops from infected patients (Below).

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Dec. 2023/ Vol.9 No.28

Vaccine Information
Appendix 3:Estimated number of infectious disease patients in the U.S. aged 65 years and older from 2011 to 2019 (8 years).

*a: https://www.cdc.gov/vaccines/pubs/pinkbook/dip.html*b: https://academic.oup.com/cid/article/68/10/1634/5087840*c: https://www.cdc.gov/vaccines/pubs/surv-manual/chpt16-tetanus.html*d: https://www.cdc.gov/shingles/surveillance.html*e: https://www.cdc.gov/pneumococcal/surveillance.html*f: https://www2.census.gov/programs-surveys/popest/tables/2010-2019/national/asrh/

References

14) CDC. Vaccines and Preventable Diseases - Diphtheria, Tetanus, and Pertussis Vaccine
Recommendations-

1) MedCheck Editorial Team. To be Vaccinated, or Not ? Points You should Know -SARS-

https://www.cdc.gov/vaccines/vpd/dtap-tdap-td/hcp/recommendations.html (Accessed

CoV-2 Vaccines Doubles the Risk of COVID-19! MedCheck in English. 2022; 8 (No25): 40-

13 December 2023).

52.

15) CDC. Morbidity and Mortality Weekly Report -Use of Recombinant Zoster Vaccine

2) Stories from The University of Texas Health Science Center at Houston (UTHealthin Immunocompromised Adults Aged ≥19 Years: Recommendations of the Advisory

Houston). Several vaccines associated with reduced risk of Alzheimer’s disease in adults

Committee on Immunization Practices - United States, 2022

65 and older.

https://www.cdc.gov/mmwr/volumes/71/wr/mm7103a2.htm (Accessed 13 December

https://www.uth.edu/news/story/several-vaccines-associated-with-reduced-risk-of-2023).

alzheimers-disease-in-adults-65-and-older (Accessed 13 December 2023).

16) CDC. Vaccines and Preventable Diseases -Pneumococcal Vaccine Recommendations

3) U.S. Pharmacist. Vaccines for Older Adults Appear Protective Against Alzheimer’s.

https://www.cdc.gov/vaccines/vpd/pneumo/hcp/recommendations.html (Accessed 13

htt ps : / / w w w. u s p h a r m a c i st . co m /a r t i c l e / va c c i n e s -fo r- o l d e r- a d u l t s - a p p e a r-

December 2023).

protective-against-alzheimers#:~:text=The%20researchers%20found%20a%20

17) Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J

statistically,8%2Dyear%20follow%2Dup. (Accessed 13 December 2023).

Med 2013;369(6):540-8. doi: 10.1056/NEJMoa1215740

4) ScienceDaily. Several vaccines associated with reduced risk of Alzheimer's disease in18) Wang M, Ding D, Zhao Q, et al. Kidney function and dementia risk in community-

adults 65 and older. https://www.sciencedaily.com/releases/2023/08/230816170628.htm

dwelling older adults: the Shanghai Aging Study. Alzheimers Res Ther 2021;13(1):21. doi:(Accessed 13 December 2023).

10.1186/s13195-020-00729-95) Harris K, Ling Y, Bukhbinder AS, et al. The Impact of Routine Vaccinations on19) Li YP, Cai JW, Liao LJ, et al. Effect of BCG Vaccination against SARS-CoV-2 Infection. Jpn

Alzheimer's Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using

J Infect Dis 2022;75(3):302-08. doi: 10.7883/yoken.JJID.2021.406

Propensity Score Matching. J Alzheimers Dis 2023;95(2):703-18. doi: 10.3233/JAD-221231

20) Pittet LF, Messina NL, Orsini F, et al. Randomized Trial of BCG Vaccine to Protect

6) United States Census Bureau.

against Covid-19 in Health Care Workers. N Engl J Med 2023;388(17):1582-96. doi:

https://www2.census.gov/programs-surveys/popest/tables/2010-2019/national/asrh/

10.1056/NEJMoa2212616(Accessed 13 December 2023).

21) Hosseini-Moghaddam SM, He S, Calzavara A, et al. Association of Influenza

7) CDC. Morbidity and Mortality Weekly Report -Surveillance of Vaccination Coverage

Vaccination With SARS-CoV-2 Infection and Associated Hospitalization and Mortality

Among Adult Populations - United States, 2018.

Among Patients Aged 66 Years or Older. JAMA Netw Open 2022;5(9): e2233730. doi:

https://www.cdc.gov/mmwr/volumes/70/ss/ss7003a1.htm (Accessed 13 December 2023).

10.1001/jamanetworkopen.2022.33730

8) CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases- Diphtheria-.

22) Kapoula GV, Vennou KE, Bagos PG. Influenza and Pneumococcal Vaccination and thehttps://www.cdc.gov/vaccines/pubs/pinkbook/dip.html (Accessed 13 December 2023).

Risk of COVID-19: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 2022;12(12)9) Skoff TH, Hadler S, Hariri S. The Epidemiology of Nationally Reported Pertussis in thedoi: 10.3390/diagnostics12123086

United States, 2000-2016. Clin Infect Dis 2019;68(10):1634-40. doi: 10.1093/cid/ciy757.

23) Wang R, Liu M, Liu J. The Association between Influenza Vaccination and COVID-19

10) CDC. Manual for the Surveillance of Vaccine-Preventable Diseases- Chapter 16:

and Its Outcomes: A Systematic Review and Meta-Analysis of Observational Studies.

Tetanus-. https://www.cdc.gov/vaccines/pubs/surv-manual/chpt16-tetanus.html

Vaccines (Basel) 2021;9(5) doi: 10.3390/vaccines9050529(Accessed 13 December 2023).

24) Taheri Soodejani M, Basti M, Tabatabaei SM, Rajabkhah K. Measles, mumps, and

11) CDC. Shingles (Herpes Zoster) - Shingles Burden and Trends-

rubella (MMR) vaccine and COVID-19: a systematic review. Int J Mol Epidemiol Genet.

https://www.cdc.gov/shingles/surveillance.html (Accessed 13 December 2023).

2021;12(3):35-39. PMID: 34336136; PMCID: PMC8310886.

12) CDC. Pneumococcal Disease- Surveillance and Reportinghttps://www.cdc.gov/pneumococcal/surveillance.html (Accessed 13 December 2023).
13) Jackson LA, Jackson ML, Nelson JC, et al. Evidence of bias in estimates of influenza
vaccine effectiveness in seniors. Int J Epidemiol 2006;35(2):337-44. doi: 10.1093/ije/
dyi274

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New Products
GLP-1 agonist for obesity: Semaglutide (Wegovy®)
Too many harms including suicide. Do not use ！
Translated and revised from Med Check (in Japanese) Sep 2023; 23 (109) ：108-111
Med Check Editorial Team

Abstract● Semaglutide is one of the glucagon-like peptide-1 (GLP-1) agonists already marketed for type 2 diabetes(Ozempic® subcutaneous injection, Reversus® tablets). In March 2023, the same ingredient was approved for thetreatment of “obesity” as Wegovy® subcutaneous injection. It will be launched in Japan in February 2024. The
maintenance dose of Wegovy® (2.4 mg once weekly) is approximately five times the standard maintenance dosefor diabetes (0.5 mg once weekly).
● The purpose of obesity treatment is to improve patients’ health and extend their life expectancy by reducing
weight of severely obese individuals.
● Semaglutide reduces weight by decreasing appetite. However, this is the result of the action of semaglutide on
the brain to stimulate the nerves, causing a high incidence of gastrointestinal problems, such as severe nausea,
vomiting, and/or diarrhea. It also affects health by increasing pancreatitis, gallstones, cholecystitis, retinopathy,
and other harms contrary to the original purpose of this treatment. Carcinogenicity is also a common adverse
effect of GLP-1 agonists observed in animal studies.
● Significant increase in suicidal ideation associated with liraglutide, another GLP-1 agonist for obesity, was found.
European Medicines Agency (EMA) is investigating the causality with GLP-1 agonists, including semaglutide.
● The basic weight control methods for severe obesity consists of thorough program for diet and exercise. The
indication for Wegovy is strictly defined by the package insert, but even if it were indicated it should not be used.
Conclusion: Do not use semaglutide (Wegovy®) even if the indication criteria were met.

Keywords:

obesity, weight loss, nausea, vomiting, carcinogenicity, cosmetic and slimming, suicidal ideation

Slightly overweight people live longest
There are many studies with millions of people
by life insurance companies that have examined the

expectancy compared with those with a BMI of 26 to
28. Obesity which could shorten life expectancy may
be 35 to 40 of BMI or higher in the United States. It
may be true also in Japan.

relationship between obesity index and life expectancy

T h e r e fo r e , i t c a n b e s a i d t h a t p e o p l e w h o a r e[1-3]. In all studies, people with a body mass index

over weight (BMI=25 to 30) are healthier or have

(BMI) of about 25 kg/m2 (units omitted below) have thesimilar risk as those who have a BMI of 22, the so-lowest risk of death, and the risk is not much higher

c a l l e d s t a n d a r d w e i g h t , a n d a r e n o t e l i g i b l e fo r

in people with a BMI up to 28 [1-5]. The same is true

treatment at all [4, 5].

for people with diabetes and hypertension. Moreover,

There are no studies showing that weight reduction,

among Japanese people with diabetes, those withespecially drug-induced weight reduction, increases

a BMI of 31 or higher had no difference in life

life expectancy.

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Dec. 2023/ Vol.9 No.28

New Products
states that the goal of obesity treatment is to “prevent

Med Check’s Evaluation: Unnecessary and harmful

or improve health problems through weight reduction”
and that “weight reduction defeats the purpose if it

Generic Name: Semaglutide
Product Name: Wegovy®Subcutaneous Injection

leads to health impairment”.
I t also states that the basis of weight reduction

Indications: Obesity, but it is limited to cases withtreatment is diet and exercise, which is appropriate in

hypertension or dyslipidemia or type 2 diabetes mellitus in

itself. It also mentions about the effectiveness of a life

which diet and exercise therapy do not provide adequate

diary and a weight diary with graph after achieving

relief and in which the following conditions are met:

●BMI of 27 kg/m2 or higher and two or more obesity-related
health problems●BMI of 35 kg/m2 or higher with at least one of the above
problems
Dosage and administration: Usually initial dosage ofsemaglutide for adults is 0.25 mg of subcutaneous injection
once weekly. Thereafter, the dose should be increased at
4-week intervals in the order of 0.5 mg, 1.0 mg, 1.7 mg, and
2.4 mg once weekly by subcutaneous injection. 2.4 mg is themaintenance dose.

weight reduction goals through diet and exercise, andthe practice of the chewing method [6]. However, it
ignores “life expectancy”, which is the most important
goal of healthcare.
The problem with the Society ’s guidelines is thatthe goal of pharmacotherapy is the prevention ofcardiovascular disease (cardiovascular death andcombined incidence of myocardial infarction and stroke) ,and all-cause mortality is not considered [7].
The inappropriate use of glucagon-like peptide-1

Price: It will be launched in February 2024. But drug price(GLP-1) agonists in non- obese people has been

not yet listed

rampant since several years ago under the name of

Manufactured and distributed by: Novo Nordisk Pharma

GLP-1 diet [8], and national consumer affairs centers
nationwide have been receiving an increasing numberof consultations regarding clinics offering cosmetic

Japan’s guideline for obesity is disease mongering

medicines online since around 2017 [9]. Moreover, theJapan Medical Association [10] and Japan Diabetes

However, the 2022 guidelines of the Japan Society

Society [11] and pharmaceutical companies [12] havefor the Study of Obesity [6] define obesity as a BMI

successively issued warnings against the off-label useof 25 or higher, and among the people whose BMI isof the drugs for slimming and cosmetic purposes.

25 or higher, those who have at least one of the 11
diseases or health problems, including hypertension,

Let us now take a closer look at Wegov y ®
subcutaneous injection.

d y s l i p i d e m i a , d i a b e t e s o r c o ro n a r y d i s e a s e s, a rediagnosed as “obesity syndrome” and are subject totreatment for weight reduction.

Weight reduction effect by Wegovy®

The basis for this is the studies which examined

The initial dose of semaglutide formulation (seeonly the relationship with the development of

B ox for summar y) is 0.25 mg subcutaneously once

hyper tension and diabetes, and none of themweekly. The dose is titrated up ever y 4 weeks, andexamined the relationship with mortality, especiallythe maintenance dose is 2.4 mg once week ly. Thisto t a l m o r t a l i t y. S e ve re l y o b e s e p e o p l e ( B M I 3 5 o r

maintenance dose is 4.8 times the usual maintenancehigher: 90 kg or more for a height of 160 cm and 102 kg ordose (0.5 mg/week) for type 2 diabetes.

more for a height of 170 cm), for whom weight loss could

If the patient loses appetite and weight with thepotentially increase life expectancy, account for only

drug, it is considered a harm of the drug. “The effect

0.9% of the adult population in Japan.

of Wegovy (=weight reduction) ” takes advantage of thisharmful effect. The appetite-lowering and weight-loss

Treatment of Obesity
The Japan Society for the Study of Obesity also

effec ts of GLP-1 agonists are primarily the resultsof their ac tion on GLP-1 receptors in the brain to
reduce appetite and slow gastrointestinal motility
MED CHECK

Dec. 2023/ Vol.9 No.28 ・ Page 53

New Products(delayed release) to cause indigestion, as mentioned byt hro ug ho ut t he bo dy, i ncludi ng t he he a r t, brain ,the manufacturer [13] and regulatory authorities [14].

gastrointestinal tract, pancreas, blood vessels, kidneys, and

The tolerance is built for delayed emptying of gastricimmune system [16], GLP-1 agonists can cause symptoms

contents after a short period of time, but the central

and adverse reactions in various organs.

effect is maintained for a long time [15].

Gastrointestinal disorders: Nausea, vomiting, diarrhea,

The weight reduction effect was obvious. After 68

constipation, belching, abdominal pain, andweeks, the placebo group lost weight by 2-3%, but theg a st ro e so pha g e a l re flux di se a se, a re pa r t i cular ly

Wegovy 2.4 mg group lost weight by 10-15%. In thecommon. Serious adverse events include cholecystitis,

largest study, the Wegovy 2.4 mg group lost weight bycholelithiasis, acute pancreatitis, atrial fibrillation,

15.6%.

atrial tachycardia, acute myocardial infarction, bile
duct stones, ureteral stones, pyelonephritis, vertigo,

Faster pulse, increased heart diseaseketoacidosis, and diabetic retinopathies [13, 14].

and death

Carcinogenicity: In a carcinogenicity animal study

Adrenergic-mediated action is essential for weight lossof semaglutide [22], the lowest dose of semaglutide

with GLP-1 agonists, because GLP-1 did not decreasei n c re a s e d t hy ro i d C - ce l l t u m o r s ( i n c l u d i n g b e n i gn

body weight of triple beta-adrenoreceptor knockout

tumors) in both mice and rats. In particular, thyroid

mice [16]. When GLP-1 receptors in the sinus node, whichC- cell adenocarcinoma was increased in rats withregulates heart rhythm, are stimulated, β1 adrenaline acts

We g ov y at o n e - e i g ht h t h e d o s e u s e d i n h u m a n s.

to accelerate the pulse rates [17]. Thus, the weight-loss

A significant increase in cancer was also obser ved

effects of GLP-1 agonists and their β-adrenergic stimulationin clinical trials of GLP-1 agonists [15], and biliar y

are inseparable, and long-term use of GLP-1 agonists may

adenocarcinoma and renal clear cell carcinoma wereincrease cardiovascular disease and psychiatric disorders.

also seen in clinical trials of Wegovy. The most recent

A meta-analysis of clinical trials of GLP-1 agonists insystematic review revealed that GLP-1 agonist

diabetes reported a reduction in cardiovascular disease

treatment was associated with a significant increase[18, 19]. However, in clinical trials, the frequency of nausea

in the risk of overall thyroid cancer and odds ratio

and vomiting was extremely high in the GLP-1 agonist

was 1.76 [95% CI 1.00, 3.12] (P = 0.05) by meta-group, and it was easy to determine whether the assigned

analysing studies with two years or more [23].

substance was GLP-1 agonist or placebo. This can breakdouble blinding shortly after the start of the trial, making it
susceptible to data manipulation [15].

Psychiatric effects including completed

I n addition, pulse rate is faster in clinical trials

suicideof Wegovy [13, 14], as well as in trials of other GLP-

Suicidal ideation and self-harm have been reported in

1 agonists. Long-term use of drugs that increase the

Iceland and the EMA has initiated a review [24]. In a review

pulse rate worsens heart diseases, which contradictsof clinical trials of liraglutide [25], the incidence of suicidal

the results of meta-analysis which showed a reduction

behavior showed non-significant increase in the liraglutide

in cardiovascular disease.

group: 0.3% (9/3384) versus 0.1% (2/1941) in the placebo

In fact, a trial comparing the GLP-1 agonist

group (P = 0.208).

liraglutide to placebo in heart failure patients, 60%

However, in the supplementar y appendix of theof whom had diabetes complications, showed areport [25], it is revealed that the number of events insignificant 34% increase in death + cardiovascular

the liraglutide group was eleven.

re a d m i s s i o n + e m e rg e n c y d e p a r t m e nt v i s i t s at 6
months [20, 21].

Kelly et al. [26] reported three suicidal cases (onecompleted and two attempted suicide) among 125

liraglutide treated adolescents while no suicidal

Too many harms
Because GLP-1 receptors are expressing on cells
Page 54 ・ MED CHECK

Dec. 2023/ Vol.9 No.28

event was reported in the placebo group. The metaanalysis of both reports yielded a pooled odds ratio(OR) by conditional maximum likelihood as 4.57

New Products
Figure : Outcome, adverse and overall events from SELECT trial

Primary composite outcome events, death from any cause and serious adverse events were less reported in the Wegovy group but adverse events leading to permanent
discontinuation of trial product, irrespective of seriousness were far more reported in Wegovy group than in Placebo group. Overall events were more reported in Wegovy
group: Odds ratio was 1.17 (95%CI: 1.13, 1.22) (p<0.0001). Because participants with permanent discontinuation of trial product were censored at the point of discontinuation,
those who had primary composite outcome events might not have been counted as having event. The reported results are extremely distorted by the unbalanced proportion of
those with permanent discontinuation of trial product. Moreover, they have not report about suicidal events that FDA’s documents pointed out.

(exact Fisher 95%CI: 1.04, 41.71) (p=0.036, I2 =0%).

Pr i m a r y c a rd i ov a s c u l a r e f f i c a c y e n d p o i n t w a s

In the documents reviewing Wegovy by the Fooda composite of death from cardiovascular causes,

and Drug Administration (FDA) [27] the followings

nonfatal myocardial infarction, or nonfatal stroke,

we re re p o r te d : “ 5 s u i c i d a l i d e at i o n a m o n g 2 6 5 0

assessed in a time-to-first-event analysis.

par ticipants in semaglutide 2.4mg group, while 2

As shown in the Figure, the pr imar y composite

among 1529 participants with placebo group wereoutcome events, death from any cause and serious

reported.” Meta-analysis of 3 data above yield pooled

adverse events were less repor ted in the Wegov yodds ratio 2.98 (95%CI: 0.98, 12.11)(p=0.05, I2=0%).

group, while adverse events leading to permanent

Moreover, in the same document [27] it was reported that

discontinuation of trial product, irrespective of“Blinded data: Blinded data as reported in the NDA and 120-seriousness (odds ratio was 2.24) were far more

day safety update identified 4 subjects in the SELECT CVOT

repor ted in Wegovy group than in Placebo group.

with fatal events of suicide (1 suicide attempt and 3 completed

Overall unwanted events (sum of these events) weresuicides that were listed as fatal events) . As the events are

more reported in Wegovy group: Odds ratio was 1.17

blinded, an assessment of suicide with semaglutide cannot(95%CI: 1.13, 1.22) (p<0.0001).

be completed at this time.”

It is assumed that the participants with permanent
discontinuation of trial product were censored at the
point of discontinuation. If it is correct, those who

SELECT trial reported nothing about suicidal

had primar y composite outcome events might not

eventshave been counted as having events. The repor ted

Semaglutide Effects on Cardiovascular Outcomes inresults would have been extremely distorted by the

People with Overweight or Obesity (SELECT) trial tested theu n b a l a n ce d p ro p o r t i o n o f t h o s e w i t h p e r m a n e nt

hypothesis that the addition of semaglutide to standard carediscontinuation of trial product.

would be superior to placebo in reducing the risk of major
adverse cardiovascular events among patients 45 years ormore of age with overweight or obesity and preexistingMoreover, they have not reported about suicidal
events that FDA’s documents [27] pointed out.

cardiovascular disease who did not have diabetes [28].
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SELECT results may be distorted byblinding failure
Hazards (or odds) of events varied by the period after
the start of the study. For example, Figure 1B of themg) of Wegovy, annual incidence of retinopathy (persons/100
person-years) was 3.5 in the placebo group, 5.5 in the lowdose group, and 6.7 in the clinical dose group. Retinopathy
increased with increasing dose (dose-response relationship, p= 0.0012) [13].

SELECT trial [28] is the time-to-first-event analysis for

I n a study of semaglutide for diabetes [30], thedeath from cardiovascular cause. Odds ratio (95%CI) of

risk of developing retinopathy was also significantly

cardiovascular death within every 6 months after the starti n c re a s e d, 1 . 7 6 t i m e s t h at o f t h e p l a ce b o gro u p,of the trial extremely fluctuate: 0.44 (0.24, 0.83) during theand all- cause mor talit y was slightly higher in thefirst 6 months to as high as 2.08 (1.25, 3.46) during 18 tosemaglutide group than in the placebo group (hazard

24 months and as low as 0.24 (0.12, 0.49) during 36 to 42

ratio 1.05).

months.
As Wegov y induced frequent gastrointestinal
adverse reactions, allocation was very easy to beContinuous unnatural stimulation

speculated and the blinding may be easily broken.
Very high odds ratio (2.24) for the adverse events

Physiological GLP-1 in the body plays an important roleleading to permanent discontinuation of trial

by working in tissues throughout the body, but its effects

product and the fluctuating odds ratios may be theare short-lived and only activated when necessary. The

results of blinding failure (details will be discussed

half-life of physiological GLP-1 is 1-2 minutes, meaning itin the next issue).

is completely eliminated within in 5 to 10 minutes if notneeded. However, a GLP-1 agonist, such as Wegovy®,

Obese people have less suicidal ideation
As a reason for increased risk of suicidal ideation, it

which requires only once-weekly injection, continuously
stimulates various parts of the body even when GLP-1 isunnecessary.

is sometimes claimed that severely obese individuals

Physiological GLP-1 also stimulates the receptor

have a pre-existing mental illness, which increases

vascular endothelial growth factor ( VEGF),

their risk of suicidal ideation. However, this is incorrect.

w h i c h i n c re a s e s va s c u l a r e n d o t h e l i a l ce l l s a n d

A follow-up survey of approximately 14,000 men

proliferates blood vessels [31,32], but does not work

and women between the ages of 18 and 26 in thewhen not needed. However, if a GLP-1 agonists

United States [29] revealed the opposite results.

are continuously used when it is unnecessar y, it

Among women of any BMI group, there was almost

may cause blood vessels to proliferate, causing or

no difference. For men, compared with the reference

worsening retinopathy. Sustained stimulation of

BMI (18.5-24.9), odds ratio of overweight people (BMI

VEGF has also been found to increase cancer [32].

25-29.9) was significantly lower at 0.62, and even those

who are fully obese (BMI 30 or higher) it was 0.5 to 0.75.

These explain why there are so many unfavorable
effects.

Severely obese people with BMI of 40 or above did nottend to have more suicidal ideation: OR was only 0.5

In practice[29].

Semaglutide may reduce weight, but it is not a healthy
way to lose weight. The basic principle of weight reduction

Retinopathy should not be overlookedtreatment for obesity is to stick with a thorough regimen ofdiet and exercise with behavioral therapy.

Wegovy, as a hypoglycemic agent, reduces elevation

Wegovy should not be used, even if it meets strictof blood glucose levels, but increases retinopathy [13]. By

indication criteria. Nor should it be used for weight loss of

combining the data from three randomized contolled trials

non-obese people.

(RCTs) comparing placebo, low dose, and clinical dose (2.4
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Appendix:
Importance of Behavioral Therapy and Supportshould be improved based on the recording of usual
food intake and physical activity at each visit or
nutritional counseling. (The recording is essential because

Diet and exercise are the mainstays of weight reduction

the examination is based on objective data on actual foodtreatment. However, for individuals with severe obesity

intake and physical activity.) Then the patients take homewhich requires treatment, patiently sticking with diet andthe homework and practice it. The basic approach is

exercise might be challenging. Behavioral therapy isthat medical professionals assist the patients in a way

important in changing the behavior itself, includingthat maintains their motivation to lose weight andeating behavior.

encourages them to move to the next step. It is also

I n a b e h av i o ra l a p p ro a c h , a s a m e t h o d o f s e l f management, patients and medical professionals

important that their family and friends support themso that they can stay motivated.

examine together what has been achieved and what

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No.28

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Editor-in-Chief: HAMA, Rokuro (MD)
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