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August2018

Volume 4-The Informed Prescriber

N 11

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What we learned from epidemiologicalstudies on drug-induced pneumonia
Japanese Guideline for Hypertension is fordisease mongering
CONTENTS （August 2018, Vol. 4, No. 11）

Editorial
What we learned from epidemiological studies on drug-induced
pneumonia

16

New Products
A new cholesterol lowering agent: lomitapide is highly toxic

17

Reviews
Japanese Guideline for Hypertension is for disease mongering

20

Medical checkups create “patients” and shorten their lifespan by “treatment”

Adverse Reactions
Pneumonia induced by benzodiazepines
Evidence shows causal relations

Page xvi ・ MED CHECK - TIP August 2018/ Vol.4 No.11

24

M
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-The Informed Prescriber

HECK

Editorial

What we learned from epidemiological studies
on drug-induced pneumonia
Translated from the Editorial in Med Check-TIP (in Japanese) May 2018 ; 18 (77)

It is well known that corticosteroids and cytotoxic

increase infectious diseases. Even if the substance

anticancer agents cause infections. The labels of non-is not tested in humans and adverse effects are notsteroidal anti-inflammatory drugs ( NSAIDs ) warn

known yet, increase of infection can be predicted fromthat they may conceal signs of infection (fever andits fundamental mechanisms of action.

inflammation ). Many drugs including H2 blockers

Secondly, in Japan, a large-scale database systemand proton pump inhibitors ( PPI: MedCheckTIP

is needed to study harms of drugs. All studies that

No73 and No74 ),both of which suppress theshowed association between benzodiazepines andsecretion of gastric acid, cholesterol lowering agentspneumonia analysed large-scale databases in which

and angiotensin receptor antagonists ( ARB ) for

the total number of subjects was 17,000 to 240,000,

hypertension increase infectious diseases.

and they used appropriate methods, such as adjustingbaseline characteristics to prove the association

When we critically appraised the efficacy andbetween benzodiazepines and pneumonia.

safety of diazepam for prevention of febrile seizures( The Informed Prescriber, Jan. 2007), we found that

We hope that the medical information database

it increased fever ( a symptom of infection ) by 26%"MID - NET" project starting this fiscal year (FY 2018)

compared to placebo in a randomized controlled trial

would work for research on adverse reactions to(RCT). Diazepam is one of the typical benzodiazepines.

drugs. However, considering that the project is one

At that time, there was no study that showed increasedof the complement systems for "Conditional Early

pneumonia by benzodiazepine use, but we thought

Approval System", which was implemented in Octoberthat immunosuppressive action of diazepam was2017 by the Manager of the Ministry of Health, Labor

related to increased signs of infection.

and Welfare, it is likely to end up as disappointment.

In this issue, we examined the relationship between

This is because "Conditional Early Approval System"

benzodiazepines and community acquired-pneumonia

emphasizes its importance by stating that "An analysis(CAP, a typical infection), and a strong causal relationshipof data using only the persons who used the drug

was confirmed (p.24). Some other sleeping pills suchafter approval as real-world data requires far fewer

as svorexant (orexin antagonist: MedCheckTIP No. 74 orparticipants, and can be completed in short period

English edition No. 9) and ramelteon (melatonin agonist:of time with far smaller cost. This might substituteibid No. 75) also have immunosuppressive effect and

RCTs, which require a large population, a large

increase infectious diseases.

amount of money for a long period of time. Poorly
designed observational studies could produce results

We have learned the followings from the"no association between drugs and adverse events is

epidemiolog ical survey which showed strong

observed" or “the drug is effective” even if the truth isassociation between sleeping pills and CAP:

opposite.

First, drugs that act on the basic mechanism of thebody, such as proton pumps and benzodiazepine
receptors, have immunosuppressive effects andPage 16 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

MID-NET system, along with "Conditional Early
Approval System", requires strict monitoring.

New Products
A new cholesterol lowering agent:

lomitapide is highly toxic

Fat accumulates in the liver and small intestine

Translated from Med Check-TIP in Japanese Jul 2018 ; 18 (78):82-83
Hama R., Hamasaki T., Okuyama H., Ogushi Y.

Summary●Lomitapide (Juxtapid®) is a cholesterol lowering agent with a novel mechanism of action. It was launched in Japanin December 2016 with an indication for homozygous familial hypercholesterolemia (HoFH).
●Lomitapide lowers plasma LDL-cholesterol level by inhibiting triglyceride (TG) transfer to chylomicron and VLDL byinhibiting microsomal triglyceride transfer protein (MTP) in the same way as hepatitis C virus does in the liver cells
leading to steatosis of the liver cells. It also inhibits MTP in the intestinal epithelial cells leading to their steatosis.
●Animal toxicity tests showed that one tenth of human dose of lomitapide induced liver cell steatosis and single cell

necrosis of liver cells. Liver cancer and intestinal cancer (normally very rare) were also observed by administering one
third of human dose of lomitapide in another animal toxicity test (male mice).
● It also causes diarrhea due to poor lipid absorption in the small intestine leading to hemorrhage because

absorption of lipophilic vitamins especially vitamin K decreases.
● The efficacy for reduction of mortality from myocardial infarction and from all-cause is unknown, as no randomized

controlled trial comparing placebo has been carried out. On the contrary, it is highly toxic carcinogen causing humanliver steatosis commonly and small intestinal cancer by about 200 times more than general population.

Conclusion: We strongly recommend against using lomitapide even restricting its use to HoFH.

Keywords:
Lomitapide, homozygous familial hypercholesterolemia, HoFH, non-comparative study, liver steatosis, diarrhea, liver cancer,
hemorrhage, intestinal cancer, carcinogenicity.

Introduction
Lomitapide ( Juxtapid® ) has been approved for anindication of homozygous familial hypercholesterolemia

trial (RCT) comparing cholesterol lowering therapy withplacebo in patients with HoFH has never been conducted
for all-cause mortality as outcome [5-8].

( HoFH ) with a condition where "Inadequate effect or

HoFH is associated with a high incidence of myocardialpoor tolerability with other oral lipid lowering drugs isinfarction and high mortality not because of highobserved" [1-4].

cholesterol level but of other causes, because genetic

For HoFH, drug therapy with statins or statins +constitutions for high cholesterol level and other various

ezetimibe (Zetia®) or removal of serum LDL-cholesterol

factors which easily induce atherosclerosis are closely( apheresis ) has traditionally been performed [5-7].

related [8, 9]. The latter include (1) difficulty of utilizing

However, the evidence basis of these treatments hasenergy (leading to ischemic stress) through cholesterol-

been unknown so far, because randomized controlled

carrying lipids by the cells, especially myocardial cells,
MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 17

New Products(2) prone to inflammation by inducing more

Figure 1: Role of MTP (microsomal triglyceride transport protein) and
its inhibitor

TNF-α and other cytokines, (3) increased
coagulability, (4) hypersensitivity of vascularendothelium [8, 9].
Therefore, cholesterol lowering therapy for
HoFH does not lead to longevity, and it isconsidered to be only harmful if it is toxic. We
will critically examine the results of animal
toxicity tests and clinical trials [3-7], whichwere the basis for the approval of lomitapide.
Lomitapide is a poison similar to hepatitis C virus

In the liver cells, cholesterol and triglyceride ( TG)

Within intestinal epithelial cells, lipids arecarried to MTP are added one after another to ApoB

resynthesized to triglycerides (TG), taken up into large( as pre-VLDL ). Then, VLDL, which is rich in TG andparticles of fat (chylomicron), secreted and circulated

has very low density, is formed and secreted outside

throughout the body. Also in the liver cells, TG is taken

the liver cells. This turns into LDL in the blood. In the

up by very low density lipoprotein (VLDL), which is theintestinal epithelial cells, TG-rich chylomicrons are

source of LDL-cholesterol, secreted into the blood andformed and secreted into the lymphatic vessels in thecirculated throughout the body. A protein called MTP

same manner, and are distributed to the whole body.

(microsomal triglyceride transfer protein) plays the role of

The core protein of hepatitis C virus (HCV) inhibits MTP

carrying TG to chylomicrons and VLDL in the intestinal

in the liver cells and induces fatty liver (liver steatosis).

cells and liver cells respectively (Figure. 1).

Lomitapide, like HCV, inhibits MTP in the liver cells. In

Lomitapide is a cholesterol lowering agent of novel

addition, it inhibits MTP in the intestinal epithelial cells,

mechanism of action, which resembles that of hepatitis

accumulates triglycerides in these cells, and causes cell

C virus (HCV). Since HCV inhibits the action of MTP

injuries.

in the liver cells, it induces fatty liver (liver steatosis)[10, 11]. Lomitapide, like HCV, inhibits the function ofReport of small bowel cancer even in humans

MTP in liver cells. As a result, liver cells produce lessIn mice carcinogenicity studies, liver cancer occurred

VLDL, and the blood concentration of LDL-cholesterol

three times more frequently in lomitapide group thandecreases (Figure. 1). In addition, lomitapide inhibits

in control group with just one third of human dose (p =MTP required for absorption of lipids into the body

0.002). In addition, small intestinal cancer, an extremely

within intestinal epithelial cells (see Figure. 1,
footnote [4]).

Because of this series of actions, TG
accumulates in the liver cells and intestinal
epithelial cells. In animal toxicity tests, it
induced single liver cell necrosis with atenth of the human dose. As the absorptionof lipids in the small intestine decreases,
diarrhea frequently occurs and absorptionof lipid-soluble vitamins such as vitamins A,
D and K (especially vitamin K), decreases, andhemorrhage is easily caused [4].

Page 18 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

Figure 2: Incidence of cancer of liver and intestine in carcinogenicity study(mice, male)rare disease, occurred in one animal with one third of theConclusion

human dose. and occurred in 9 out of 60 animals (15%)

Lomitapide (Juxtapid®) has the effect of "loweringwith 5 times of the human dose (Figure 2). Inhibitingcholesterol", but it causes cell necrosis in the small

the action of MTP is extremely dangerous because of its

intestine and liver, and is a poison with carcinogenicity.

potential toxicity and carcinogenicity.

Lowering cholesterol of persons with homozygous

The small intestinal cancer in humans is extremelyrare with annual incidence rate only 0.22 to 0.57

familial hypercholesterolemia ( HoFH ) provide nobenefit, but only harm.

persons per 100,000 persons (Western countries) [12].
Lomitapide has been used in 1,173 HoFH patients, andone case (63 years old woman) of ileal cancer has beenreported [4]. This result shows that intestinal cancer
is 213 times more likely to occur in patients who aretreated with lomitapide than in general population (pReferences<0.006).

1) Lomitapide: Label2)Lomitapide: Interview form

Results of major clinical trials
In the pivotal clinical trials [4, 5], which served as the3)Lomitapide: Examination report by regulators
4)Lomitapide: Summary basis of approval5) Cuchel M Meagher EA, du Toit Theron H et al. (Phase 3 HoFH Lomitapide Study
investigators), Efficacy and safety of a microsomal triglyceride transfer protein

basis of the approval, lomitapide 5 mg daily was initiallyinhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm,

given to 29 HoFH patients, and the dose was gradually6) Blom DJ, Cuchel M et al. Long-Term Efficacy and Safety of the Microsomal

open-label, phase 3 study. Lancet. 2013;381(9860):40-6. PMID: 23122768

increased up to 60 mg. After 26 weeks of treatment,

Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous

lowered LDL-cholesterol was observed. From 26 weeks

28716835

onwards until 78 weeks, safety assessment is conducted

treated patients with homozygous familial hypercholesterolemia: Rationale andFamilial Hypercholesterolemia. Circulation. 2017;136(3):332-335. PMID:
7) Blom DJ, Fayad ZA et al (LOWER investigators) LOWER, a registry of lomitapide-more frequently and the treatment continued. The

design. J Clin Lipidol. 2016;10(2):273-82. PMID: 27055957

median dosage of lomitapide is 40 mg daily.

healthiest peaple patient who need treatment-The guidelines for longevity by Japan

LDL-cholesterol level fell by 50% at 26 weeks, 44%8)MedCheckTIP Editorial team, Guidelines by Japan Atherosclerosis Society make aSociety for Lipid Nutrition is appropriate. MedCheckTIP2018：18(78)：76-81
9) Okuyama H, Hamazaki T, Hama R, Ogushi Y et al A Critical Review of theat 56 weeks, and 38% at 78 weeks, compared with theConsensus Statement from the European Atherosclerosis Society Consensus Panel

baseline.

10) Perlemuter G, Sabile A et al. Hepatitis C virus core protein inhibits microsomal

By 26 weeks, six people dropped out. The reasons2017. Pharmacology. 2018;101(3-4):184-218 PMID: 29353277
triglyceride transfer protein activity and very low density lipoprotein secretion: amodel of viral-related steatosis. FASEB J. 2002;16(2):185-94.PMID:11818366

for dropout were due to 4 adverse events, 3 of which

11) Popescu CI, Dubuisson J. Role of lipid metabolism in hepatitis C virus assembly

were gastrointestinal disturbances. The most common12) National Cancer Center Rare Cancer Center、 intestinal cancer (duodenal

adverse event was gastrointestinal disturbance. By

and entry. Biol Cell. 2009;102(1):63-74. PMID: 19857204
cancer, jejunum cancer, ileal cancer)
https://www.ncc.go.jp/jp/rcc/about/small_intestine_cancer/index.html

26 weeks, 27 ( 93% ) complained of gastrointestinal13) Harada-Shiba M, Ikewaki K, et al. Efficacy and Safety of Lomitapide in Japanesesymptoms.

2017;24(4):402-411. PMID:28154305

Patients with Homozygous Familial Hypercholesterolemia. J Atheroscler Thromb.

The amount of fat in the liver was 1.0% at thebaseline, and has increased to 8.6% at 26 weeks, whichis extremely high. It seems that almost everyone hasdeveloped fatty liver in varying degrees. The effect oncoronary artery disease is unknown.
In Japan, a similar test [4, 13] was conducted with
9 HoFH patients, and eight of them continued for 52
weeks. The result was similar as the above study [4, 5].

MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 19

Review
Annual theme of 2018: critical appraisal series for treatment guidelines (3)Japanese Guideline for Hypertension is fordisease mongering
Medical checkups create “patients” and shorten their lifespan by “treatment”
Translated from Med Check-TIP(in Japanese) May. 2018;18(77):58-60
MedCheckTIP editorial team

Summary● Following popularization of general health-checks and revision of hypertension guidelines, one in three or four
adults and one in two elderly people take antihypertensive medications in Japan today.
● Antihypertensive therapy used to be recommended only for those with sustained systolic blood pressure above 180
mmHg before 2000. Since the revised hypertension guideline in 2000 (HT-GL 2000) lowered the treatment target to130/85 or lower, the number of "patients with hypertension" has been continuously increasing. Almost one half ofpeople aged 75 years or older now use antihypertensive agents in Japan.
● In Japan's hypertension guideline revised in 2014, the target value was changed to below 140/90 mmHg, admittingthat "it was a mistake to set the treatment target at 130/85 mmHg or lower". A randomized controlled trial (RCT)
conducted in Japan called JATOS study compared a strict treatment group maintaining systolic blood pressure below
140 mmHg with a mild treatment group maintaining it above 140 mmHg and below 160mmHg. This study foundno difference in stroke and myocardial infarction, but the mortality rate tended to be higher in the strict group. In
addition, there are many studies which show harmful effects of lowering blood pressure.
● The most widely marketed angiotensin receptor antagonist (ARB) is carcinogenic and increases septic death as well.
The criteria for lowering blood pressure should be returned to those before the 2000 guidelines.
● Check the causes of high blood pressure carefully, eliminate stress and sleep debt, and avoid carelessantihypertensive therapy.
Keywords:
hypertension, hypertension guidelines, antihypertensives, ARB, carcinogenicity, sepsis, total mortality rate, stress

Introduction

Hypertension treatment until the 1990's

As a result of a systematic review of many randomized

Only one RCT showed prolongation of lifespan incontrolled studies (RCTs), it was found that general healthwhich antihypertensive drugs were used in patientscheckups, subsequent lifestyle changes and medicalwith diastolic blood pressure above 115 mmHg [2].

interventions do not extend the lifespan. According to

The results of three RCTs [3-5] which compared

the review, mortality rate increased in people aged 65

antihypertensive agents and placebo (or no treatment)

years old and above, and particularly, it increased byon mild hypertension with diastolic blood pressure

62% in those aged 75 years and above [1]. Hypertensionof 90mmHg to 109 mmHg, published in the 1980's,

is most frequently detected out in health checkups. If

showed no significant difference in mortality. There wasantihypertensive agents shorten life, the impact may be

no difference in all-cause mortality by the meta-analysis

significant. Let's examine the reasons why general healthof these RCTs: the pooled odds ratio (OR) = 0.94 (p = 0.50).

checkup could shorten the lifespan of older people,

Therefore, until 2000, it was thought that no

focusing on hypertension as an example.
Page 20 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

antihypertensive intervention was needed unless thediastolic blood pressure was sustained at 95 mmHg or

people since the revision in 2004. The target value washigher (especially 100 mmHg or higher) or the systolic

set at lower than 130/85 mmHg and 140/90 mmHg forblood pressure was sustained at 170 mmHg to 180

people under 65 years old and those aged 65 years or

mmHg or higher, and 160/95 mmHg was recommended

older, respectively.

as the target blood pressure to be achieved [6] . For
the elderly people, the target blood pressure was below

Increased proportion of antihypertensive drug users

180/100 mmHg [7].

and health checkup/guidelines
In Japan general health checkups started in 1950s

Lowering the cut-off blood pressure for intervention[12,13]. The proportion of antihypertensive drug users

and the target blood pressure

was 11 to 13% until 1994, the year in which a stricter

The hypertension guidelines ( HT-GL) [8-11] which

policy for general health checkups was implemented[14].

were frequently revised after 2000 changed this situation

It exceeded 16% during the period of 1995 to 1997

completely. They recommend using antihypertensive[15](Figure). In 2016, one in three adult men, one in four

agents to lower blood pressure very strictly (Table). In

women, one in two men and women over the age of 70

particular, strict criteria have been applied to elderly

years were on antihypertensive agents.

Figure: Strengthening health examination and changing ratio of antihypertensive drugs

Data sourse : National Health and Nutrition Survey (in Japanese)
http://www.mhlw.go.jp/bunya/

kenkou/kenkou_eiyou_chousa.html

Table: Changes in the target blood pressure in hypertension treatment

S : Target systolic blood pressure

D : Target diastolic blood pressure

MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 21

Review
ReviewAmong them, angiotensin receptor blockers ( ARB ),significantly higher in the antihypertensive group.

which was first marketed in Japan in 1998, currently

In Japan there are two clinical trials [23, 24]

have the largest market share. HT-GLs have been revised

comparing the “strict group” whose blood pressure wasseveral times in Japan since 2000, and the cut-off blood

lowered to below 140/90 mmHg and the group whichpressure for intervention and target of treatment havereceived less intensive treatment ( mild group ): JATOS

been lowered by every revision. In addition, "health(n=4418) [23] and VALISH (n= 3079) [24].

checkup to find metabolic syndrome" was implemented

In the JATOS, there was a difference in achieved bloodin 2008. Through these measures, "hypertensive

pressure by about 10 mmHg: 172/89 mmHg at thepatients" increased very rapidly (Figure) [16-20].

baseline dropped to 136/75 mmHg in the strict groupand 146/78 in the mild group. In VALISH, there was a

Authorities admitted “There was no evidence

difference of about 5 mmHg: it dropped from 170/82

supporting the target <130/85”

before the start to 137/75 mmHg in the strict group and

HT-GL 2014 changed the target for treatment of

142/77 mmHg in the mild group.

hypertension from "below 130/85 mmHg", which have

There was no difference between the strict group andbeen recommended since 2000, to "below 140/90

the mild group in the incidence of stroke and myocardial

mmHg". One of the most important reasons was that

infarction in both RCTs. On the other hand, the number

there had been no evidence supporting the reduction ofof people who died was bigger in the strict group (n=54)

mortality rate nor cardiovascular disease by loweringthan in the mild group (n=42) after two-year follow-up.

blood pressure to below 130/85 mmHg.
In fact, no RCT has proven it as evidence anywhere in
the world. In 2015, a RCT named SPRINT was published

Although it is not a significant difference, it suggests
the possibilities that more people may die with strict
blood pressure control.

[21]. In this study, mortality was improved significantly
in people with systolic high blood pressure of 139 and
BMI averaged 30 with cardiovascular disease and renal
impairment whose systolic pressure was lowered to

A number of studies show harm of strict control
There are many other studies that show harm of strict
control of blood pressure (for details, web supplement).

below 120 mmHg as compared with those whose blood

For example, in the HOT study [25], which was thepressure was lowered to about 135 mmHg. However,basis for changing the WHO's Hypertension Treatment

there was a big contradiction that the mortality rate

Guidelines, the mortality rate was the highest in the

declined despite severe hypotension and acute renal

lowest blood pressure group although the myocardial

failure needing hospitalization or emergency care

infarction decreased.

increased by 1.7 times and renal impairment increased

There are several large cohort studies in Japan. In

by 3.5 times ( p <0.001 for both). Hence, this study is

NIPPON-DATA [26], people who lowered their blood

unreliable.

pressure using antihypertensive agents had less ADL(Activity of Daily Life) after 14 years follow-up than thoseMortality may increase even with the target of below

who did not use antihypertensives in all blood pressure

140/90groups.

The target of “below 140/90 mmHg” by GL 2014

In the Ibaraki prefecture survey [27], people who

is not evidence based, either. There is only one RCT

took antihypertensives and had blood pressure of below

in Japan comparing antihypertensive agents ( calcium

160/95 showed higher mortality rate and higher cancer

antagonists) and placebo ( JATE study) [16]. The result

death rate than those whose blood pressure was higher

was that after 3 years, even in the placebo group, thethan 160/95 without antihypertensive treatment.

blood pressure dropped from 170 mmHg on average at

The PATE study [28] is a RCT conducted in Japanthe beginning to 140 mmHg as in the antihypertensive

comparing ACE inhibitors and calcium antagonists. As agroup. There was no difference in cardiovascular disease

result of using an antihypertensive agent, the incidence

incidence in both groups, and malignant tumors wereof cardiac disease in people with systolic blood pressure

Page 22 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

of 130-139 mmHg, 140-149 mmHg, 150-159 mmHg

Referencesand 160 or higher did not differ, but it rather increased

1)MedCheckTIp eritorial team, Do general health checks prolong lifespan?

in those whose blood pressure fell to below 130 mmHg.

2)Veterans Administration Cooperative Study Group on Antihypertensive Agents.

The incidence of cardiac disease in the people whose
blood pressure fell to below 120 mmHg increased
significantly than those with blood pressure of 130-139
mmHg. It shows that excessive drop in blood pressure isharmful.

MedCheckTIP in English 2018: 4(10)；11-15
JAMA 1967: 202:1028-1034 .
3) Management Committee The Australian therapeutic trial in mild hypertension.
Lancet 1980 : 1261-67.
4) Helgeland. Treatment of mild hypertension. Am J Med 1980: 69: 725-732.
5)MRC trial of treatment of mild hypertension: principal results. BMJ, 1985: 291:
97-104. :6) Ministry of Health and Welfare and Japan Medical Association, Guidance formanagement of hypertension, 1990
7)Takishita S. J Clin Therapeutics & Medicines, 2000：16：1363-76
8)The Japanese Society of Hypertension, Guidelines for the management of

The guidelines neglect the carcinogenicity of ARB
A meta-analysis result of RCTs clearly shows that
ARBs, which currently have the largest market share,
increase cancer incidence by 11% (p = 0.001). When only
the trials which are eligible for strict comparison are

Hypertension2000, 2000
9)ibid, Guidelines for the management of Hypertension2004, 2004
10) ibid, Guidelines for the management of Hypertension2009, 200911) ibid, Guidelines for the management of Hypertension2014, 201412) Iwatsuka T, The history and current state of comprehensive general healthchecks in Japan, Jananese J Health Checks 1994: 21 (4): 370-376.
https://www.jstage.jst.go.jp/article/jhep1985/21/4/21_4_370/_pdf
13) Miyashita M, Relationship of The Japan Society of Ningen Dock and the Japan

concerned, it shows 15% increase (p = 0.0025)[29]. In

Society of General Health Checks. Complete Medical Checks 2013: 28 (1): 5-6.

addition, the risk of mortality from sepsis increased by

14) Ministry of Health, Labor and Welfare, White paper of Health, Labor and Welfare

50% (p = 0.025) [29]. However, Japanese hypertension
guidelines in 2014 ignored this important evidence.

https://www.jstage.jst.go.jp/article/ningendock/28/1/28_5/_pdf(2008 Ed) Chapter 1, Transition of Measures concerning Health in Japan
http://www.mhlw.go.jp/wp/hakusyo/kousei/14/dl/1-01 .pdf

http://www.mhlw.

go.jp/wp/hakusyo/kousei/14/dl/1-01.pdf15) National Health and Nutrition Survey (in Japanese)
http://www.mhlw.go.jp/bunya/ kenkou/kenkou_eiyou_chousa.html

In practice
We recommend people with high blood pressure tofind the causes such as stress and sleep debt, and resolve
them. Health care workers should give them appropriate16)MedCheck Hypertension 2001, 1 (2)17) MedCheck, Do not depend medicines for management of hypertension, 2007: 7(25).
18) MedCheck, Hypertension Part 1: 2010: 10 (38)19) MedCheck, Hypertension Part 2: 2010: 10 (39)20) MedCheck, Changing reference level of health indicators 2014: 14 (55)21) The SPRINT Research Group、N Engl J Med 2015;373:2103-16

guidance and be careful not to thoughtlessly follow the22) The Japanese Society of Hypertension, http://www.jpnsh.jp/topics/475.html

authority-oriented guidelines and not to adversely affect24) Ogihara VALISH. Hypertension. 2010; 56: 196-202.

patients with antihypertensives.

23) JATOS Study Group. Hypertens Res. 2008;31(12):2115-27.
25) Hansson L et al HOT RCT Lancet 1998: 351: 1755- 6226)Ueshima H et al. Report of NIPPON DATA 80 (1980-1994), 1995
27)Irie F et al. Nihon Koshu Eisei Zasshi, 2001：48(2)：95-108.
28) Sipahi I et al. Lancet Oncol. 2010 Jul;11(7):627-36. Epub Jun 1129)Hama R, ARB and increase of cancer and sepsis, TIP 2010；25(7)：97-101

MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 23

Adverse Reactions
Pneumonia induced by benzodiazepines
Evidence shows causal relations

Translated from Med Check-TIP (in Japanese) May. 2018 ; 18 (77):61-63
Yasuda Y., Hama R

Summary● Benzodiazepines (BZD) are commonly used as sleeping pills and/or anxiolytic agents. BZDs generally induce infectious
diseases including pneumonia by suppressing the immunity of those who took them.
● The risk of pneumonia is particularly high in the following situations.
1) within 30 days after starting BZD, 2) ultra-short-acting agents, 3) high dose (more than usual dosage) and two or morekinds of BZDs, 4) otherwise healthy persons (0 for Charlson comorbidity index). It is reported that pneumonia caused by
BZD leads to an increased mortality rate.
● BZDs are easily prescribed for mild symptoms such as headaches and stiff shoulders. However, they do not cure thesymptoms, but only mask them with risk of dependence and addiction. They cause big social problems.
● Especially in elderly people with declined renal, liver and immune functions, not only falls and delirium, but also
pneumonia increases. Uncritical use should be prohibited.

Keywords:

benzodiazepine, anxiolytics, hypnotics, pneumonia, infection, immunosuppression, robust association,

causality, case-control study, cohort study

Introduction

BZRAs have many well-known harms such as dizziness,

Benzodiazepine receptor agonist (abbreviated as BZRA:

drowsiness, falls, bone fractures, addiction, etc. In thisNote 1) is used extensively throughout the world, andarticle, we discuss less known harms such as infections,harm caused by inappropriate use or abuse is an issue .

especially pneumonia.

According to the report of the International Narcotics
Control Board (INCB) in 2010 [1], the consumption of

Infectious diseases increase

BZRAs in Japan is significantly higher than that in other

Although there are various research methods, theAsian countries. In addition, there is a possibility thatmost reliable research is the result of meta-analysis,

inappropriate prescription or abuse might be involved.

which comprehensively analyzes multiple randomized
controlled trials (RCT).

Note1: In addition to benzodiazepines (BZD), agents

Joya et al. meta-analyzed RCT data, which was theacting on the benzodiazepine receptor (BZR) are also calledbasis of FDA approval, on four sleeping agents (Note 2),"nonbenzodiazepines" or "z-drugs". Zolpidem (Ambien)

namely eszopiclone, zaleplon, zolpidem, and ramelteon

and zopiclone (Imovan) are representative drugs. In this[2].

article, these groups of drugs are collectively classified as

The study dealt with the frequency of all infectious

benzodiazepine receptor agonists (BZRA) or BZDs. Theirdiseases. As a result of comparing 8,828 participants inchemical structures are different, but they basically share thehypnotic drug groups and 4,383 participants in placebo

same harmful effects.

groups who were involved in 36 RCTs, increased risk ofinfection was observed. The total risk (risk ratio: RR) was

Page 24 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

1.44 (p <0.00001).

extracted 12,002 persons who were hospitalized for

As a result of the meta-analysis of individual drugs,

pneumonia and the same number of persons for control

infections increased about 1.5 times (p <0.00001) forgroup (4) matched with baseline characteristics (Note 3),

eszopiclone and about 2 times (p = 0.006) for zolpidem.

and examined the relationship between BZD exposure

The Table 1 summarizes the results of meta-analysis

and pneumonia [3].

of RCTs reporting the relationship between BZRAs andAs a result, the adjusted odds ratio (OR) was 1.86 (pinfectious diseases, and the results of observational<0.0001) and a significant association was confirmed.

study investigating the relationship between BZRAs andIn addition, in this study, there was a tendency that thepneumonia. There are three kinds of risk levels (OR, RR,

risk increased as the dose of BZD increased. Chen et al.

HR).

estimated that if two kinds of drugs were used at thedose exceeding the usual dose (DDD: Note 4), incidence ofNote2: BZRA except for ramelteon. Ramelteon is a melatoninagonist.

pneumonia increased by 3.5 times (Figure).

Note 3: The control group was selected by matching cases
and baseline characteristics by using propensity scores.

Pneumonia increases
As for the relationship between BZRAs and infection,
the relationship with pneumonia has been studied most.
In a cohort case-control study using Taiwan National
Health Insurance Research Database, Chen et al.

Note 4: The daily standard dose (routine dose) of medicines
defined by the WHO is referred to as DDD (daily defineddose) [11]. DDD for representative drugs include diazepam
10 mg, zolpidem 10 mg, triazolam 0.25 mg, flunitrazepam 1
mg, etc.

Table 1: Risk of infections or pneumonia by benzodiazepines

RCT: meta-analysis of randomized controlled trials, CC: case-control study, CH: cohort study
BZRAs, BZDs and Z-drugs：See Note 1. OR: odds ratio, RR: risk ratio, HR: hazard ratio
Patients with Alzheimer disease were the subjects in the Ref.[6], and patients with chronic renal diseases were the subjects in the Ref.[7]Figure: benzodiazepines and pneumonia: a dose-response (from Ref. 3)

DDD: daily defined dose, aOR: adjusted odds ratio, 95% CI: 95% confidence interval

MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 25

Obiora et al. conducted a case-control study withinwith chronic obstructive pulmonary disease (COPD) overcohort using the electronic medical chart of the UK

66 years of age in Province of Ontario, Canada, andprimary care clinic. They extracted 4,964 cases ofcompared 48,915 people who newly used BZRA andcommunity pneumonia and 29,697 persons for control

another 48,915 people in a control group whose baseline

group, and examined the association with BZD exposure.

characteristics were matched [7]. As a result, the risk

They reported that the risk increased by 1.5 times

ratio (RR) of emergency visits for COPD or pneumonia(OR=1.54, p <0.0001) [4].

was 1.92 and significant (p <0.0001).

They also conducted a cohort study in their study.

Wang MT extracted 4,533 pneumonia patients andIt reported that among 4,964 people who previously

16,388 patients who were matched with the former assuffered from pneumonia, 22% increase was found in

a control from 36,880 chronic kidney disease patientsmortality within 30 days (HR=1.22, p=0.004) and 32%

registered in Taiwan National Health Insurance Database

increase was observed in mortality from long-term

to examine pneumonia risk for using BZD [8]. As a result,follow-up (mean follow-up period of 2.8 years) (HR=1.32,

the study reported that the odds ratio (OR) was 1.31, and<0.001). People without complications are particularly

the risk was especially high within 30 days after the startat high risk, and pneumonia and mortality increased 2of BZD use with about 2.5 times higher OR (OR = 2.47, p

to 3 times and about 2 times, respectively. Increased<0.0001).

mortality should be taken as a serious outcome.
Jung et al. matched at least gender and age ofabout 190,000 people as a control with about 50,000

Reports that were unable to detect associations are
small in scale

pneumonia patients aged 65 years or older who were

The reports that suggested the association which

members of the Kaiser Permanent Health Organization.

we have mentioned above are all large-scale studies

They compared the use of BZDs and Z-drugs (see Note 1)

involving total 13,000-240,000 persons (Table 1). In

in the past one year before contracting pneumonia (caseaddition, with a purpose of investigating the relationshipcontrol study) [5]. The risk of short-term use (90 days or

between BZRA and pneumonia, control groups whoseless) for BZDOR was OR=1.69, and for Z-drugs OR=1.57 (pbaseline characteristics were matched were selected, or<0.0001 for both).

4-6 times more patients were selected for control groups
to enhance statistical power.

Pneumonia also increases in certain disease groups

On the other hand, reports by Almirall et al. [9] and

BZDs also increase the risk of pneumonia even in

Dublin et al. [10], which deny the relationship between

studies with specific disease groups, such as Alzheimer's

benzodiazepines and with pneumonia, are small in scaledisease, chronic obstructive pulmonary disease (COPD)(about 3000 or less for cases and controls in both studies:and chronic kidney disease (CKD).

Table 1) and did not specifically examine the association.

Taipale et al. used Finnish data of about 50,000

Therefore, the results are not reliable.

Alzheimer’s disease patients and selected BZRA nonusers whose baseline characteristics were matched 1:1

Mechanism for the induction of infection - especiallywith those of 8,501 BZRA users to compare the risk of

immunosuppression

pneumonia in these two groups [6]. Hospitalization or

It is generally believed that BZDs may cause

death due to pneumonia increased with the hazard ratio

pneumonia due to aspiration as they have sedative and(HR) = 1.22 for the entire BZRA. In the first 30 days ofmuscle relaxant actions [4,8]. However, this hypothesis

BZRA use, pneumonia risk was the maximum with HR:

cannot explain the mechanism by which not only

2.09, but it was not significant after prolonged use. They

pneumonia but all infectious diseases, including urinary

say that strong effect is observed in the early stage oftract infection, increase.

the use as sedation effect is remarkable before tolerance
develops.
Vozoris NT et al. used a database of 177,355 people
Page 26 ・ MED CHECK - TIP August 2018/ Vol.4 No.11

BZD receptors are expressed in peripheral bloodand immune cells such as leukocyte, and laboratory
researches have been conducted on their effect onTable2 : Effects of BZDs on Immune System (extracted from Ref.12)

immune system of animals and humans ( Table 2 )In practice[7,12]. A mice experiment reported that the function of

Benzodiazepines used as anxiolytic and hypnotic

macrophages was suppressed as BZD stimulated GABAA

agents are by no means mild drugs. They act on thereceptors, leading to increased pneumococci in the lungwhole body and decreases immunity, resulting inand thus increased mortality, but it recovered by using

increased infectious diseases, particularly pneumonia.

GABAA receptor antagonist [13].

The risk is high especially for people withoutcomplications. Shorter the duration of use is, greater the

Examining causality
A robust association between BZRA and increased

effect. There is clear dose-dependency, and the causality
is certain. Never use them uncritically.

infection (p <0.0001) is confirmed by the most reliablemeta-analysis of RCTs.
Regarding increased pneumonia, a strong association( mostly p <0.0001 ) with BZRA use before pneumonia
was observed in multiple studies (cohort studies and casecontrol studies) in which bias was excluded as much as

possible. Studies with conflicting results were smallscale studies of poor quality. Even with a comprehensive
analysis including these poor-quality studies, risk for
causing pneumonia with short-term use of BZRA is
as high as 1.73 (1.54-1.94), and the P value is as low
as <0.0001, suggesting a strong relationship. The
presence of dose-response relation also supports thestrong association. In addition, many animal and humanexperiments have repeatedly shown that BZDs suppress

References
1) INCB: Report of the International Narcotics Control Board on the Availability ofInternationally Controlled Drugs：
http://www.benzo-case-japan.com/docs/International_Narcotics_Control_Board.
pdf2) Joya FL et al, Meta-Analyses of Hypnotics and Infections: Eszopiclone, Ramelteon,
Zaleplon, and Zolpidem. J Clin Sleep Med, 2009: (4):377-83. PMID: 19968019
3) Chen TY et al, The Use of Benzodiazepine Receptor Agonists and the Risk of
Hospitalization for Pneumonia(A Nationwide Population-Based Nested CaseControl Study) CHEST 2018; 153(1):161-171 PMID: 28782528
4) Obiora E et al, The impact of benzodiazepines on occurrence of pneumonia
and mortality from pneumonia: a nested case-control and survival analysis in a
population-based cohort. Thorax 2013;68:163–170. PMID: 23220867
5) Jung S et al The Risk of Pneumonia in Older Adults Using Nonbenzodiazepine
Hypnotics. J Manag Care Spec Pharm. 2016; 22(8):932-8. PMID: 27459656
6) Taipale H et al, Risk of pneumonia associated with incident benzodiazepine
use among community- dwelling adults with Alzheimer disease. CMAJ 2017 April
10;189:E519-29. PMID: 28396328
7) Wang MT et al, Benzodiazepine and Z-drug use and risk of pneumonia in patientswith chronic kidney disease: A population-based nested case- control study PLoS
One. 2017 Jul 10;12(7):e0179472 PMID: 28692645
8) Vozoris NT, Fischer HD, Wang X, et al, Benzodiazepine drug use and adverse

the function of various immune cells and proliferate

respiratory outcomes among older adults with COPD. Eur Respir J. 2014;44(2):bacteria, leading to increased mortality in animals. In this9) Almirall et al, New evidence of risk factors for community- acquired pneumonia: away, the association can be explained by the mechanismof action as well. The causality between the use of
BZRA and infectious diseases, particularly pneumonia,
is certain. In addition, pneumonia is likely to occur
within 30 days or less after the start of the medication.
Furthermore, ultra-short acting hypnotics with shorthalf-life showed greater risk.

332-340. PMID: 24743966
population-based study. Eur Respir J 2008; 31: 1274–1284 PMID: 18216057
10) Dublin S, Walker RL, Jackson ML, et al, Use of opioids or benzodiazepines andrisk of pneumonia in older adults: a population-based case-control study. J Am
Geriatr Soc. 2011;59(10):1899-1907. PMID:22091503
11) WHO,ATC/DDD Index https://www.whocc.no/atc_ddd_index/?showdescription=yes&code=N05BA
https://www.whocc.no/atc_ddd_index/?showdescription=yes&code=N05CD
12) Caroff DA et al, The Relationship Between Sedatives, Sedative Strategy, andHealthcare-Associated Infection: A Systematic Review. Infect Control Hosp
Epidemiol. 2016 Oct;37(10):1234-42. PMID:27322888
13) Sanders RD et al. Benzodiazepine augmented gamma-amino-butyric acidsignaling increases mortality from pneumonia in mice. Crit Care Med. 2013; 41(7)PMID:23478657

MED CHECK - TIP August 2018/ Vol.4 No.11 ・ Page 27

M
C

ED

HECK

The Informed Prescriber
2018

Vol.4

No.11

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

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