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2019

Volume 5

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Accelerated Approval, Ignoring Harm, is a Crime
New Direct-acting Antiviral for Hepatitis C (Epclusa）
Hemorrhage caused by an Anti-influenza Agent,
Baloxavir
CONTENTS （April 2019, Vol. 5, No. 13）

Editorial
Accelerated Approval, Ignoring Harm, is a Crime

2

New Products
New Direct-acting Antiviral for Hepatitis C (Epclusa）

3

Adverse Reactions
Hemorrhage caused by an Anti-influenza Agent, Xofluza

7

Review
Critical Assessment of Diabetes Guidelines

10

Advance in hepatitis C with prior treatment failure or decompensated cirrhosis

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April 2019/ Vol.5 No.13 ・ Page 

M
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Editorial

HECK

Accelerated Approval, Ignoring Harm, is a Crime
Translated from the Editorial in Med Check(in Japanese) May 2019 ; 19 (51)

Sales of an anti-influenza agent, Xofluza (genericcause of death. Denying the causality between Xofluza

name: baloxavir), in 2018/19 winter is estimated to be

and death is a usual practice and deliberate decision

more than 270 million US dollars, and more than 10

by the MHLW.

million people may have been treated with the agent:similar extent of use with that of Tamiflu in 2009/10
season in Japan.

Xofluza was designated as an agent for "preferential
treatment system in examination" at the trial stage,

At the same time, as high as 22.5% of influenza

and the examination period was greatly shortened andAH3N2 viruses are resistant to Xofluza in thisit was approved quickly. This designation requires allseason. Tamiflu resistant virus does not prolong thefour criteria below to be fulfilled:course of influenza. However, Xofluza resistant virus(1) the substance is innovative with a new mechanism

delays patient's recovery from influenza. High ratesof action,of resistance and delayed healing were well-known(2) the target disease is serious,

before approval (See MedCheck No. 80). In addition,(3) the substance has extremely high efficacy andtoxicity tests of Xofluza showed bleeding toxicity:

safety, andprothrombin time (PT) was prolonged by up to 2.4(4) the substance is developed and applied first intimes by fasting before autopsy. Although PT-INR was

Japan.

not shown, it could be dangerous enough to cause

Influenza is basically a mild and self-limiting

bleeding. However, the manufacturer (Shionogi & Co.,

infection and does not meet the criterion (2). Xofluza

Ltd.) explained that supplementation with the dietdoes not outperform Tamiflu in efficacy. It has

and vitamin K prevented prolongation of PT and suchunacceptable harm of bleeding, which was alreadybleeding will not occur in humans. Japan’s Ministry ofdetected in animal studies. Therefore, it does not meet

Health, Labor and Welfare (MHLW) accepted such an

criterion (3).

explanation and approved the agent for marketing.
Simply because Xofluza is a product with
Serious hemorrhagic cases became reality in thisa mechanism of act ion different from that ofseason as described in this issue (p7). Since its launchneuraminidase inhibitors and was first developedin March 2018, 25 cases with bleeding have been

in Japan, the regulator approved it in a rush. They

reported, including 3 deaths. However, the MHLW

neglected to confirm the efficacy and safety in high-stated that causal relationship cannot be denied inrisk persons even though increased risk of harm isonly 13 survivors and denied the causality of all otherexpected in them based on animal experiments.

bleeding cases, including 3 deaths.

Anti-influenza drugs are unnecessary for otherwise

Although the manufacturer has disclosed only 3

healthy people. It is the high-risk people for whom ansurvived cases, and the MHLW has not disclosed fatalanti-influenza drug should be effective. However, if

cases either, even in some of the disclosed cases,

you have severe flu symptoms, you may lose appetite

immeasurable PT, PT-INR or prothrombin activity

and cannot eat. Then, you have to avoid using Xofluza(below 10%) was frequently observed.

due to the high risk of bleeding. After all, just like

If a patient died following bleeding after taking
Xofluza, it is reasonable to consider that hemorrhage
was an adverse reaction to the agent and was the

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April 2019/ Vol.5 No.13

Tamiflu, Xofluza has no place in use for influenza
infection.
Accelerated approval, ignoring harm, is a crime.

New Products
New Direct-acting Antiviral for Hepatitis C (Epclusa)
Advance in hepatitis C with prior treatment failure or decompensatedcirrhosis
Translated from Med Check in Japanese May 2019 ; 19 (83): 52-54
MedCheck-Editorial Team

Summary●A new antiviral targeting hepatitis C virus (HCV) (brand name: Epclusa) was launched in February, 2019. It is acombination of direct acting antivirals (DAA), sofosbuvir and velpatasvir.
●The combination yielded a sustained virological response (SVR) in all types of HCVs. In Japan, sofosbuvir ＋

velpatasvir taken for 24 weeks in combination with ribavirin was approved for chronic hepatitis C and compensatedcirrhosis in which existing DAAs were ineffective.
●What is noteworthy is that a 12-week regimen of this combination as a single drug therapy was approved fordecompensated cirrhosis (advanced cirrhosis), which was previously not subjected to antiviral treatment.
●The rate of SVR obtained by various DDAs is approximately over 90%. Therefore, no randomized controlled study

has been conducted to compare the combination with placebo nor interferon therapy, and thus the effect on longterm prognosis, such as prevention of cirrhosis and hepatic cancer or overall mortality, is unknown. The recent
study reported that markedly lower rate of decompensation of cirrhosis and overall mortality were observed inpatients who used DAA as compared with non-DAA users. The study seems to be reliable as important baselinecharacteristics were well matched.
●Hypoglycemia occurred in chronic hepatitis C patients with diabetes who were treated with DAAs and achieved

SVR. This is because glucose metabolism improves when viremia resolves and hepatocellular function is recovered.
This is a preferable outcome, but requires careful monitoring to prevent hypoglycemia.
Conclusion: The combination offers an advance in chronic hepatitis C with prior treatment
failure or decompensated cirrhosis. It is recommended.

Keywords:
direct-acting antiviral, sofosbuvir, velpatasvir, Epclusa, chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis,
hypoglycemia

Brand name: Epclusa
generic name: sofofbuvir ＋ velpatasvir
・sofosubvir 400 mg ＋ velpatasvir 100 mg per tablet(See the figure for the mechanism of action)■ Indication:
1. HCV decompensated cirrhosis: Usual dosage: 1 tablet/day taken orally for 12 weeks in adults.
2. Chronic hepatitis C or HCV compensated cirrhosis in which existing DAA treatments failed: Usual dosage: 1 tablet/day in
combination with ribavirin taken for 24 weeks in adults.
■ Cost: about 60,000 yen (536 USD)/tablet, 5 million yen (45,000 USD)/12 weeks, 10 million yen (90,000 USD)/24 weeks

MED CHECK

April 2019/ Vol.5 No.13 ・ Page New Products
rate of hepatic decompensation was observed

Figure: HCV genome and mechanism of action of anti-HCV agentsin DAA group compared with No-DAA group(HR=0.32; 95% CI=0.13-0.84, p=0.02). (Table 2). It
is not a randomized control study (RCT), but aretrospective cohort study. However, it seems
to be reliable because propensity scores of 16
baseline characteristics which are all importantfor prognosis of cirrhosis were well matched
for the 2 groups, using previous surgical cases
as control. Moreover, it may be true that virus
elimination by DAAs is related to recoveryof glucose metabolism and improvement of
hepatocellular function.
Known facts

What's new?

Hepatitis C virus ( HCV ) interferes with utilization

Velpatasvir (VEL) is effective when used alone in casesof triglyceride to form lipoprotein in hepatocytes andin which ledipasvir and daclatasvir are ineffective (types

causes fatty liver and hepatocellular necrosis, leading to

3-6 ). When combined with sofosbuvir and ribavirin,

liver cirrhosis and hepatic cancer over a long period of

it yields high rates of SVR in all types of HCVs. It istime. Table 1a is a summary of direct-acting antivirals

slightly less effective in type 3. However, an overseas(DAAs) which have been approved in Japan in prior to

study shows that when it was used for 24 weeks inthe approval of the new combination: sofosbuvir (SOF)

combination with ribavirin, SVR was obtained in 84.6%

and velpatasvir ( VEL) (hereafter SOF/VEL combination ).

of patients (11/13 patients).

It also shows whether each drug requires ribavirin
in combination [1,2]. When used alone or combined

Table 3 summarizes the result of a clinical trial
conducted in Japan.

with ribavirin for 12-24 weeks, they avoid the use ofinterferon and yield higher rates of sustained virologicalresponse (SVR).

Harm
Since the clinical trial has no control, it is extremely

Table 1b and Table1c show differences between
existing DAAs and SOF/VEL combination.

difficult to assess causality between the test agent andadverse events.

However, in order to evaluate whether DAAs areWith a 24-week SOF/VEL ＋ ribavirin regimen for 60

truly useful or not, prolongation of life span must be

patients with chronic hepatitis C or HCV compensatedconfirmed in DAA users as compared with non-DAA users

cirrhosis, in whom other DAA therapies had failed, 4in a long-term randomized controlled study. The trial

adverse events ( ≧ grade 3) occurred, including 2 hepatic

conducted with DAAs did not have non-users as control,

cancer, 1 hepatic angiosarcoma and 1 pneumonia. In

and thus it is impossible to judge whether they are truly

6 cases (10%), ribavirin was discontinued or the dose

useful or not.

had to be adjusted due to anemia. In 2 cases ( 3%), all

The recent study [3] retrospectively involved patients

regimens were discontinued.

with hepatic cell carcinoma and cirrhosis which had beenWith a 12-week regimen for 51 patients withsurgically resected or ablated between 2015 and 2018decompensated cirrhosis, 2 adverse events ( ≧ grade

and treated with DAAs and propensity-matched patients3 ) occurred ( 1 rectal adenocarcinoma and 1 esophageal

between 2007 and 2015 without DAA treatment.

varices ). No death occurred in a single-drug therapy

Total mortality was significantly lower in DAA group

group while 3 deaths occurred in a ribavirin combinationcompared with No-DAA group ( hazard ratio [HR]=0.39,

group due to bacterial sepsis, gastric variceal bleeding

95% CI:0.17–0.91, p=0.03). A significant reduction in theand hepatocellular carcinoma. Causal relationship has

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April 2019/ Vol.5 No.13

Table 1a: DAA Regimens without interferon for patients with chronic hepatitis C or HCV
compensated cirrhosis

Cited from Ref.1 and revised by MedCheck
DAAs: direct-acting antivirals comb Tab:combination tablet, comb. Tx: combination
therapy
ASV :Asunaprevir, BCV :Beclabuvir, D CV :Daclatasvir, EBV:Elbasvir, GCR:Glecaprevir, GZR:
Grazoprevir, LDV:Ledipasvir, OBV:Ombitasvir,
PBV:Pibrentasvir, PTV:Paritaprevir, RBV:
Ribavirin, RTV : Ritonavir, SMV:Simeprevir, SOF:
Sofosbuvir, TVR:Telaprevir, VEL:Velpatasvir※ Types of HCVs: Genotype is a classificationof HCVs determined by differences in theirgenes. There are genotypes 1 to 6, and there
are also subclassifications, such as 1a and 1b.

Table 1b: Regimen for chronic hepatitis C or compensated HCV cirrhosis with previous DAA
treatment failure

Genotype 1b comprises 70 - 80 % of Japanesepatients while genotype 2a and 2b comprise
10 - 20% and below 10% , respectively. Thereis another classification called serogroup,
which is determined by differences in antibody.
Genotypes 1a and 1b correspond to serogroup
1, and genotypes 2a and 2b to serogroup 2.

Table 1c: Regimen for patients with decompensated HCV cirrhosis

Japan’s national health insurance covers a test
to identify serogroups, but not genotypes.

Table 2: Effect of DAAs on overall mortality, progression to decompensated cirrhosis andrecurrence of HCC

Table 3: Rates of SVR by treatment duration and combination with/without ribavirin

been denied. However, it cannot be denied in some cases,
such as gastric variceal bleeding.

Cited from Ref.3, SVR: Sustained virologicalresponse (viral response is sustained for
12 weeks or over), HCC: Hepatic cell
carcinoma, DAAs: Direct-acting antivirals,
95% CI: 95 % confidence interval, -: no data
The study covered 163 DAA users and
328 non-users, who underwent surgery for
initial hepatic cell carcinoma in 2015-2018
and 2007-2015, respectively. Propensity
scores of 16 baseline characteristics, which
are important in determining prognosisof cirrhosis and hepatic cell carcinoma,
were matched. From each group, 102
patients, whose propensity scores were wellmatched, were followed.

SVR: sustained virological response rate(viral response is sustained for 12 weeks orover), HCV: hepatitis C virus, -: no data*: Total 3 deaths occurred in combination
with ribavirin

In practice
In patients with chronic hepatitis C or HCVIn clinical trials, no hypoglycemia was reported.

compensated cirrhosis who failed previous treatment

However, after marketing, it occurred frequently inwith existing DAAs, SOF/VEL combination taken for 24

patients with diabetes who were on hypoglycemic agents.

weeks in combination with ribavirin is recommended for

HCV inhibits utilization of triglyceride to synthesize

all types of HCVs.

lipoprotein in hepatocytes, and causes fatty liver. As a

Furthermore, in patients with advanced,

result, hepatocellular function and glucose metabolism

decompensated cirrhosis, SOF/VEL combination taken

are impaired, leading to hepatocellular necrosis [4,5].

for 12 weeks is recommended for all types of HCVs.

When HCV turns negative, hepatocellular function andIn many patients with diabetes who are on

glucose metabolism improve. Therefore, if hypoglycemic

hypoglycemic agents, as viral load decreases, glucose

agents are not reduced or discontinued, hypoglycemia

metabolism may improve and glucose level may

might occur.

drop. Therefore, it is necessary to carefully monitorchanges in viral load and glucose level, and the dose of
hypoglycemic agents should be adjusted.
MED CHECK

April 2019/ Vol.5 No.13 ・ Page New Products
References
1) PMDA, Report of examination results on Epclusa, 2018,11.30
2) Giliad Science Co. Ltd. Summary Basis of Approval for Epclusa
3) Cabibbo G et al HCV (RESIST-HCV), Italian LiverCancer (ITA.LI.CA.) Group. Direct
acting antivirals after successful treatment of early hepatocellular carcinoma
improve survival in HCV-cirrhotic patients.
J Hepatol. 2019 Apr 5. doi: 10.1016/j.jhep.2019.03.027. PMID: 30959157
4) Mirandola S et al. Hepatic steatosis in hepatitis C is a storage disease due to HCVinteraction with microsomal triglyceride transfer protein (MTP). Nutr Metab (Lond).
2010;7:13. PMID: 20178560
5) Hama R et al. A new cholesterol lowering agent: lomitapide is highly toxic、
MedCheckTIP in English、2018; 4 (11)：17-19.
https://www.npojip.org/english/MedCheck/Med% 20Check-TIP% 2011-08-29.pdf

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Adverse Reactions
Hemorrhage caused by an Anti-influenza Agent, Xofluza
Serious toxicity necessitating suspension of its use
Translated from Med Check (in Japanese) May 2019 ; 19(83):56-57
Nakanishi T and Hama R

Keywords:
baloxavir marboxil, Xofluza, hemorrhage, prothrombin time, INR, vitamin K, fresh frozen plasma, fasting, influenza

Introduction:

denies the causality between Xofluza and 3 deaths, but

On March 1st, 2019, Japan’s Ministry of Health,

it cannot be trusted. (See page 2) Moreover, hemorrhage

Labor and Welfare ( MHLW ) requested Shionogi, theoccurred on the first day of treatment even without

manufacturer of Xofluza (baloxavir marboxil), to revise

interaction with warfarin.

“Precautions” in its package insert [1]. The MHLW alsoThis article gives warning that high-risk patients, suchannounced that 25 cases of hemorrhage, including 3

as the elderly and those in fasting, have markedly highdeaths, had been reported since the drug was launchedrisk of hemorrhage, and thus they should avoid using thein March, 2018 [2].

agent.

In response to this request, on March 25th, thepackage insert was revised. The revised Important

Case 1: Potential risk of serious hemorrhage due toPrecautions say that the risk of hemorrhage, whichinteraction with warfarinmight occur a few days after administration, should be

The patient was a woman in early eighties who wereexplained to patients and their families. Moreover, under

on warfarin 1 mg and other medications. Drip infusion

Clinically Significant Adverse Reactions, it was added

was given intravenously on the following day of Xofluza

that in case of hemorrhage, an appropriate management

treatment as the patient complained of difficulty inmust be done. Under Drug Interactions, prolongation of

dietary intake. Fever resolved on the next day. Hematuria

prothrombin time (PT) (Note 1), which implies bleeding

was observed 6 days after the treatment. It aggravatedtendency, due to interaction with warfarin was included.

after 8 days, and warfarin was discontinued. On day 9,

As mentioned in MedCheck No. 80 [4], there is no

PT was markedly prolonged (PT83.3 seconds) (Note 1)

difference in efficacy between Xofluza and Tamiflu

and PT-INR (hereafter INR) was 8.06 (INR exceeding 3.0

although the former is a one-dose treatment due to its

suggests extremely high risk of hemorrhage). Vitamin K1 10long half-life. However, more viruses resistant to Xofluza

mg×2 was intravenously administered.

have been detected, and in toxicity studies, coagulopathy

On day 10, both PT and INR were immeasurable.

was observed, suggesting the risk of hemorrhage. This

Vitamin K1 10 mg×2 was intravenously administered,will be discussed later on.

but it was ineffective. On the following day, after

Total 4 cases are discussed here. They include a casetotal 5 units ( 80mL×5 ) of fresh frozen plasma werereported in the adverse reaction monitoring by Japan

administered intravenously. INR improved and returnedFederation of Democratic Medical Institutions (MIN-IREN)

to 1.13.

[7] as well as 3 hemorrhage-related cases published

Activity of coagulation factors in prior to thein the “notice about the revised precautions” issued

administration of fresh frozen plasma was AT III=75%,

by Shionogi [8]. Particularly, in cases 1 and 2, serious

factor V=100 % , factor X=37 % and factor X III=86 % .

hemorrhage could have occurred anytime. The MHLW

Decreased activity of factor X was observed.
MED CHECK

April 2019/ Vol.5 No.13 ・ Page Adverse
Adverse Reactions
ReactionsNote1: PT stands for "prothrombin time". The standard timeand skin. It should be noted that there are cases in

is 12 ± 1.5 seconds. It is a test commonly used to measure

which bleeding occurred on the day of the treatment

activity of several coagulation factors comprehensively.

(cases 3 and 4) and those in which bleeding occurred andPT ratio is a ratio to control time and the normal ratio is 1.

abnormality in coagulation factors was detected several

Prolongation of PT comprehensively indicates abnormality

days after the treatment (cases 1 and 2). In the latter, PT

in extrinsic coagulation factors (I, II, V, VII, X). Hepaticand PT-INR were immeasurable and there were increased

disorders and warfarin treatment can cause prolongation. PT
and PT ratio greatly vary among those computed in various
institutions. PT-INR is an internationally normalized PT ratio.
In presence of warfarin, appropriate PT-INR is 1.5-2.2 [9].
Warfarin suppresses vitamin K, which activates factors II, VII,
IX and X, and prolongs PT

potential risks of irreversible hemorrhage and death.
Xofluza is metabolized by esterase (Note 2) into an
active form. In most people, an unchanged form ismetabolized into an active metabolite so rapidly that it is
not detected in the blood. Then within a few hours, bloodconcentration of the active metabolite reaches its peak.
In cases 3 and 4, bleeding occurred within relatively

Case 2: Interaction with warfarin

short period time. The time of bleeding coincides with

A 61-year-old woman showed PT immeasurable

the time of maximum concentration. It suggest that

due to more than 60.0 seconds, and INR was also

bleeding might be induced by the direct action of Xofluza

immeasurable on 7 days after the treatment withmetabolite.
On the other hand, in cases 1 and 2, why did bleeding

Xofluza..
Warfarin was discontinued. Eight days after thetendency emerged after several days? It may be related

treatment, bruises, which seemed to be subcutaneousto the large interindividual variability of esterase activity.

hemorrhage, were observed and INR was 5.43. On day

In an extremely poor metabolizer, concentration of the11, INR was 4.07. Warfarin was resumed at a lower

active metabolite increases very slowly. In addition,

dose. On day 13, INR was 4.01 and warfarin dose wasas the effect of Xofluza persists with a single-dose

reduced further. On day 17, INR recovered to 2.30.

treatment, its half-life is extremely long: average for 4

Warfarin dose was returned to the initial level. On day

days. This is probably related to why bleeding can occur

32, INR was 2.66.

even a few days after the treatment.
Moreover, in both cases, patients were treated with

Case 3: Melena on the day of Xofluza treatment

warfarin. It interferes with vitamin K reductase, inhibiting

A 22-year-old woman presented with diarrhea every

vitamin K cycle and activation of vitamin K-dependent

30 minutes in the evening on the day of the treatment

coagulation factors II (fibrinogen), VII, IX, and X, andwith Xofluza. Later it led to melena. Tenderness was felt

works as an anticoagulant.

on the left lower quadrant of the abdomen on palpation.
The symptoms resolved after 6 days.

Note2：An enzyme which hydrolyzes ester. There arevarious kinds of esterase.

Case 4: Intraoral bleeding after 3 hours
A 73-year-old woman presented with bleeding in

Hemorrhage could be predicted based on the results ofanimal tests:

the mouth 3 hours after Xofluza treatment. Bleeding

The package insert explains that mechanism of onset

was from the whole mucosa of oral cavity. Hemostatic

and risk factors of hemorrhage due to interaction withagents, including tranexamate, were given, and thewarfarin are unknown [3,8]. However, at least vitamin

symptom relieved on the following day.

K deficiency is related (Note 1). In the results of toxicity
studies [5,6], PT was prolonged with fasting while no

Immediate and delayed bleeding reactions:
Locations of bleeding seem to include all kinds oforgans, such as oral, gastrointestinal, urinary mucosa

Page  ・ MED CHECK

April 2019/ Vol.5 No.13

abnormality was observed in animals that were given
food and vitamin K. This coincides with the fact thatfactor X was lacking in Case 1.

Blood products for bleeding cases in which vitamin K is

References

ineffective:

1) Health and Safety Bureau, Ministry of Health, Labor and Welfare

In Case 2, INR improved after warfarin was temporarily
discontinued, but it was immeasurable at one point. In
Case 1, not only INR was immeasurable, but vitamin K
was also ineffective. Only after fresh frozen plasma wasused, INR improved.
In cases in which PT and INR are immeasurable,
serious hemorrhage can occur anytime. This is a serious
situation that may lead to life-threatening events, such as
intracranial hemorrhage and intraperitoneal hemorrhage,or sequalae from falls.
Regarding the mechanism of action, in Case 1, itcannot be denied that factor X was directly inhibitedor other coagulation factors were lacking. Since humanprothrombin complex ( Kcentra ) contains coagulation
factors II, VII, IX and X, and proteins C and S, it could

Https://www.mhlw.go.jp/hourei/doc/tsuchi/T190304I0030.pdf
2) PMDA, https://www.pmda.go.jp/files/000228446.pdf
3) The package insert of Xofluza (Revised March 25, 2019)4) Xofluza Baloxavir (Xofluza?) for Influenza: No Value: No difference from Tamiflu
in efficacy, and suppresses immunity, MedCheckTIP in English 2018: 3 (12): 37-39.
https://www.npojip.org/english/MedCheck/Med% 20Check-TIP% 2012-12-18.pdf
5) PMDA, Report of examination results of Xofluza, p36
6) Shionogi & Co., Ltd., "Toxicology" in the Summary basis of approval of Xofluza.
7) Monitoring information <512> by Min-iren. https://www.min-iren.gr.jp/?p=37200
8) Information on the Revision of package insert of Xofluza https://www.shionogi.
co.jp/med/download.php?h=cf6889cd9995da00b7f136879bfc6eee9) Optimal INR value for warfarin treatment, MedCheckTIP, 2015: 15 (61): 115-120
10) Cochrane team criticises the ECDC experts' draft advice on oseltamivir use:,
MedCheckTIP in English: 2016: 16 (66): 90-91 https://www.npojip.org/english/
MedCheck/Med% 20Check-TIP% 2004-04-05.pdf https://www.npojip.org/
english/MedCheck/Suppl% 20Critical% 20comments% 20to% 20ECDC% 20by%
20Cochrane% 20team.pdf
11) Pharmaceutical and Medical Device Safety Information No. 227, August 2006
(in Japanese)
12) Pharmaceutical and Medical Device Safety Information No. 359, December 2018
(in Japanese)
13) Shionogi & Co., Ltd., Http://www.shionogi.co.jp/company/news/
qdv9fu000001dgz1-att/180717.pdf
14) On the trial of the "preferential examination designation system" (April 1, 2015)
Https://www.pmda.go.jp/files/000204929.pd

have been effective. However, because there might havebeen unknown factors, the use of fresh frozen plasma
was an appropriate choice. As of now, the mechanismof hemorrhage caused by Xofluza is not understood.
Therefore, there might be no treatment other than blood
product ( Kcentra ) or blood transfusion ( fresh frozen
plasma). The use of blood or blood products is associatedwith increased risk of unnecessary infection (Kcentra
is partly produced from blood from non-donors). Anotherproblem is that they are valuable medical resource thatcan be obtained only from blood donations. In case of
emergency, they are not easily accessible. It also requires
consent from patients (their families) prior to treatment.
The MHLW denies causality between the drug anddeaths, but this cannot be trusted [10-12]. High-riskpatients are essentially the ones who need an effective
antiviral agents, but the risk of hemorrhage is higher
in such patients. Xofluza was subjected to "preferential
examination designation system" and was approved
too quickly (4 months) [12-13]. There are various issues
involving this drug (see page 2).
Harm outweighs benefits. Do not use Xofluza.

MED CHECK

April 2019/ Vol.5 No.13 ・ Page Review
Annual theme: Critical appraisal series for treatment guidelines (6)Critical Assessment of Diabetes Guidelines
Do not aim at normalizing glucose level with medicines
Translated from Med Check (in Japanese) Nov 2018 ; 18(80):134-138
MedCheck Editorial Team

Summary● Patients are supposed to lead a comfortable life even with diabetes when they receive treatments based on theguideline, if it gives truly useful guidance. Moreover, their lifespan should be lengthened by the treatments.
● However, hypoglycemic attacks and cardiovascular diseases may occur frequently and lifespan might beshortened when blood glucose is lowered with drugs to the "excellent" level (HbA1c<6.2%) recommended by the2010 guideline of the Japan Diabetes Society (GL2010). Moreover, by following the 2016 guidelines (GL2016) (HbA1c<7.0%), the same harms may be induced, as well.

● Recently, the American College of Physicians (ACP) has released an excellent guidance statement (ACP guidance).
It recommends clinicians to “achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes”,
and to “consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1clevels less than 6.5%”. This guidance is based on the findings that the recommended treatment would greatly
reduce hypoglycemic attacks and cardiovascular diseases and increase lifespan, as compared with the treatment
recommended by the Japanese Diabetes Society (HbA1c < 6.2% or 7.0%).
● When the ACP guidance is followed, only 11.6% of the diabetes patients in Japan would need additional
treatment. However, if GL2010 or GL2016 is followed, 84.6% or 46% of the patients would be subjected to theadditional treatment, respectively. In other words, 7.3 times or 3.8 times more diabetes patients would have to
receive additional treatments, respectively, as compared with the ACP guidance.
● According to the ACP guidance, when HbA1c levels less than 7.0% are achieved, pharmacologic therapy could be
deintesified, and when HbA1c levels are reduced to less than 6.5%, it should be deintensified. This means that 27%of the diabetes patients may choose milder treatment, and 7.5% of them should deintensify their pharmacologic
therapies.
● The recent diabetic medicines are all costly. If the guidelines of the Japanese Diabetes Society are followed, highdrug costs and medical costs would be needed. In addition, hypoglycemic attacks and cardiovascular diseases would
occur frequently and life expectancy would be negatively affected, as well. On the other hand, the ACP guidance
would reduce medical costs and improve health and life expectancy of patients with type 2 diabetes.
● Type 2 diabetes may develop and aggravate by persistent exposure to strong stress, such as sleep deprivation,
continuous intake of excessive carbohydrate and intake of low-quality vegetable oil. The basic therapy is the
low-carb diet based on the severity of the disease. Furthermore, enough sleep time should be ensured without
depending on hypnotics, specific causes of excessive stress for individual patient should be identified and resolved,
and high quality fat should be taken. These measures would reduce dependence on diabetes drugs as much as
possible.
● In case medication is needed, the only useful drug is insulin.

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April 2019/ Vol.5 No.13

Keywords:
Guideline of the Japanese Diabetes Society, ACP guidance, HbA1c, blood glucose level, glycemic control, cardiovascular disease,
total mortality rate, sleep time, stress, low-carbohydrate diet, VK2-osteocalcin inhibitory vegetable oil, insulin, hypoglycemic agent

Introduction

Note1: In order to avoid confusion of % used to describe

The "MedCheck" No. 45 ( Feature: Diabetes, Part 2,

HbA1c levels with % for incidences of adverse events and2012 ) [1] explained that "if the guidelines are really

proportions of patients, % for HbA1c levels is omitted after

useful, patients are supposed to have a comfortable life

the summary.

by receiving the recommended treatments, and theirlifespan should be lengthened. However, if we follow

Differences in HbA1c levels targeted by various

the guidelines, the lifespan would be shortened.” The

guidelines (Figure.1)

guideline of the Japanese Diabetes Association (GL 2010)

Figure 1 compares target HbA1c levels set by various[2] targeted strict glycemic control, and hemoglobin A1c

guidelines and clinical trials and the actual levels(HbA1c) levels were evaluated as follows; less than 6.2

achieved.

(excellent, thereafter % is omitted: Note 1), less than 6.2-6.9

As mentioned above, GL 2010 [2] targeted the(fair), 6.9 and over (poor), 7.4 and over (bad), and 8.4 andintensive g lycemic control, using the follow ing

over (failure). The guideline followed this classification

classification of HbA1c levels; less than 6.2 (excellent),of HbA1c levels, even though the ACCORD study [3]less than 6.2-6.9 (fair), 6.9 and over (poor), 7.4 and over

had already confirmed that intensive glycemic control(bad) and 8.4 and over (failure). Although this guidelineincreased cardiovascular deaths, leading to increased

was revised after the results of ACCORD study weretotal mortality, and the classification was flawed (this will

published, it persisted on this classification. GL 2016 [4]be discussed in details later).

changed the description and stated that HbA1c level less

The guideline was revised in 2016 [4]. Has the existing

than 6.0 should be targeted “only if it can be achieved

policy been revised? This article critically evaluates thesolely by appropriate diet and exercise therapies or by

guidelines referring to the ACP guidance [5] publishedpharmacologic therapies without side effects, including

by the American College of Physicians (ACP) in March,hypoglycemia”. Practically, it gave up on achieving the2018, and other new research findings.

intensive target level with medication. However, it still
recommends HbA1c level

Figure 1: Comparison of Target and Achieved HbA1c Levels in Some Guidelines:
The Japan Diabetes Society (JDS), J-DOIT3、 ACCORD and ACP Guidance

less than 7.0 as a target levelfor preventing complications(Figure. 1).
On the other hand, J-DOIT3
study [6] published in 2017targeted HbA1c level lessthan 6.2 for the intensive
therapy group because it was
launched in 2006. However,actually, only HbA1c 6.8(median value) was achieved.
Even for the standard caregroup, only HbA1c 7.2 wasachieved while the target was

JDS: The Japan Diabetes Society, int.: intensive therapy, conv.: conventional or standard therapy

less than 7.0.

GL2010[2]、ACCORD [3], GL2016[4]、ACP Guidance [5]、J-DOIT3 [6]MED CHECK

April 2019/ Vol.5 No.13 ・ Page 11

Review
Review
Intensive target levels were hardly achieved
Table summarizes the main results of the ACCORD

Difference in total mortality rate by achieved HbA1c
value

study and the J-DOIT 3 study. The ACCORD study is a

The incidences of cardiovascular diseases and total

randomized controlled trial (RCT) comparing intensive

mortality were higher by 35% and 22% in the intensive

therapy group targeting HbA1c level less than 6.0 andtherapy group than in the standard therapy group,

standard therapy group targeting a HbA1c level from 7.0

respectively. If the intensive control is continued for 3.5

to 7.9. Among the participants who targeted HbA1c lessyears, additional 1 person in 95 persons would die asthan 6.0, a half of them achieved only less than 6.4. Less

compared with those who receive the standard therapy

than one-fourth of them achieved HbA1c level less than

(NNTH=95: Table). This is a frightening outcome.

6.0 (quartile range 6.1-7.0: Note 2). Another one-fourth

The lifespan of people who achieved “excellent” levelof them achieved HbA1c level above 7.0. Meanwhile, inof HbA1c in the GL2010 standard was shortest while

the standard therapy group, a half of the participantsthat of people with “poor” or “bad” levels was longer.

nearly achieved the target value of 7.0-7.9 (quartile range

The result was totally opposite of what was expected.

7.0-8.1).

Therefore, the study, which was originally planned for

As a result, hypoglycemia requiring any assistance

5 years, was discontinued after 3.5 years as a result

occurred frequently in the intensive therapy group;of the interim analysis. The patients on the intensive

16.2% of the participants; while it occurred in 5.1% oftherapy switched to the standard therapy later on. Other

the participants in the standard therapy group ( odds

three studies (ADVANCE [7], UKPDS [8-10], VADT [11-12])

ratio 3.6). Moreover, hypoglycemia requiring medicalthat were used for assessment by the ACP guidanceassistance was 10.5% versus 3.5%, and odds ratio waswere all flawed. Furthermore, their results did not show

3.2.

significant improvement in total mortality rate.

If the targeted HbA1c level, less than 6.0, is achieved,
hypoglycemia would occur more frequently.

The J-DOIT3 study conducted in Japan involved
interventions not only for diabetes, but also forcontrolling blood pressure and cholesterol level.
However, because the participants’ blood pressure wasaround 120-129/80 mmHg, and their LDL cholesterol

Note2: When you arrange the values in order from lowest

levels were around 120 mg/dL, they required almost no

to highest and divide the whole into four, three boundaries

interventions for their blood pressure and cholesterol

are created. The boundary between the lowest quarter andlevel, and their main concern seemed to be glycemic

second quarter (the 25th percentile) is the first quartile. The

control. When people who achieved “excellent” and “fair”

boundary between the third and fourth quarters (the 75th

HbA1c levels in the GL2010 standard are compared, thepercentile) is the third quartile. The quartile range of 6.1-7.0

hazard ratio of total mortality was 1.01 and there wasrefers to the range between the first quartile, 6.1, and thethird quartile, 7.0.

no significant difference. The biggest reason may be thatthe difference between achieved HbA1c levels in the twogroups was only 0.4.

Table: Comparison of target and achieved levels of HbA1c and total mortality in ACCORD study and J-DOIT3 study* a: The baseline and achieved levels of HbA1c are expressed as median. HR: Hazard ratio. 95% CI: 95% confidence interval.
NNTH: number needed to treat to harm: NNTH=95 indicates that when 95 persons receive the intensive therapy for 3.5 years, 1
additional death would occur as compared with those who received the standard therapy. In the ACCORD study, the hazard ratioof cardiovascular death was as high as 1.35 (95% CI: 1.04-1.76, p=0.02).

Page 12 ・ MED CHECK

April 2019/ Vol.5 No.13

The authors of the J-DOIT3 study highlighted thatmorbidity of cerebrovascular diseases (stroke) decreased

glucose level between 81-108 mg/dL, and it stayed ataverage 110-119 mg/dL (median 107 mg/dL) [13].

significantly, but stroke alone was not the primary

The incidence of severe hypoglycemic attacks withendpoint. Furthermore, myocardial infarction + stroke

glucose level less than 40 mg/dL was 0.5 % in thewas originally set as the primary endpoint, but they wereconventional control group and 6.8% in the intensive

not able to collect an adequate number of such events.

control group, and significant difference was observed

Then, they added cases of revascularization and set the(odds ratio 14.7, 95% CI 9.0-25.4, p<0.001).

complex event as the primary endpoint in the middle ofIn this study, the hazard ratios for death at day 90,

the study, but no significant difference was observed.

comparing cases of moderate and severe hypoglycemia

That is why statistically significant difference in strokewith those with no hypoglycemia, were 1.4 and 2.4,

cannot be claimed (Note 3). The study reported that

respectively (p<0.001 for both) [14].

renal impairment was reduced, but for the same reason,

In type 2 diabetes, increased risk of death due tosignificant difference cannot be claimed. Moreover, thehypoglycemia was reported, as well. According toincidences of hypoglycemia and edema increased by 2

the analysis in the ACCORD study [3] ( discontinued

times and 1.6 times, respectively. This contradicts withafter 3.5 years), the adjusted hazard ratio for death inother findings, and undermines the credibility of the

hypoglycemia cases which required any assistancestudy.

at least once was 1.3-2.9 [15]. The other study also

Note3: As for efficacy of a drug, significant differences can
be claimed only by predefined endpoint. Roughly speaking,if p value of the primary endpoint is sufficiently small, and
it is less than 0.05 in total when it is combined with p valueof the secondary endpoint, significant difference can beclaimed by the secondary endpoint, as well. In the case of
the J-DOIT3 study, p value exceeded just with the primary
endpoint, and significance cannot be claimed with thereported that clinical symptomatic hypoglycemia ( mildor severe) demonstrated higher hazard ratios (propensity
score, adjusted) for all-cause hospitalization (2.51 [2.00–
3.16]) and total mortality (2.48 [1.41–4.38]) [16].

ACP guidance and guidelines by various societies
Giving weight to the results of the ACCORD study, The
American College of Physicians (ACP) reviewed guidelines

secondary endpoint. This is sometimes expressed as “p value

by various societies and announced the statement. The

is consumed by the primary endpoint”.

points are as follows; ① HbA1c level can be between
7.0-8.0; ② If it is less than 6.5, pharmacologic therapy

Even for severe cases, milder control is bettershould be deintensified;③ hypoglycemia should be

Not only the ACCORD study, but also other studies

minimised and pharmacologic therapy should be avoided

suggest that the intensive control leads to higher

in people whose life expectancy is below 10 years as

risk of death. Among the RCTs that evaluated theharm may outweigh benefit, but the treatment should

effect of intensive control in hyperglycemia by using

focus on improving their symptoms only.

insulin, NICE-SUGAR study was the largest and most

The American Diabetes Association ( ADA ) quickly

appropriately planned study, and produced a similarargued against this statement [17,18]. However, the ADA

result [13].

standard focuses on improving surrogate endpoints

The study was conducted with 6140 patients withfor complications of diabetes while the ACP guidance

severe hyperglycemia who were hospitalized in ICU. In

emphasizes life expectancy. Therefore, the ACP guidance

the conventional control group, insulin was administeredis much more reliable.

if the blood glucose level exceeded 180 mg/dL. Insulin
administration was reduced and then discontinued if

Why do the guidelines by various societies persist on

the blood glucose level dropped below 144 mg/dL (8.0

low glycemic levels? (Figure. 2)mmol/L). Glucose level stayed at average140-149 mg/dL

Figure 2 shows a distribution of HbA1c levels of type

range (median 142 mg/dL). For an intensive treatment

2 diabetes patients in Japan in 2016 [19]. This figuregroup, insulin injection was administered to maintainalso shows the percentage of patients who would need
MED CHECK

April 2019/ Vol.5 No.13 ・ Page 13

Review
Reviewadditional treatment, comparing when the ACP guidance

no benefits, except for insulin. There are some clinicaland the guidelines of the Japan Diabetes Society aretrials that claim that the drugs improve life expectancy,

followed.

but none of them are reliable [17,18].

If the ACP guidance is followed, only 11.6 % of the

Because the recent diabetes drugs are expensive,

diabetes patients in Japan would need additional

high costs for drugs and medical care are needed. In

treatment, but with GL2010 (J-DOIT3), 84.6% of them

addition, they might cause hypoglycemic attacks andwould need additional treatment. This suggests thatcardiovascular diseases frequently, leading to shorter life

surprisingly, 7.3 times more patients would be subjected

expectancy.

to additional treatment as compared with the ACP

On the contrarily, if the ACP guidance is followed,

guidance. Even if the standard of GL2016 ( HbA1c lessmedical costs can be reduced, and improved lifespan andthan 7.0) is targeted, 44% of them would need additional

health can be expected.

treatment; 3.8 times more patients as compared with the
ACP guidance.

Diabetes societies in Japan and the U.S. are led bythose who have conflicts of interest with pharmaceuticalIn the ACP guidance, when HbA1c level is less thancompanies. This is probably because why they

7.0, glycemic control can be deintesified. The guidance

persistently promote the use of medications to lower

also recommends that it should be deintensified when

glucose level as much as possible.

HbA1c level is below 6.5. Patients with HbA1c level
below 7.0 (27% of the diabetes patients) may have milder

Non-pharmacotherapy is the first-line treatment forpharmacologic therapy, and those with HbA1c below

type 2 diabetes.

6.5 (7.5% of the diabetes patients) should deintensify thepharmacologic therapy.

Diabetes is caused by an absolute and relative lackof insulin secreted by cells in the pancreas ( β cells)[17,18]. Insulin is secreted according to the load of

The recent agents for diabetics

carbohydrate. It also contributes to metabolism of

As MedCheck-TIP has thoroughly investigated thelipids and protein and cell proliferation as well. When

recent diabetes medications, they lower glucose level,

these cells are continuously overloaded with excessive

but do not increase life expectancy, and they have almost

carbohydrate and are exposed with ischemic stress due
to systemic stress, absolute and relative

Figure 2: Distribution of HbA1c levels of type 2 diabetes patients (2016, Japan)

deficiency of insulin secretion may
occur. In particular, persistent exposure
to systemic stress, such as sleep debt,
e x c e s s i ve i n t a k e o f c a r b o h y d r a t e[20,21] and intake of vegetable oil that
inhibits vitamin K2 [22,23] may reduce
secretion of necessary insulin, cause or
aggravate diabetes, and promote arterial
calcification.
The basic treatment for diabetes is
to follow low-carbo diet according to
the severity of the disease. Moreover,

Only 11.6 % of the patients (HbA1c ≧ 8) would need additional treatment with the
ACP standard. Total 84.6 % of the patients (HbA1c ≧ 6.2) would need additional
treatment with the GL2010. As compared with ACP guidance, 7.3 times morepatients would need additional medications. With GL2016 (HbA1c ≧ 7), 3.8 times
more patients would need additional medications as compared with ACP guidance.
The data of the distribution of HbA1c levels were taken from Japan Diabetes Clinical
Data Management Study Group [19]. GL2010 [2], GL2016 [4], ACP: American
College of Physicians Guidance Statement [5], J-DOIT [6]Page 14 ・ MED CHECK

April 2019/ Vol.5 No.13

sufficient sleep hours should be ensured
without depending on hypnotics, andcauses of stress should be identified
and resolved. High-quality vegetableoil should be included in the diet. With
these measures, diabetes can be treatedwithout medication or the use of pharmacologic therapy
for diabetes can be minimized.

20) American Diabetes Association. Life with Diabetes Third Edition. American
Diabetes Association, Alexandria, 2004.
21) Bao J et al Prediction of postprandial glycemia and insulinemia in lean, young,A study that reviewed epidemiological studies fromhealthy adults: glycemic load comparison with carbohydrate content alone. Am J Clinall over the world on carbohydrate intake suggests22) Okuyama H et al. Medicines and vegetable oils as hidden causes of cardiovascular

Nutr. 2011; 93 (5): 984-96.

that people whose carbohydrate intake accounts todisease and diabetes. Pharmacology 2016; 98: 134-70.

40-43% of total calorie intake live the longest [24]. The

and its complication prevention "Diabetes. However, the major cause may be lipid",current amount of intake of vegetable oil that inhibits24) Associations of fats and carbohydrate intake with cardiovascular disease and23) Japan Society for Lipid Nutrition ed. Lipid nutrition guidelines for diabetes
Quality Care, 2017

vitamin K2 is almost equivalent to the amount thatmortality in 18 countries from five continents (PURE): a prospective cohort study.

induced complications of diabetes, such as stroke, renal25) Okuyama H, Kasamoto S, Hamasaki T. Mechanisms of Atherogenesis

impairment and testis toxicity, in animal studies, and thisAtherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular

Lancet. 2017; 390: 2050-2062.
Without Involving Elevated LDL-Cholesterol, and Critical Evaluation of the Japancannot be taken lightly [25]. Moreover, it is noteworthy

Diseases 2017. J Lipid Nutr 2018; 28: 21-29.

that the most appropriate proportion of calorie intake

composition of breast milk and powdered milk for infants with permission criteria.

from carbohydrate is 40 % [24]. This may not be26) Department of Health, Ministry of Health, Labor and Welfare. Component
H t t p s : / / w w w. m h l w. g o . j p / f i l e / 0 5 - S h i n g i k a i - 1 0 9 0 1 0 0 0 - K e n k o u k y o k u Soumuka/0000041888.pdf

coincidence that it is very similar to the carbohydratecontent in breast milk; 44% by calorie [26].
If medication is needed, the only useful drug is insulin[17,18].
The intensive control of glucose level, which mightcause hypoglycemia, must be avoided. Choose nonReferences
1) Hama R, Sakaguchi K, Criticisms on the guidelines by the Japanese Diabetes
Association - The lifespan shortens if patients follow the guidelines. MedCheck 2012:
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2) Japan Diabetes Association ed, Evidence-based Practice Guidelines for Diabetes
2010,3) ACCORD research group, Effects of Intensive Glucose Lowering in Type 2 Diabetes
N Engl J Med 2008; 358: 2545-59.
4) Japan Diabetes Association ed, Practice Guidelines for Diabetes 2016, Nankodo
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therapy for nonpregnant adults with type 2 diabetes mellitus: A Guidance Statement
Update from the American College of Physicians. Ann Intern Med 2018; 168: 569-76
6) Ueki K et al. Effect of an intensified multifactorial intervention on cardiovascularoutcomes and mortality in type 2 diabetes (J-DOIT 3): an open-label, randomised
controlled trial. Lancet Diabetes Endocrinol. 2017: 5: 951-64
7) The ADVANCE Collaborative Group. Intensive Blood Glucose Control and Vascular
Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2008; 358: 2560-2572.
8) UKPDS 33. Lancet 1998; 352: 837 - 853.
9) UKPDS 34. Lancet 1998; 352: 854-865.
10) UKPDS 80. 10-year follow-up of intensive glucose control in type 2 diabetes. N
Engl J Med 2008; 359: 1577-1589
11) VADT. Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med 2009; 360: 129-139
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diabetes N Engl J Med 2015; 372: 2197-2206
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894-900, 2013.
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19) Study Group on Diabetes Data Management http://jdd.m.jp/index.html

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M
C

ED

HECK

2019

Vol.5

No.13

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

Page 16 ・ MED CHECK

April 2019/ Vol.5 No.13

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
MUKAI, Junji (Pharmacist); SEGAWA,Yusuke; SUMIDA, Sachie(MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro(Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
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