M
C

Volume 2 December

ED

2016

-The Informed Prescriber

N6

HECK

o

Nivolumab (brand name: Opdivo)

Benefit and harm on survival offset each other:strict restriction on use is needed

GLP-1 Agonists (liraglutide)
No evidence of improving prognosis in patients with diabetes:
Not recommended

CONTENTS （December 2016, Vol. 2, No. 6）

Editorial:
Don’t be misled by new “mab” drugs
New Products
New anticancer drug
Nivolumab (brand name: Opdivo)
GLP-1 Agonists (liraglutide etc.)

28

29
35

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 27

M
C

ED

-The Informed Prescriber

HECK

Editorial

Don’t be misled by new “mab” drugs
Translated from the editorial in Med Check-TIP (in Japanese) Jul 2016 ; 16 (66)The human body, through the activation of its

many “mab” drugs have been approved as anticancer

immune system, eliminates foreign substances fromand antirheumatic agents. In cases of severeboth outside and inside itself, including tissues

rheumatoid arthritis, monoclonal antibodies may

damaged by ischemia and cancer cells. Autoimmune

mitigate inflammation caused by excessive cytokines

diseases and malignant tumors develop and aresuch as tumor necrosis factor-alpha (TNF-α) andaggravated by excessive stimulation and/or failure

IL-6. However, they also weaken the function ofof the immune surveillance system. The idea thatcytokines to eliminate foreign substances from bothexcessive stimulation can be mitigated and the failure

outside and inside the body, leading to aggravation ofof immune surveillance reversed by using an antibody

infections such as tuberculosis and sepsis, as well asthat binds to a causative molecule, or that the growth

proliferation of cancer cells.

of cancer cells can be stopped by suppressing excess

Nivolumab was approved in Japan for treatment ofexpression of a certain kinase receptor on cancer

non-small-cell lung cancer in 2015. It is a monoclonalcells, has led to the development of “mab” and “nib”

antibody that works on PD-1, an important protein

agents.

on cytotoxic T lymphocytes (killer T cells), whichattack cancer cells. By binding to PD-1 on killer T

The new drugs featured in this issue all include

cells, nivolumab protects the function of PD-1 and“mab” in their generic names, namely nivolumab,

restores the lost cancer-fighting power of killer T

b e v a c i z u m a b, a n d r a n i b i z u m a b. “ M a b” i s a ncells suppressed by cancer cells with PD-L1. Whenabbreviation of monoclonal antibody, and indicates

one considers only this action, nivolumab indeed

that the drugs whose generic names end with it areseems to be a dream-like new drug.

monoclonal antibodies. The prefix “Mono” means

Videos posted by the manufacturer of drugs

one, and “clonal” is an adjective form of clone, which

explain the drugs' mechanisms from start to finish.

is a cell or organism that is genetically identical to

Misleading and deceptive wording such as “thethe unit or individual from which it was derived.

world’s first new immunotherapy”, “a long-awaited

A monoclonal antibody is an antibody made by

new drug that will save lives”, and “a new drug thatproliferated B lymphocytes with a single gene that

prolongs lives of patients”, are often found on the

produces a particular antibody.

internet or in other media. Medical professionals also

There are also many drugs that have “nib”,

explain drugs to their patients using such phrases.

especially “tinib”, at the end of their generic names.

H o w e ve r P D - L 1 , w h i c h b i n d s t o P D - 1 a n dThis signifies that the drugs inhibit kinase enzymes,

suppresses the action of killer T cells, is also

which activate protein in the body. “Tinib” indicates

expressed on other immune cells, such as antigen-that the drugs are tyrosine kinase inhibitors. The

presenting cells (APCs) and regulatory T cells.

first “nib” drug in Japan was gefetinib (brand name:

Toxicity and clinical studies, as well as post-marketing

Iressa), an inhibitor of the epithelial growth factor

spontaneous reports, have shown that nivolumab may

receptor (EGFR) tyrosine kinase and anti-lung cancer

suppress the functions of these normal immune cells,

agent approved in 2002.

and thereby promote cancer or cause aggravation of

As of June, 2016, 35 “mab” and 28 “nib” drugs

infection and development of autoimmune diseases.

(total 63) were on the market in Japan. Among these,
16 “mab” and 16 “nib” drugs (total 32) were first

Neither “mab” nor “nib” drugs are dream-like newmarketed in 2013 or later, showing a recent rapid

drugs. Their risk factors for shortening life haveincrease in the number of these drugs.

already been identified. The harm-benefit balance of
these drugs should be accurately reassessed.

In Japan, since rituximab was launched in 2001,

Page 28 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

New Products
New anticancer drug
Nivolumab (brand name: Opdivo)
Benefit and harm on survival offset each other: strict restriction
on use is needed
Translated from Med Check-TIP (in Japanese) Mar. 2016 ; 16 (66):79-82

Abstract● Nivolumab (brand name: Opdivo) is a monoclonal antibody (Note 1) against Programmed cell Death-1 (PD-1),
approved for treatment of non-small-cell lung cancer.
● Receptor protein PD-1 which is expressed on cytotoxic T cells (killer T cells

or killer cells) to promote apoptosis

of foreign cells. They eliminate cancer cells and viral-infected cells. However, cancer cells on which one of theligand proteins (PD-L1) that binds to PD-1 is expressed can escape attack by cytotoxic T cells and proliferate.
● It is believed that when nivolumab binds to PD-1 receptors, it prevents PD-L1 on cancer cells from binding to
PD-1, restoring the ability of cytotoxic T cells. Cytotoxic T cells promote apoptosis of cancer cells, thus shrink
cancer.
● However, PD-L1 is expressed not only on cancer cells, but also on normal immune cells such as antigenpresenting cells (APCs), monocyte-macrophages, vascular endothelial cells, and regulatory T cells. Nivolumab
may disrupt the functions of these normal immune cells and suppress immunity, causing serious harms such as
aggravation of infection, and development of autoimmune diseases and worsening of cancer .
● Among cases with squamous cell non-small-cell lung cancer and those with nonsquamous-cell non-small-celllung cancer, only those with a high PD-L1 expression level (Note 2) showed significantly higher response rate
to nivolumab and improved overall survival. Among nonsquamous-cell lung cancer patients with a low PD-L1
expression level, nivolumab was associated with higher mortality rate at the initial stage of the trial. Patients with ahigh PD-L1 expression level represent only approximately 35% of non-small-cell lung cancer patients.
● In non-small-cell lung cancer (especially nonsquamous-cell lung cancer) patients with a low PD-L1 expression
level, nivolumab is not only ineffective, but also harmful as it increases death at the initial phase. Moreover,nivolumab might be ineffective or harmful in patients aged 75 years or older and those who have previously
received two or more anticancer drugs.
●The use of nivolumab should be restricted to patients with cancer of a high proportion of PD-L1 expression
determined by the PD-L1 expression level testing. After considering age and other factors, it should not be used topatients in whom favorable effect is not expected.

Note 1 (monoclonal antibody):The prefix “Mono” means one, and “clonal” is an adjective form of clone, which is a cell or organism thatisgenetically identical to the unit or individual from which it was derived. A monoclonal antibody is an antibody made by proliferated B lymphocyteswith a single gene that produces a particular antibody. Names of monoclonal antibody drugs end with “mab”, an abbreviation of monoclonal
antibody. For instance, rituximab and ranibizumab are also monoclonal antibodies.
Note 2: “Patients with a high PD-L1 expression level” were defined as those whose proportion (%) of cells with PD-L1 among cancer cells is high. The
cut-off value (%) which is used to determine whether a patient has a “high expression level” or “low expression level” were 1%, 5% and 10%. Amongthsese, 10% or higher may be appropriate for “high expression level (positive)”.

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 29

New Products
Introduction:
Nivolumab (brand name: Opdivo) is believed to boost theimmune system. As such an effect has been highlighted, ahigh drug price was set, and 30-40 million yen is required
for annual drug cost per patient. In September, 2014, thedrug was indicated for malignant melanoma in which radical
excision was impossible. In December, 2015, it was indicatedfor non-small-cell lung cancer. Based on the estimation by the
National Cancer Center Japan [1], the number of lung cancer
patients is increasing and was reported to reach 130,000
in 2015. Among them, approximately 80% is non-smallcell lung cancer patients. Suppose that Opdivo is used forapproximately 50,000 patients at the least, estimated 1.75
trillion yen is needed annually just for the medication [2].
One reason why such a high price was set for Opdivo
is that in the previous indication, malignant melanoma,
the number of targeted patients was only less than 1,000[2]. Another reason is that a new mechanism of its action,
immune checkpoint inhibition, was recognized. This meansthat the drug inhibits immune checkpoint, boosts immunity,
and attacks cancer cells, producing safe and effective anticancer effect.
This article reviews scientific evidence to examine its safety,
especially, whether the drug also attacks normal cells or not.
It also discusses whether its benefit-harm balance meets thehigh drug price. The first indication, malignant melanoma,
will be discussed in the next issue.
Interaction between PD-1 and PD-L1 is essential for normal
immune reaction:
Programmed cell Death-1 (PD-1) is a receptor protein thatis expressed on activated lymphocytes such as T cells andB cells [3-5]. PD-L1 is a substance that binds specifically to
PD-1 receptor, and is called a ligand. When PD-L1 binds toPD-1 receptor, cells on which PD-1 is expressed is inactivated[3-5].
PD-L1 plays a key role in the normal immune functionthat eliminates foreign objects [6]. For instance, PD-L1 isexpressed on dendritic cells [3-6], which functions as antigen
presenting cells (APCs), monocyte-macrophages, vascularendothelial cells, and regulatory T cells [6] (Table 1). Whilethese immune cells are involved in treating and eliminating
foreign substances (thus, they include foreign substances in themand they themselves become like foreign substances), they express
PD-L1 to escape attack by cytotoxic T cells (killer T cells) tomaintain their normal functions (Figure 1, A). Regulatory
T cells plays an essential role in terminating inflammatory
reaction at the final stage of tissue repair [6].
Cancer cells without PD-L1 are attacked by killer T cells
and disappear through apoptosis (Figure 1, B). There areseveral mechanisms with which cancer cells escape the attackby immune system in order to proliferate. Expression of
PD-L1 on cancer cells is one of them [3-5].
The reaction pathway through which PD-L1 binds to PD-1
(PD-1/PD-L1 pathway) is believed to be an immune checkpoint.
It is essential when cancer cells escape attack by immune cells
and proliferate. Drugs that inhibits the binding is believed to
be useful for treating cancer as immune checkpoint inhibitors[7, 8].
Nivolumab is a human monoclonal antibody against humanPD-1. It prevents PD-L1 from binding to PD-1 by binding toPage 30 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

extracellular domain of PD-1 (ligand binding domain), activates
killer T cells and enhances their cytotoxic activity, regulating
the proliferation of tumors [3-5].
At the same time, normal immune cells expressed with
PD-L1, which is essential for normal immune reaction may be
exposed to attack by killer (cytotoxic) T lymphocytes because
PD-L1 on the normal immune cell cannot bind to PD-1 on
the killer T cells and cannot escape the attack of killer T
cells. For example, PD-L1 is expressed on antigen-presenting
cells (APCs), which recognize foreign substances and play
an important role at the initial stage of immune reaction, as
well as monocyte-macrophages, vascular endothelial cells,
and regulatory T cells. Therefore, a monoclonal antibody
against PD-1 might inhibit such normal immune functions
and downregulate immunity, reducing the function thatrecognizes cancer cells as foreign substances. As a result, thismight aggravate infection and/or facilitate growth of cancers.
Moreover, if regulatory T cells, key players in terminating
inflammatory reaction at the final stage of tissue repair, areattacked by killer T cells, immune/inflammatory response
would not end, and inflammation might become chronic,
leading to serious adverse reactions such as autoimmune
diseases including thyroid diseases [6].
Toxicity test showed hypothyroidism:
Cynomolgus monkeys (6 males and 6 females per dose group)
were treated with saline control, nivolumab 10 mg/kg, or
50 mg/kg. Lowered thyroid hormone T3 was observed withnivolumab 50 mg/kg. However, it was not interpreted as asign of toxicity and no-observed-effect-level (NOEL) was set at
50 mg/kg, because it was claimed that no abnormality was
found in other indicators by the pharmaceutical company.
Based on the ratio of AUC for 50 mg/kg in monkeys and 3
mg/kg in human, the safety factor was set at 105 fold [9].
However, considering the mechanism of action of nivolumab,
lowered thyroid hormone T3 is a sign of toxicity, NOEL shouldbe estimated to be 10 mg/kg, and the safety factor would be
only 20 fold.
Homology of human PD-1 to cynomolgus monkey PD-1
is not mentioned. Even if they are 100% homologous atTable 1 ：Cells expressing PD-1, PD-L1, and PD-L2 and the expression degree

PD-1: Programmed cell Death-1
PD-L1, PD-L2: There are 2 types of ligand that bind to PD-1. PD-L1 is themain ligand.
CD4 T cells: so-called “helper T cells”
CD8 T cells: cytotoxic T cells, so-called “killer T cells” or “killer cells”
CD4 T reg: regulatory T cells
APC (DCs): antigen-presenting cells (dendritic cells)
The table is an extract of Fig.1 in Francisco et al. [6].
a*: extracted from the text in ref [6]..

Figure 1: PD-L1 plays essential role for normal immune function

PD-1: Programmed cell Death-1, PD-L1: main ligand of PD-1. APC (DCs): antigen-presenting cells (dendritic cells),
MP: macrophage, Endoth cell: endothelial cells, T reg: regulatory T cells,
Nivolumab, an anti-PD-1 antibody protects PD-1 on killer T cells and escaps PD-L1 on various cells to bind to PD-1 to inactivate
killer cells. This causes killer cells to attack not only cancer cells, but also immune cells expressing PD-L1 for maintaining normal
immune function and causes reduced immunity. As a result, cancer might progress and infection might aggravate. Reduced
function of regulatory T cells (T reg) interrupts termination of inflammation, leading to induction of autoimmune diseases.

extracellular domain, it does not mean that they totally match[10]. Therefore, even a slight sign should not be missed. In
fact, many cases of hypothyroidism have been reported inhuman.
Similar to nivolumab, anti-LAG-3 antibody activates killer T
cells, inactivates regulatory T cells, and induces autoimmune
diseases [11]. In a toxicity study with monkeys, anti-LAG-3
antibody and nivolumab were administered concurrently.
In this study, one of the 3 animals exhibited systemic
symptoms and was sacrificed in extremis (classified as dead).
Pathologically, vasculitis in the brain and the spinal cord, andinflammation in the testicle and the epididymis were found [9].
Although the details are unknown, it is highly possible that
autoimmune inflammatory diseases were induced in the brain
and the testicle.
Clinical studies on non-small-cell lung cancer:
Phase I to III clinical studies on non-small-cell lung cancer
were conducted abroad, involving patients in which platinumbased chemotherapy had been ineffective [4, 12]. In thephase I, three trials were conducted with five dose levels
on malignant melanoma, non-small-cell lung cancer, andrenal cancer. In the phase II, one trial was conducted only
on squamous-cell non-small-cell lung cancer ( SQ-NSCLC ).
In the phase II and III, all the patients in nivolumab groups

received 3 mg/kg every two weeks. In the phase III, non-blind
controlled studies were conducted on nonsquamous nonsmall-cell lung cancer (NSQ-NSCLC) [7, 12] and squamous-cell
non-small-cell lung cancer [8, 12] separately.
In the phase III trial on NSQ-NSCLC [7, 12], the medianoverall survival (OS) (95% CI) was 12.2 months (9.7-15.0) withnivolumab and 9.4 months (8.1-10.7) with docetaxel. Hazard
ratio (HR) (95%CI) was 0.73 (0.59-0.89, p=0.002), and OS wassignificantly longer with nivolumab (median, 2.8 months longer).
In the phase III trial on squamous-cell lung cancer [8, 12],
median OS (95% CI) was 9.2 months (7.3-13.3) with nivolumab
and 6.0 months ( 5.1-7.3 ) in docetaxel group ( 3.2 months
longer). HR (95% CI) was 0.59 (0.44-0.79, p<0.001), and OS wassignificantly longer in the nivolumab group.
However, it should be noted that in best response, there
were more cases of progressive disease (PD) in the nivolumab
group. In squamous-cell lung cancer, the odds ratio for PD
was 1.3 (p=0.275). Furthermore, in nonsquamous lung cancer,
cases of PD represented 44% of the nivolumab group ascompared with 29 % in the docetaxel group. Odds ratio was
1.91 (95% CI 1.36-2.69, p=0.0002). Tumor progression wasobserved almost twice more frequently with nivolumab, andit was significant (Table 2). The significant increase of tumor
progression should be considered as an adverse reaction ofnivolumab.

Table 2: Response rate and progression rate

The response rates (CR+PR) are significantly higher in the nivolumab group than docetaxel group. However the
progression rates are also higher in the nivolumab group. Especially in the NSQ-NSCLC, the progression rate issignificantly higher in the nivolumab group than in the docetaxel group and even higher than the response rate.

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 31

Figure 2 Overall survival (OS) of nonsquamous non-small-celllung cancer: comparison of nivolumab and docetaxel

Overall survival (OS) of cancer with high PD-L1 expression ( ≧ 10％ ) was significantly higher in nivolumab
group than control, but no difference was found in patients with low PD-L1 expression ( ＜ 10 ％ ). Notehigher mortality in Nivolumab group during very early phase of the trial indicating essential role of testingfor PD-L1 expression level before Nivolumab use to NSCLC.

Figure 3 Overall survival (OS) of squamous cell lung cancer by
the level of PD-L1 expression level

Overall survival (OS) of cancer with high PD-L1 expression ( ≧ 10％ ) was significantly higher in nivolumab
group than control, but no significant difference was found in patients with low PD-L1 expression ( ＜10％ ). As one of the reasons why OS showed tendency of improved survival, PD-L2 on the cancer cells as
one of the other ligands that bind to PD-1 on the killer cells.

In Japan, 2 uncontrolled phase 2 trials were conducted,
involving 76 nonsquamous lung cancer patients and 35
squamous lung cancer patients [5, 12].
Survival benefit is expected only when various conditions aremet:
If we can identify for what kind of patients a drug iseffective, ineffective or harmful, we can efficiently utilize thedrug. In published papers [7, 8], no information was included
to analyze such conditions. However, thorough analysis isgiven in the summary basis of approval (SBA).
Ineffective in patients with a low PD-L1 expression level,
especially with nonsquamous lung cancer:
Nivolumab specifically inhibits binding of PD-L1 to PD-1.
It is logical and easily presumed that if a ligand that binds toPD-1, particularly PD-L1, is not expressed at a high level, thedrug is likely to be ineffective.

Page 32 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

In fact, in nonsquamous lung cancer, in which PD-L1 isexpressed at a high level (10% or higher) on cancer cells,
nivolumab significantly improved OS, and survival benefit was
confirmed (Fig. 2, A). However, in patients with a low PD-L1
expression level ( lower than 10%), no survival benefit wasobserved at all (Fig.2, B). The drug rather increased the initialmortality.
Likewise, in squamous lung cancer patients with a highPD-L1 expression level, survival benefit was clearly observed(Fig. 3, A) while in those with a low PD-L1 expression level,survival benefit was not significant (Fig. 3, B). In squamouslung cancer, even in the cases with a low PD-L1 expression
level, OS improved more than in nonsquamous lung cancer.
The possible association between this tendency and PD-L2,
another ligand that binds to PD-1, needs to be examined.
Because PD-L1 antibody has already been marketed [13],PD-L1 expression level testing should be conducted as one ofthe preconditions for using nivolumab.

Figure 4 ： Factors related with no survival benefit or risk of mortality

Ineffective or harmful in patients aged 75 years or older:
In addition to presence or absence of a high PD-L1
expression level, HRs and 95% CIs of OS are described byvarious characteristics of the participants in details in the
SBA for clinical trials [12]. Among them, factors with which
the drug might be ineffective on survival benefit or adversely
shorten life are extracted and shown in Figure 4. The factors
with which the drug might not prolong progression freesurvival (PFS) or adversely shorten it are extracted and shownin Figure 5.
In squamous-cell lung cancer, in “rest of the world (regions
other than Europe and North America) (HR=1.53)” and “patients
aged 75 years or older ( HR=1.85 )”, nivolumab is possibly
ineffective or more harmful.
In nonsquamous lung cancer, in “patients with priortreatment with 2 or more drugs (HR=1.34)” and “rest of theworld (HR=1.49)”, harm might outweigh with nivolumab. In“patients aged 75 years or older (HR=0.90)”, “non-smoking( HR=1.02 )”, “patients with EGFR mutations (HR=1.18)”,“patients without K-RAS mutations (HR=0.98)” and “patientswith metastases to central nervous system (CNS) (HR=1.04)”,
the drug was found to be ineffective.
PFS (Fig.5) was significantly shortened in nonsquamouslung cancer in “patients with prior treatment with more than
one drug (HR=1.70, 95%CI: 1.00-2.90)” and “patients without
K-RAS mutations (HR=1.52: 1.03-2.25)”. In patients in which
K-RAS mutation was undetected, in particular, PFS was
1.95 months versus 4.83 months, and was more than twice
shorter. The data also showed that the drug might shorten
PFS in “patients aged 75 years or older” with squamous lungcancer (HR=1.76), and “rest of the world (HR=1.42)”, “nonsmoking (HR=1.39)” and “patients with EGFR mutation-positive(HR=1.46)” with nonsquamous lung cancer.
EGFR mutation and K-RAS mutation are mechanisms forescaping immune surveillance. In many patients with EGFR
mutation-positive, PD-L1 is not expressed while K-RAS
mutation is associated with expression of PD-L1. Further
analysis is needed to determine the factors with which thedrug is expected to be more effective, ineffective or harmful.

Figure 5 ： Factors related with no benefit or risk of PFS

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 33

Limited financial resource must be efficiently utilized.
On adverse reactions:
In the phase 3 trials, serious adverse events occurred lessfrequently with nivolumab than with docetaxel in squamouscell lung cancer. Contrarily, it occurred more frequently
with nivolumab in nonsquamous lung cancer. In general,
diarrhea, alopecia and hematologic disorders caused by thecytotoxic effect were observed frequently with docetaxel.
Cancer progression and resulting hypercalcemia (7.7% versus
0% in squamous lung cancer), and hypothyroidism (5.3% versus
0% in squamous lung cancer, 6.6% versus 0% in nonsquamouslung cancer) were more marked with novolumab. These areconsidered to be adverse reactions caused by the mechanismof action of the drug [12]).
Cancer progression with respect to the best response
was observed almost twice more frequently withnivolumab, particularly in nonsquamous lung cancer, andit was significant. As the drug inhibits PD-1 on antigenpresenting cells ( APCs), it might reduce the function thatrecognizes cancer cells as foreign bodies, promoting theproliferation of the cancer cells. Furthermore, consideringthat hypothyroidism occurred significantly more frequently
with nivolumab in both trials on squamous lung cancer andnonsquamous lung cancer, and that thyroid hormone T3
was reduced in animal toxicity studies, the drug certainly
increases autoimmune diseases. In fact, deaths were reported
and warnings for autoimmune diseases have been issued [14,15].
Therefore, based on the mechanism of action of nivolumab,
cancer progression and increased autoimmune diseases areadverse reactions to the drug.
In practice:
When nivolumab is used for treating non-small-cell lungcancer with a high PD-L1 expression level, it prolongs mediansurvival for approximately 3 months.
However, when a PD-L1 expression level is low, nivolumab
might shorten life under some conditions. The drug isworthless as it possibly shortens life while the annual drug
cost amounts to as high as 35 million yen. Conditions inwhich the drug is ineffective or harm outweighs, such as“aged 75 or older”, “EGFR mutation”, “K-RAS mutation”,“non-smoking” and “types of prior medications”, should bedetermined. Under such conditions, the drug should not be
used.

References
1) Center for Cancer Control and Information Services, National Cancer
Center Japan
http://ganjoho.jp/reg_stat/statistics/dl/index.html
2） Kunito H, speech at an Advisory Panel for Financial System April 42016
http://www.mof.go.jp/about_mof/councils/fiscal_system_council/subof_fiscal_system/proceedings/proceedings/zaiseia280404.html
3） Examination report of Nivolumab for malignant melanoma by PMDA
June 2014
4） Examination report of Nivolumab for non-small cell lung cancer by
PMDA Dec. 2015
5） Examination report of Nivolumab for malignant melanoma by PMDA
Feb. 2016 (addition of Use and administration methods)
6） Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance
and autoimmunity.
Immunol Rev. 2010; 236: 219-42. http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC2919275/
7） Borghaei H, Paz-Ares L, BrahmerJR et al. Nivolumab versus Docetaxel
in Advanced
Nonsquamous Non-Small-Cell Lung Cancer. NEngl J Med.
2015;373(17):1627-39.
http://www.ncbi.nlm.nih.gov/pubmed/26412456
8） Brahmer J, Reckamp KL, Baas P et al Nivolumab versus Docetaxel in
Advanced Squamous-Cell
Non-Small-Cell Lung Cancer. NEngl J Med. 2015;373(2):123-35
http://www.ncbi.nlm.nih.gov/pubmed/26028407
9） Summary Basis of Approval (SBA) of nivolumab for malignant
melanoma, “on toxicity”
http://www.pmda.go.jp/drugs/2014/P201400114/index.html
10） Hama R, The crucial negligence of the regulatory authority and thecompany ─ Normal evaluation of the results of animal experimentation
could have prevented the TGN1412 tragedy

─ Clin Eval. 2006: 34(Suppl24)：171-84
http://npojip.org/sokuho/no73-4.pdf11） Okazaki T Discovery of a proteins that regulates various autoimmune
diseases
http://www.jst.go.jp/pr/announce/20110207-3/
12） SBA of nivolumab for non-small cell lung cancer
http://www.pmda.go.jp/drugs/2015/P20151222005/index.html
13） Marketing product of anti-PD-L1 antibody
http://www.cosmobio.co.jp/product/detail/pd-l1-antibody-pgi.
asp?entry_id=14736
14) Pharmaceuticals and Medical Devices Safety Information
No332(2016.4)
http://www.mhlw.go.jp/file/06-Seisakujouhou-11120000Iyakushokuhinkyoku/0000121724.pdf
15) Management of immune related adverse events (irAE) (orautoimmune reactions) to Opdivo
https://www.opdivo.jp/contents/lecture/

Page 34 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

Appendix
Figure 6 ： PFS of NSQ-NSCLC by expression level of PD-L1

Note that the cut off level of PD-L1 expression is 5 %. Kaplan-Meier curves using 10% for cut off level were not provided by the SBA. If provided, the difference
might be more distinct.

Appendix
Figure 7 ： PFS of SQLC by expression level of PD-L1

Note that the cut off level of PD-L1 expression is 5 %. Kaplan-Meier curves using 10% for cut off level were not provided by the SBA. If provided, the difference
might be more distinct.

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 35

New Products

GLP-1 Agonists (liraglutide etc.)
No evidence of improving prognosis in patients with diabetes
Not recommended
Translated from Med Check-TIP (in Japanese) Mar. 2016 ; 16 (67):108-112

Abstract
A anti-diabetic medicine is valuable only if it can prolong life or at least it tends to prolong life andsignificantly reduce serious complications such as retinopathy, renal failure, cardiovascular disease andcancers. Incretin related drugs (DPP-4 inhibitors and GLP-1 agonists) were introduced from 2009 onwards
in Japan. Just like other agents for diabetes, they were approved only because they lowered HbA1c levels,
which is merely a surrogate endpoint, without proof of survival prolongation.
In June 2016, a randomized controlled trial (RCT) comparing placebo reported for the first time thatliraglutide, a GLP-1 agonist, had improved cardiovascular events. However, as a result of close examination,
we conclude that this claim is not reliable because of the highly probable blinding failure presumed fromvarious contradicting data in the trial. Moreover, increased pancreatic cancer, combined with results ofanimal tests and other clinical and epidemiological findings, suggests that the agent has carcinogenicity.
Therefore, Med Check-TIP recommends not to use these agent.
Introduction
For the treatment of a diseases with certain mortality,
the strongest and unbiased endpoint is whether thetreatment can improve survival or not [1]. The purpose ofa diabetic medicine is to prevent complications (retinopathy,
nephropathy, neuropathy, cardiovascular events, and malignant

issue, placebo controlled non-inferiority trials (Note 1) for
these drugs were conducted.
Among incretin related drugs, none of the DPP-4 inhibitors( saxagliptin [5], alogliptin [6], sitagliptin [7]) nor a GLP-1
agonist ( lixisenatide ) improved prognosis of patients withdiabetes. Among these trials, one trial [5] aimed at proving

tumor) by improving systemic metabolism, and prolong life

(decrease total mortality).
DPP-4 inhibitors and GLP-1 receptor agonists ( GLP-1
agonists ) are incretin related medicines, which have been
in clinical use since 2009. Their unique feature is claimed
that they do not usually cause hypoglycemia [2, 3]. They
are widely used as they are expected to be new dreamlike medicines [2]. Six DPP-4 inhibitors (5 ingredients) wereranked among 100 top-selling medicines in fiscal year 2015.
In particular, the total sales of two products of sitagliptin
amounted to over 100 billion yen [4].
However, just like other hypoglycemic agents, they wereapproved as “new products” only for their lowering effect on
glycohemoglobin ( HbA1c), a surrogate endpoint. Later on,
because of the reasons described in the column (P,38)of thisNote 1: Non-inferiority and superiority trials
Superiority trial: a trial to show the superiority of an intervention by
showing the risk reduction of the primary outcome expressed by thehazard ratio, odds ratio or risk ratio and their upper limit of the 95%
confidence interval (95%CI) less than 1.0.
Non-inferiority trial: a trial to show the non-inferiority of an intervention
comparing the control group by showing the hazard ratio, odds ratio orrisk ratio and their upper limit of the 95% confidence interval (95%CI)
less than a certain level for instance 1.3. The risk may be considered to
be within a permissible level compared with control.
On the protocol, the LEADER trial was designed as a non-inferiority
trial, whose upper limit of 95% CI for hazard ratios (HR) was set at 1.3.
Superiority analysis was not included even as a secondary analysis in the
protocol [9, 10].

Table １ ： Fundamental design and the results of pivotal RCTs of incretin related agents*a： No： hypothesis was not proven
Yes： hopothesis was proved*b： Protocol of the LEADER did not state that it is conducted as a superiority study at all.

Page 36 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

superiority ( Note 1 ). All the other trials were designed toprove non-inferiority against a placebo. Although the goal
was achieved, superiority was not proven (Table1).
In 2012, the Med Check stated that these incretin related
drugs should not be used because non-clinical and clinical
trials had shown their carcinogenicity and they were unlikely
to bring benefit, including benefit on survival, even after
long-term human use [9]. In June 2016, a clinical trial for
liraglutide (LEADER study) reported for the first time that the
drug reduced more cardiovascular events as compared witha placebo [10,11]. This paper verifies it.

2 minutes. DPP-4 inhibitors were developed to prolong theactivity of endogenous GLP-1. Contrarily, GLP-1 agonists act
like GLP-1 which is not easily inactivated by DPP-4 and hasvery long half-life. Incretin related drugs include both DPP-4
inhibitors and GLP-1 agonists (Table 2: approved/marketeddrugs as of August, 2016 in Japan).
It should be examined whether these agents activating
short-acting biological substances for 24 hours, 365 days are
beneficial or not for humans.

Incretin related drugs

The LEADER trial [9, 10] is a non-inferiority RCT (Note1), involving 9340 patients with cardiovascular risk, whowere on treatment for type 2 diabetes and had HbA1c levelof 7.0% or higher (average 8.7%). In addition to the standard
treatment they were assigned, in a 1:1 ratio, to receive either
1.8 mg of liraglutide (Group L: 4668 patients) or placebo (saline)(Group P: 4672 patients) subcutaneously per day. The primary
outcome was the occurrence of composite cardiovascular
events. The median follow-up was 3.8 years.
No marked difference was found in the baselinecharacteristics between the 2 groups. The average BMI was
32.5 and average body weight was 91.7 kg. 10% of thepatients were from Asia (China, South Korea, Taiwan), but none
was from Japan. It is also noteworthy that 1.8 mg/day ofliraglutide (the approved dose in the West) is twice as high as
the usual dose (0.9 mg/day) in Japan.

Food intake stimulates the cells of small-intestine tosecrete hormones ( intestinal hormones ) which stimulate
β cells in the pancreas, inducing secretion of insulin, while
suppressing action of glucagon. The intestinal hormone
is generally termed as an incretin. The major intestinal
hormone is GLP-1 (glucagon-like peptide-1) [12].
GLP-1 receptors, on which GLP-1 acts, exist on
pancreatic β cells, and cells on the peripheral and central
nervous systems, cardiovascular system, heart, kidneys, lungs
and gastrointestinal mucosa. When GLP-1 binds to a GLP-1
receptor, it increases intracellular cAMP and alters activityof ion channels. In pancreatic β cells, insulin synthesis isenhanced, and insulin is secreted by the cells [12].
Endogenous GLP-1 is rapidly inactivated by the enzyme
dipeptidyl peptidase-4 (DPP-4) with a plasma half-life of 1 to

The LEADER trial: design, methods and baselinecharacteristics

Table 2: List of incretin related drugs (as of August, 2016)

Tmax (h): time to maximum plasma concentration. t1/2 (h): elimination half life, sc: subcutaneous injection

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 37

《column》

Why methods assessing anti-diabetic agents favor industry?
Translated from the editorial in the No67 issue of Med Check TIP (in Japanese) 2016
Since 2000, 55 products that contain 26 ingredientsand belong to 4 classes of anti-diabetic agents have been
approved. They include insulin analogues, GLP-1 agonists,
DPP-4 inhibitors and SGLT-2 inhibitors. The last three,which have completely new mechanisms of action, were firstmarketed internationally in 2005, followed by launching inJapan in 2009.
Drugs for the treatment of diseases that might be fatal are
valuable if they prolong life. Even if they don’t, they shouldat least show tendency to prolong life and significantly
reduces serious complications of the disease, or relieve pains
or serious discomforts. Serious complications, for example,
of diabetes, are retinopathy, renal failure, cardiovasculardisease and cancers. In order to assess this, in a randomized
controlled trial (RCT) in which participants are all given witha standard treatment and are randomly assigned to a study
agent or placebo, “superiority” of the agent over placebo haveto be proven.
However, the long-term post marketing studies for theseagents did not aim at establishing “superiority” but only “noninferiority”, except for one trial, in their protocols. This meansthat new products with high price are approved for marketing“if they are not inferior to or demonstrate the similar level ofbenefit and harm with placebo".
FDA officially guaranteed
It is the US Food and Drug Administration (FDA) that
officially endorsed such strange evaluation methods. For all
anti-diabetic agents marketed before 2008 in the UnitedStates, neither survival benefit nor reduction of cardiovascular(CV) diseases has been proven. Rosiglitazone even increased
cardiovascular events. In December, 2008, the FDA’s
Endocrinologic and Metabolic Drugs Advisory Committee(EMDAC) confirmed the followings.
(1) Importance of glycemic control on microvascular risk
reduction is affirmed(2) HbA1c remains primary efficacy endpoint for drug approval(3) CV benefit is not a requirement for approval of these drugs

Endpoints and major result
The primary composite outcome in the time-toevent analysis was “the first occurrence of death fromcardiovascular causes, nonfatal myocardial infarction,or nonfatal stroke” The results showed that these eventsoccurred less frequently with liraglutide ( 13.0% ) thanwith placebo (14.9%) (HR=0.87, 95% CI: 0.78-0.97, p=0.01 as
superiority). Based on this result, the authors claimed thesuperiority of liraglutide than placebo. They also argued forthe superiority of the drug with regard to total mortality (thispoint will be discussed later).
However, although not significant, both benign andmalignant tumors were observed more frequently with

Page 38 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

(Glycemic control alone will be difficult to demonstrate CV risk
reduction as observed in numerous outcomes trials)
FDA consulted the Panel inquiring “It should be assumed
that an anti-diabetic therapy with a concerning CV safety
signal during Phase 2/3 development will be required to
conduct a long-term cardiovascular trial. For those drugs or
biologics without such a signal, should there be a requirement
to conduct a long-term cardiovascular trial, or to provide
other equivalent evidence to rule out an unacceptablecardiovascular risk?” The majority answered “Yes: 14/16”
Non-inferiority trials for those approved drugs wereconducted successively. It has been considered that theadverse effect may be acceptable unless the upper limit of the
95% confidence interval of the risk (hazard ratio) exceeds 1.3.
Reduction of HbA1c increased mortality (ACCORD study)
In fact, in June, 2008 about a half year before the Advisory
Panel decided as above, the ACCORD study was published,which showed that the mortality of the intensive therapy
group was higher than that of the standard therapy group.
This clearly indicates that HbA1c never be the appropriate
primary efficacy endpoint for drug approval. The Panel
ignored the evidence from the ACCORD study and decided
that confirming no evidence of worsening is sufficient because
it may be difficult to confirm significant improvement.
FDA and the National Institute of Health (NIH) endorsed
these "weak" studies by funding them. Such an incoherent
technique is unacceptable.
Superiority is reported only in the fraudulent studies
Masking failures and management differences were highly
suspected in the studies for liraglutide and empagliflozin.
Only in these fraudulent studies, the drugs showed superiority
on the CV benefit over placebo. Why should we pay morethan 200 billion yen (2 billion dollars) for these agents thathave only the same benefit as placebos? The clinical study
reports should be disclosed and closely examined.

liraglutide (Table 3). Similar to cardiovascular diseases,
malignant tumor heavily affects prognosis of diabetic
patients, especially their survival, and is an important
outcome. If malignant tumor is included in the primary
composite outcome, no significant difference was foundbetween the groups (Table 3).
Pancreatic cancer occurred in 5 patients in the placebogroup and 13 patients in the liraglutide group ( p=0.059).
Although this is not significant at p less than 0.05 for thelevel of significance, considering the carcinogenicity of GLP-1
agonists and a possibility to miss true association (beta error:
Note 2), this has a biological significance. This will also be
discussed later.

New Products
Note 2: A significance level is commonly set at p=0.05. This value
represents a “probability of erroneously assuming association when
actually no association exist”. In a statistical term, it is called “alphaerror” or type 1 error. In contrast, an error “denying association whenassociation actually exists” is called beta error or type 2 error.

Problems in the LEADER trial
1)Change in the hypothesis
In the protocol [9, 10], the hypothesis was “non-inferiority
against placebo (Note 1)”. The prime goal was to verify thishypothesis, and proving superiority was not included in the
protocol. In other words, liraglutide was expected to be no
more effective than placebo.
In the analysis conducted after the trial, as the upper
limit of 95% CI of HR was less than 1.0, the hypothesis waschanged to claim superiority. However, this is inappropriate.
Unless included in a hypothesis, it is not supposed to beclaimed. Moreover, double blinding is extremely important,but in this study, it might not have been maintained, leading
differences in management/care between the groups. This
undermines the claim for superiority even further. This will
be discussed later on.
2)Risk of blinding failure
The LEADER trial was conducted as double blindedmanner. However, it was relatively easy to guess whichgroup the patient had been assigned to if changes in glucose
and HbA1c levels, and course of nausea, vomiting, anorexia,
and body weight were considered.
a)Changes in HbA1c levels
The trial targeted to maintain HbA1c levels at 7.0% or
below. In HbA1c levels at 3 months or later after the start of
the trial, the degree of decrease was bigger with liraglutide
than with placebo by 1.0%. Because change in glucose levels
is faster than that in HbA1c level, it was probably easy toguess the assignment at the initial stage of the trial.
b)Significant increase in nausea and vomiting
Among all adverse events, nausea and vomiting wereTable 3: Risk of major outcomes and adverse events in the LEADER trial*a: primary composite outcome: time to the first occurrence of any of the followings; cardiovascular death, non-fatal myocardial infarction and nonfatal stroke*b: expanded composite outcome: hospitalization due to coronary angioplasty, unstable angina or heart failure was added to the primary composite
outcome*c: Hazard ratio (HR) and its 95% CI calculated by the Cox proportional hazard model were 0.87 (0.78-0.97) for the primary composite outcome, 0.88
(0.81-0.96) for the expanded composite outcome, and 0.85 (0.74-0.97) for total mortality. These values are almost consistent with the odds ratios (ORs)above and their 95% CIs calculated by univariate analysis.

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 39

observed over 4 times and 15 times more frequently withliraglutide than with placebo, respectively (both p<0.0001).
Diarrhea, abdominal pain, anorexia, and abdominal
discomfort were also experienced significantly more
frequently with liraglutide (Table 3).
c)Changes in body weight
The patients in the placebo group hardly lost their bodyweights. The degree of body weight reduction was greater by
2.3 kg with liraglutide than with placebo.
GLP-1 agonists induce nausea and vomiting, enhancesatiety, reduce hunger, and reduce body weight by delaying
gastric emptying time peripherally and by the action on
the central nervous system [12-14]. These were commonly
observed in animal tests and clinical trials as the classeffect of GLP-1 agonists based on some summary basis ofapprovals (SBAs) of GLP-1 agonists. Tolerance develops tothe peripheral action such as delaying gastric emptying in ashort-term, but the central action persists for a long-term [13].
It is presumed to act mainly on the arcuate nucleus in the
hypothalamus [14]. In fact, the U.S. and European regulator
approved a preparation of liraglutide 3.0 mg for reducing
body weight in patients with obesity [15-17].
Based on these, it is very likely that physicians can easily
guess the assignment, and that double blinding failed at theearly stage of the trial.
3)The data suggesting blinding failurea)Discrepancy between serious and non-serious adverse
event leding to withdrawal
The blinding failures seem resulted in contradicting data.
The strangest point is found in discrepancy between serious
and non-serious adverse events leading to withdrawal.
In general, proportion of patients with serious and nonserious adverse events leading to withdrawal are linked toeach other. However, in the LEADER trial, serious adverse
events leading to withdrawal were observed 22% less withliraglutide (OR=0.78, p<0.0001), while the proportion of nonserious adverse events leading to withdrawal was 5.4% inliraglutide group and 2.0% in the placebo group (OR=2.78,
p<0.0001). They occurred almost 3 times more frequently inpatients who had received liraglutide.
The data suggest that the patients treated with the drug
withdrew earlier before adverse events became serious while
the patients treated with placebo continued the treatment
until adverse events became serious. This suggests a gap
between the 2 groups in the management of adverse events.
b)Acute gallstone diseases occurred frequently, but notpancreatitis.
In general, when acute gallstone diseases (choleithiatis,
acute cholecystitis) increase, acute and chronic pancreatitis
also increases because acute gallstone diseases are often
accompanied by biliary obstruction. This is a common sense
in medicine.
However, in the LEADER trial, while acute gallstonediseases occurred 63% more frequently with liraglutide ascompared with placebo (OR=1.63, p=0.0003), both acute (0.5%versus 0.4% ) and chronic ( 2 patients versus 0 ) pancreatitis
occurred less frequently with the drug.
As mentioned above, many cases of mild adverse events
seem to have led to early withdrawal in the liraglutide group.
Considering this tendency, it is possible that cases of mildPage 40 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

biliary abnormalities led to withdrawal in the liraglutidegroup while they stayed on until they become more serious
in the placebo group. This is another point that suggests
some gaps in the management or care between groups.
4)Inappropriate control of glucose levels in the placebogroup?
Failure in blinding is also suspected because of thecontradicting results in glucose levels. Usually, when a
glucose level is lowered, severe hypoglycemia increases.
However, the trial showed an opposite tendency. In
monitoring HbA1c levels, glucose levels are maintained
obviously lower with liraglutide than with placebo. In fact,
it is consistently lower by approximately 1 % . At the sametime, the proportion of patients who developed severe
hypoglycemia was 2.4% (114 patients) with liraglutide and3.3% (153 patients) with placebo (p=0.02).
Significantly more glucose-lowering drugs, such as insulin
preparations ( liraglutide group 28.6% versus placebo group43.2%, OR=0.53, p<0.0001) and SU agents (7.6% versus 10.8%,
OR=0.68, p<0.0001), were used in combination with placebothan with liraglutide. Glitazone agents (OR=0.61), metformin(OR=0.82), GLP-1 agonists (OR=0.47) (Note 3), α -glycosidase(OR=0.56), glynides (OR=0.61) were all used significantly more
frequently (p<0.001) with placebo. ORs for SGLT-2 inhibitorsand DPP-4 inhibitors were 0.76 (p=0.046) and 0.87 (p=0.23)(Note 3), respectively.
Although glucose levels were maintained lower (1% lower
by HbA1c), severe hypoglycemia was observed less frequently
in the liraglutide group. Furthermore, in the same group,
there were less cases of serious adverse events that led towithdrawal, but more cases of non-serious adverse events
that led to withdrawal. These strange phenomena raisea doubt about appropriateness of treatment given to thepatients in the placebo group. It suggests that there weresome differences in management or care between the twogroups.

Note 3: On the protocol, concomitant use of GLP-1 agonists and DPP-4
inhibitors was contraindicated.

5)BMI and contradicting results in Asian patients
HR for the primary outcome in patients whose BMI wasover 30 was 0.82 ( 95%CI 0.71-0.94). On the other hand,
it was 0.96 (0.81-1.15) in patients whose BMI was 30 orlower, and liraglutide was ineffective in this sub-group.
When analyzed by region, HR for Asia was 0.62 (0.37-1.04).
This was not significant, but there was substantial reductionin point estimation (Note 4). Although, in Asia (China, Taiwan
and South Korea ), there are probably less people whose
BMI is over 30, the trial showed a significant favorable
result, and it was nearly significant. This is possibly due todifferences in management resulted by the blinding failure.

Note 4: A statistical term. Degree of risk such as odds ratio (OR) andhazard ratio (HR) is presented as an estimate that indicates the highest
probability (point estimate) and its 95% CI. For instance, for HR in Asia,
the point estimate is 0.62 and its 95% CI is 0.37-1.04.

New Products
6)Carcinogenicity
As mentioned in the section on adverse events, thefrequent occurrence of pancreatic cancer (OR=2.6, p=0.059) isbiologically significant. Moreover, when malignant tumor isadded to the primary outcome (composite outcome), odds ratio
is not significant.
In this section, we discuss the results of the meta-analysis
of pre-approval clinical trials [18, 19] including those ofanother GLP-1 agonist, exenatide, and findings from toxicity
studies.
a) Meta-analysis of clinical trials for approval and another
GLP-1 agonist
In several RCTs for the approval of liraglutide [19],serious neoplasms (mostly malignant tumors) were observed
more frequently with liraglutide (OR=1.80, p=0.2) (Note 5).
According to the SBA of exenatide, OR for malignant tumor
was 5.06 (2.01-12.73, p=0.0001) (Note 5).
The combined odds ratio (fixed effect) for the LEADER trial
and pre-approval trials for liraglutide and exenatide was 1.18
(1.01-1.39, p=0.048), and was significant (Note 6).

Note 5: SBA of liraglutide reported that the trial involved 4211
patients (2241 person-years) in the liraglutide group and 2272
patients (1139 person-years) in the non-liraglutide group. Malignant
neoplasms were found in 20 cases (19 patients) (8.9/1000 personyears) in the liraglutide group and 6 cases (5.3/1000 person-years)
in the non-liraglutide group. According to the SBA of exenatide,combined database from 15 long-term RCTs and 8 long-term noncontrolled studies (all are non-Japanese studies) showed thatmalignant neoplasms were found in 48 patients among 3504 patients(1.4%) in the exenatide group and 5 patients among 1826 patients(0.3%) in the control group (1108 patients treated with placebo and718 with insulin).
Note 6: Pre-approval trials for lixisenatide and dulaglutide havenot been reviewed. A long-term study for lixisenatide, ELIXA [8],reported the number of cases with neoplasms, but not with malignant
neoplasms. Therefore, they were not included in the analysis in thenote 5.

b) Findings from toxicity studies
A 2-year rat carcinogenicity study showed a statisticallysignificant dose-related increase of thyroid C cell adenoma
and C cell cancer. Even the minimum dose, 0.075 mg/kg/
day of liraglutide, led to a statistically significant increaseor increasing trend in these diseases. NOAEL (no observable
adverse effect level) was not determined for either of them.
In a 2-year mouse carcinogenicity study, NOAEL for
thyroid C cell adenoma and C cell cancer was only 3-foldand 18-fold of the maximum recommended clinical dose forJapanese, respectively.
The pharmaceutical company insists that it does notsuggest carcinogenicity in humans, and thyroid C celladenoma and C cell cancer are rodent (mice and rats)-specifictumors. The Japanese Ministry of Welfare, Health andLabour accepted such an explanation by the pharmaceuticalcompany [18-21].
However, it is reported that in rodents, thyroid C celladenoma and C cell cancer increase via GLP-1 receptors[18-21]. Moreover, human medullary thyroid cancer consistsof mainly C cells [22]. In response to a request from the U.S.
Food and Drug Agency (FDA), Novo Nordisk issued a warning
about a risk of development of C cell tumors, including
medullary thyroid cancer, and launched a registry system for
medullary thyroid cancer [23].
The fact that increased thyroid C cell adenoma and C cell
cancer in mice and rats suggests that malignant cells even in
the other organs might also be proliferated by GLP-1 agonist.
c) Findings from post marketing studies
The analysis of reported odds ratio (ROR), using adverse
reaction cases reported to the FDA’s Adverse Event Reporting
System (AERS) showed that pancreatitis occurred 10.7 times
and 6.7 times more frequently with the brand name drugs in
the U.S., namely exenatide and sitagliptin, respectively. The
incidence of pancreatic cancer was 2.9-fold and 2.7-fold withexenatide and sitagliptin, respectively. Thyroid cancer was
also reported 4.7 times more frequently with exenatide. Allof these were statistically significant [24].
d) Importance of carcinogenicity in diabetics
Based on the discussion above, findings on increased
malignant tumors ( or serious tumors ) were consistent in
humans and animals. It can be concluded that “cancer” surely
increases in humans using GLP-1 agonist.
Currently, in Japan, the number one cause of death inpatients with diabetes is malignant neoplasms [25]. It has
been reported that morbidity of cancer among diabetic
patients is high [25-27].
The Japan Diabetes Society is reluctant to accept therelationship between high incidence of cancer among
diabetic patients and use of anti-diabetic drugs [3].
However, not only animal tests, but also clinical trials andepidemiological studies have pointed out carcinogenetic
property of incretin related drugs [11], pioglitazone [28] andnew insulin preparations [11].

In practice

The LEADER trial did not prove that liraglutide improvesmortality from cardiovascular events and total mortality.
The evidence that suggests the possible serious harm of
GLP-1 agonists in a long-term, such as carcinogenicity, hasbeen gradually established just as the Med Check-TIP has
been advocating. Neither GLP-1 agonists nor DPP-4 inhibitors
are recommended for the treatment of type 2 diabetes.

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 4121) SBA of exenatide:

References

22) Kumar V et al edd Robbins Basic Pathology 7th ed Saunders
1) ISDB manual “Starting or Strengthening a Drug Bulletin A Practical
Manual 2005” Chapter 8 “Reviewing a new drug: is it a therapeutic

Philadelphia, 2003
23) Dear healthcare professionals: Important drug warning concerningadvance?” http://www.isdbweb.org/documents/uploads/

Victoza®

manual_full_text.

http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/

pdf2) Japan Physicians Association、New treatment for Diabetes －SafetyAlertsforHumanMedicalProducts/UCM258828.pdf24) Elashoff M, Pancreatitis, pancreatic, and thyroid cancer with

Incretin related drugs (in Japanese)
http://www.japha.jp/doc/byoki/048.pdf
3) The Japan Diabetes Society, Evidence-based Practice Guideline
for the Treatment for Diabetes in Japan 2016 (in Japanese) (English

glucagon-like peptide-1-based therapies. Gastroenterology. 2011
Jul;141(1):150-6.
25) Hotta N

et al. Causes of Death in Japanese Diabetics Based on the2013 version is available at http://www.jds.or.jp/modules/en/index.

Results of a Survey of 18,385 Diabetics during 1991-2000―Report

php?content_id=44

of Committee on Cause of Death in Diabetes Mellitus. Diabetes 2007:

4) AnswersNews、Pharmaceutical sales ranking in 2015 (in Japanese
http://answers.ten-navi.com/pharmanews/6971/
5) Scirica BM et al (the SAVOR-TIMI 53 Steering Committee and50:47-61 (in Japanese with English abstract) https://www.jstage.jst.
go.jp/article/tonyobyo/50/1/50_1_47/_pdf
26) Kasuga, M., Ueki, K., Tajima, N. et al. Report of the JDS/JCA

Investigators). Saxagliptin and cardiovascular outcomes in patients with

Joint Committee on Diabetes and Cancer Diabetol Int (2013) 4: 81.

type 2 diabetes mellitus. N Engl J Med. 2013; 369(14): 1317-26.

doi:10.1007/s13340-013-0121-3

6) White WB et al (the EXAMINE Investigators). Alogliptin after acute27) Goto A et al. Report of the Japan Diabetes Society (JDS)/Japanesecoronary syndrome in patients with type 2 diabetes. N Engl J Med.

Cancer Association (JCA) Joint Committee on Diabetes and Cancer,

2013; 369(14): 1327-35.

Second Report. Cancer Sci 107 (2016) 369–371

7) Green JB et al (the TECOS Study Group). Effect of Sitagliptin
on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814249/pdf/
CAS-107-369.pdf28) Med Check TIP editorial team. Pioglitazone (brand name: Actos) and2015;373(3):232-42.
8) Pfeffer MA et al (the ELIXA Investigators). Lixisenatide in Patients withbladder cancer: A new type "time-related bias" Med Check TIP (inType 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015

English) 2016: 2(2): 22-25. (Original Japanese version: Med Check TIP

Dec 3;373(23):2247-57.

2016; 16(63): 14-18

9) Hama R, Assessment of agents for diabetes. MedCheck 2012:
12(45):14-27 (in Japanese)10) Marso SP et al (the LEADER Trial Investigators). Liraglutide
and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med.
2016;375(4):311-22.
11) Marso SP

et al (the LEADER Trial Investigators), Design of theliraglutide effect and action in diabetes: evaluation of cardiovascularoutcome results (LEADER) trial. Am Heart J. 2013;166(5):823-30.
12) Brunton LB et al. Goodman & Gilman’s The Pharmacological Basis ofTherapeutics 12th ed McGraw-Hill, 201113) Jelsing J, Vrang N, Hansen G et al. Liraglutide: short-lived effect on
gastric emptying -- long lasting effects on body weight. Diabetes Obes
Metab. 2012;14(6):531-8.
14) Secher A, Jelsing J, Baquero AF

et al. The arcuate nucleus mediates

GLP-1 receptor agonist liraglutide-dependent weight loss. J Clin Invest.
2014;124(10):4473-88.
15) FDA News Release, FDA approves weight-management drug Saxenda
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm427913.htm
16) Novo Nordisc, Liraglutide 3.0 mg for Weight Management NDA
206-321 Briefing Document, Endocrinologic and Metabolic Drug
Advisory Committee Sept 11, 2014
http://www.fda.gov/downloads/advisorycommittees/committeesmeeti
ngmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm413318.pdf
17) Label of Saxenda: http://www.accessdata.fda.gov/drugsatfda_docs/
label/2014/206321Orig1s000lbl.pdf
18) Examination report for liraglutide:19) SBA of liraglutide:20) Examination report for exenatide:

Page 42 ・ MED CHECK - TIP December 2016/ Vol.2 No.6

M
C

ED

HECK

The Informed Prescriber
2016

Vol.2

No.6

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

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])
Editorial Officers: PRAXTONE, Mutsumi; SAKAGUCHI, Keiko
Production Team: MATSUMOTO, Koji ;UMEKI, Yukiko; SAKAGUCHI,
Keiko
Information Technology (IT):KURODA, Akira (Systems Engineer)
Copyright NPOJIP
www.npojip.org
Registered address:#702, Ueshio 5-1-20, Tennouji,

MED CHECK - TIP December 2016 / Vol.2 No.6 ・ Page 43