A consensus statement from the Japan
Diabetes Society: A proposed algorithm for
pharmacotherapy in people with type
2diabetes
Ryotaro Bouchi
1
?
, Tatsuya Kondo
2?
, Yasuharu Ohta
3?
,AtsushiGoto
4
, Daisuke Tanaka
5
,
Hiroaki Satoh
6
,DaisukeYabe
7
,RimeiNishimura
8
, Norio Harada
5?
,HidekiKamiya
9?
,RyoSuzuki
10?
,
Toshimasa Yamauchi
11?
, JDS Committee on Consensus Statement Development
1
Diabetes and Metabolism Information Center, Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan,
2
Department of Diabetes, Metabolism and
Endocrinology, Kumamoto University Hospital, Kumamoto, Japan,
3
Division of Endocrinology, Metabolism, Hematological Sciences and Therapeutics, Yamaguchi University Graduate
School of Medicine, Ube, Japan,
4
Department of Health Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan,
5
Department of Diabetes,
Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan,
6
Department of Diabetes and Endocrinology, Juntendo University Urayasu Hospital,
Urayasu, Japan,
7
Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of
Medicine, Gifu, Japan,
8
Division of Diabetes, Metabolism and Endocrinology, Jikei University School of Medicine, Tokyo, Japan,
9
Division of Diabetes, Department of Internal
Medicine, Aichi Medical University, Nagakute, Japan,
10
Department of Diabetes, Metabolism and Endocrinology, Tokyo Medical University, Tokyo, Japan, and
11
Department of
Diabetes and Metabolic Diseases, University of Tokyo Graduate School of Medicine, Tokyo, Japan
PREFACE
In 2020, the Japan Diabetes Society (JDS) adopted a sweeping
decision to release consensus statements on relevant issues in
diabetes management that require updating from time to time
and launched a ‘JDS Committee on Consensus Statement
Development’. These consensus statements are intended to pre-
sent the committee’s take on diabetes management in Japan
based on evidence currently available for each of the issues
addressed. It is thus hoped that practicing diabetologists will
never fail to consult these statements to provide the best avail-
able practice in their respective clinical settings. Of note, while
as many as one-third of all people with diabetes in the world
are shown to be concentrated in the Asian region, diabetes mel-
litus varies in its pathology, including the extent of obesity
involved in affected patients, between the East and West. Again,
given that timely consensus statements to come out of Japan
are thus expected to have enormous implications for clinical
practice, it is also planned to make each consensus statement
available in English.
Following publication in 2020 of the committee’s ?rst con-
sensus statement on ‘Medical Nutrition Therapy and Dietary
Counseling for People with Diabetes’ (Tonyobyou 2020; 63: 91–
109) in Japanese, the committee has taken this opportunity to
propose a consensus ‘algorithm for pharmacotherapy in people
with diabetes’, in this statement. There are three reasons that
prompted the committee to address this issue. First, there are
characteristic differences in diabetes pathology between
Westerners and the Japanese, where individuals with insulin
resistance account primarily for all people with diabetes among
the former, while obese and non-obese individuals account
equally for all people with diabetes among the latter, with the
severity of insulin insuf?ciency and insulin resistance varying
from one individual to the next. Second, there are differences
in treatment strategy adopted for diabetes between the West
and Japan. Indeed, up until 2021, metformin was recom-
mended as ?rst-line therapy for Western patients, with those
shown to be effective against relevant comorbidities, e.g.,
atherosclerotic cardiovascular disease, renal dysfunction, and
heart failure (HF), particularly recommended. In contrast,
prompted by the results of the Kumamoto study (Diabetes Res
Clin Pract. 1995; 28: 103–117) and the J-DOIT3 study (Lancet
Diabetes Endocrinol. 2017; 5: 951–964), multifactorial interven-
tion including glycemic control has been recommended in
Japanese people with diabetes to reduce diabetic complications,
with the choice of one medication class over the others for each
patient remaining an issue to be determined in light of his/her
current condition. Third, an analysis of the National Database
of Health Insurance Claims and Speci?c Health Check-ups in
Japan brought a disparity in initial antidiabetic medication pre-
scribing patterns between Western countries and Japan (JDia-
betes Investig. 2022; 13: 280–291), with the judicious use of
biguanides in elderly patients likely to be widespread as per the
JDS warning message, leading to the preferential use of DPP-4
inhibitors over biguanides in these patients. Again, of note,
none of the biguanides were shown to be used as medications
of ?rst choice in as many as 38.2% of all non-JDS-certi?ed
facilities, suggesting the need for the committee to develop a
standard algorithm for diabetes pharmacotherapy.
?Chairperson.
?Committee member.
Received 30 November 2022; revised 1 December 2022; accepted 2 December
2022
a 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. C15C15 No. C15C15 C15C15C15 2022 1
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In developing the algorithm for diabetes pharmacotherapy in
patients with type 2 diabetes, the working concept was that pri-
ority should be given to selecting such medications as would
appropriately address the diabetes pathology in each patient,
while at the same time weighing the available evidence for these
medications and the prescribing patterns in clinical practice in
Japan. Speci?cally, the proposed algorithm would involve
choosing medications according to diabetes pathology in each
patient in step 1; ensuring their safety in step 2; weighing their
additional bene?ts for comorbidities in step 3; and choosing
medications with relevant patient background characteristics of
interest in mind in step 4.
It is hoped that the algorithm presented here will not only
contribute to improved diabetes management in Japan but con-
tinue to evolve into a better one over time, re?ecting new evi-
denceasitbecomesavailable.
CHARACTERISTICS OF DIABETES IN THE JAPANESE
AND ASIAN POPULATIONS
Type 2 diabetes mellitus is a metabolic disease in which insulin
insuf?ciency or decreased insulin sensitivity (insulin resistance),
combined with relative decreased insulin action to varying
degrees, accounts for such a lack of insulin action as to cause
chronic hyperglycemia
1
. Again, multiple genetic factors respon-
sible for insulin insuf?ciency or insulin resistance and environ-
mental factors (e.g., overeating or lack of physical activity and
resultant obesity) combine to lead to such a lack of insulin
action as to cause type 2 diabetes mellitus.
A comparison of the insulin-secretory capacity and insulin
resistance between Westerners and the Japanese as strati?ed by
glucose tolerance shows that the Japanese have less insulin-se-
cretory capacity than the Westerners, even while their glucose
tolerance is shown to be normal and that while Westerners
exhibit acutely increased insulin resistance as they move from
normal glucose tolerance to diabetes, Japanese tend to exhibit
lower insulin-secretory capacity than that usually associated
with increased insulin resistance
2,3
.Again,astudycomparing
insulin sensitivity and initial insulin response between East
Asians, Caucasians, and Blacks shows that these races vary in
the balance between their insulin-secretory capacity and insulin
resistance and that East Asians and Blacks are more susceptible
to diabetes than Caucasians
4
.Again,thepathologyoftype2
diabetes mellitus in Japanese is also shown to be characterized
as a decreased initial insulin response, regardless of the presence
of obesity
5
. On the other hand, a recent study in Hisayama-cho
investigated the correlation between pancreatic b-cell failure
(i.e., low insulinogenic index/HOMA-IR) or insulin resistance
and the onset of type 2 diabetes mellitus and found that while
pancreatic b-cell failure and insulin resistance are both associ-
ated with the risk of type 2 diabetes mellitus, they are associ-
ated with a markedly increased risk of type 2 diabetes mellitus
when they are found together in obese individuals
6
.
In addition, histological studies of the pancreas have shown
that, among non-diabetic Westerners, obese individuals have a
signi?cantly greater islet mass than non-obese individuals and
that, among Westerners with type 2 diabetes, both obese and
non-obese individuals have an islet mass about 50% lower than
that in non-diabetic individuals and that no increase in pancre-
atic b-cell mass is noted even in obese Japanese
7,8
.Research
also shows that, among individuals with type 2 diabetes, amy-
loid deposition is noted in more than 80% of Westerners but
only in 30% of Japanese
9,10
. Thus, it is suggested that histologi-
cal ?ndings in the pancreas differ greatly between different
races, suggesting that these differences may account in part for
differences in their diabetes pathology.
Also of note, advances in genetic analysis of type 2 diabetes
mellitus have also led to the identi?cation of numerous type 2
diabetes mellitus susceptibility loci including KCNQ1
11–13
.A
meta-analysis of genome-wide association studies (GWAS) in
type 2 diabetes mellitus has recently shown that many Japanese
individuals but very few Westerners, had the R131Q mutation
in the GLP-1 receptor gene (GLP-1R), which is known to be
involved in inducing a 2-fold increase in insulin secretion. Fur-
thermore, a cross-racial molecular biological pathway analysis
has shown that the pathways involved in the onset of maturity-
onset diabetes of the young (MODY) are most strongly associ-
ated with type 2 diabetes mellitus in both races evaluated and
that the pathways involved in the regulation of insulin secretion
are signi?cantly associated with type 2 diabetes mellitus in Japa-
nese alone
14
.
Thus, taken together, the pathology of type 2 diabetes melli-
tus clearly differs between Japanese and Westerners, not only
functionally but histologically and genetically, and a decreased
insulin-secretory capacity has a greater role to play in the onset
of type 2 diabetes mellitus in Japanese than in Westerners.
DIFFERENCES IN TREATMENT STRATEGY FOR
JAPANESE AND WESTERN PATIENTS WITH TYPE 2
DIABETES MELLITUS
As detailed above, type 2 diabetes mellitus can be primarily
characterized as having, as an underlying core pathology in
most Japanese, insulin resistance and insulin insuf?ciency,
whose respective contribution is shown to vary from individual
toindividual,incontrasttothatinWesternerswhichcanbe
characterized as having obesity and insulin resistance as a core
pathology. For its ability to reduce the risk of microangiopathy,
macroangiopathy and death, as well as for its bene?cial impact
on body weight, low hypoglycemia risk, and low cost
15,16
,met-
formin has long been recommended as ?rst-line therapy in
Western countries
17,18
.However,theStandardsofMedicalCare
in Diabetes by the American Diabetes Association (ADA) have
been extensively revised in 2022 to address compelling issues in
diabetes management, such as diabetic comorbidities (e.g.,
atherosclerotic cardiovascular disease), patient-related factors in
diabetes treatment, and therapeutic needs of affected individu-
als
19
. In contrast, the treatment strategy for type 2 diabetes mel-
litus in Japan is characterized as allowing for the choice of
medications from all classes to address the diabetes pathology
2 J Diabetes Investig Vol. C15C15 No. C15C15 C15C15C15 2022 a 2022 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
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in each affected individual, while taking into account the extent
of their metabolic derangement, but also on their age, extent of
their obesity, status of their insulin secretion/insulin resistance,
severity of their chronic complications, status of their liver/renal
function
20
. The rationale for this approach has indeed been
provided through the accumulation of relevant evidence,
including that from the Kumamoto study
21
and the Japan Dia-
betes Outcome Interventional Trial 3 (J-DOIT3)
22
,whichcor-
roborated the importance of multifactorial intervention,
including glycemic control, in reducing complications in Japa-
nese patients with diabetes.
INITIAL ANTIDIABETIC MEDICATION PRESCRIBING
PATTERNS FOR PEOPLE WITH DIABETES IN JAPAN
It is not dif?cult to imagine how signi?cantly such differences
in treatment strategy for type 2 diabetes mellitus might impact
on the choice of medications or their prescribing patterns. In
this regard, while there are studies on antidiabetic medication
prescribing patterns in Japan
23,24
, they each suffered from a
small sample size and lack of data from elderly patients and a
nationwide survey has been awaited to provide a full picture of
the prescribing patterns in clinical practice. Thus, the Japan
Diabetes Society (JDS) conducted a nationwide survey to clarify
the prescribing patterns in clinical practice as a step to develop-
ing an algorithm for diabetes pharmacotherapy
25
. The survey
demonstrated that, among the more than 1 million people with
type 2 diabetes registered with the National Database of Health
Insurance Claims and Speci?c Health Check-ups from the latter
half of the ?scal year 2014 to the ?scal year 2017, the most fre-
quently prescribed of all antidiabetic medications was, unlike
those in Western countries
26
, dipeptidyl peptidase-4 (DPP-4)
inhibitors, followed by biguanides and sodium-glucose cotrans-
porter 2 (SGLT2) inhibitors, with age shown to the factor most
strongly in?uencing this prescribing pattern; and that the older
the patients were, the more likely they were to have been pre-
scribed DPP-4 inhibitors and the markedly less likely they were
to have been prescribed biguanides and SGLT2 inhibitors. An
analysis of the initial prescribing pattern by prefecture also
showed that the biguanide and DPP-4 inhibitor prescriptions
varied from one prefecture to the next, while an analysis of the
initial prescribing pattern by facility (JDS-certi?ed vs non-JDS-
certi?ed) showed that no patients receiving initial medication
therapy had been initially prescribed biguanides at 38.2% of
non-JDS-certi?ed facilities and that the DPP-4 inhibitor pre-
scribing pattern varied greatly between JDS- certi?ed and non-
JDS-certi?ed facilities (i.e., there were not a few non-JDS- certi-
?ed facilities where almost 100% of patients had been initially
prescribed DPP-4 inhibitors alone). Thus, while the survey
results suggested that antidiabetic medications were being cho-
sen to address the characteristics of diabetes in each individual
patient and that the JDS recommendations on the use of met-
formin and SGLT2 inhibitors
27,28
were widely adhered to by
primary care physicians, the disparity in DPP-4 inhibitor and
biguanide prescribing patterns between regions and facilities,
nevertheless, pointed to the need to renew awareness of the
JDS-proposed principle of medication choice for each patient
based not only on the extent of their metabolic derangement,
but also on their age, extent of their obesity, severity of their
chronic complications, status of their liver/renal function, and
status of their insulin secretion/insulin resistance, thus a need
to formulate an algorithm as a tool to promote the proper use
of antidiabetic medications.
WORKING CONCEPT OF AN ALGORITHM FOR
PHARMACOTHERAPY IN PATIENTS WITH TYPE 2
DIABETES MELLITUS
Giventhattype2diabetesmellitusdiffersinpathologybetween
Asians including Japanese and Westerners, the Japan Diabetes
Society has long advanced a different treatment strategy for
Japanese from that for Westerners (Figure 1). By the same
token, it became clear from the survey results that the initial
diabetes medication prescribing patterns differ greatly between
Japan and Western countries
25
, suggesting that the JDS-pro-
posed treatment strategy for diabetes has become widespread
among diabetologists and general practitioners alike. It is also
likely that the initial diabetes medication prescribing patterns
re?ected the informed use of antidiabetic medications, except
imeglimin, on the part of many physicians, based on their glu-
cose-lowering ef?cacy and safety pro?les that became known
after a certain lapse of time since their approval. Furthermore,
it became also clear that the disparity in the prescribing pat-
terns of DPP-4 inhibitors and biguanides between facilities and
regions needed to be resolved to ensure the proper use of these
medications. Of note, given that evidence has recently been
accumulated, mostly overseas, that demonstrates the ef?cacy of
GLP-1 receptor agonists and SGLT2 inhibitors against diabetic
comorbidities (i.e., atherosclerotic cardiovascular disease, heart
failureandchronickidneydisease [CKD]), suggesting that these
additional bene?ts (i.e., cardio/reno-protective and mortality-re-
ducing effects) are worth considering in medication selection
for patients with type 2 diabetes mellitus. Thus, overall, based
on the basic concept that (1) medications can be selected to
address the diabetes pathology in Japanese and Asians; (2) the
medication selection should re?ect the prescribing patterns in
clinical practice in Japan; and (3) medications can be selected
for their additional bene?ts in patients with comorbidities that
call for medical attention, an algorithm for diabetes pharma-
cotherapy was developed to allow for such choice of medica-
tionsastoaddresseachpatient’s pathology/condition, with the
priority in medication selection determined, with consideration
also given to current prescribing patterns and other relevant
factors.
PROPOSED ALGORITHM ANNOTATED
Assessing the indications for insulin and determining the
HbA1c control goal
The overriding premise behind diabetes pharmacotherapy was
de?ned as ensuring safety (Figure 2). Thus, medication selection
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was ?rst assumed to involve assessing whether there were any
absolute or relative indications for insulin therapy in each patient.
Then,asindividuals65yearsoldorolderaccountformorethan
half of all people with diabetes in Japan, the HbA1c control goal
was determined, based on those proposed in the Kumamoto Dec-
laration 2013 and the JDS-proposed ‘Glycemic targets (HbA1c
values) for elderly patients with diabetes’
20,29
. It was also assumed
thatwhiletheHbA1ccontrolgoalof<7% remained valid for pre-
vention of complications in people with diabetes, the HbA1c con-
trol goal could also be determined with consideration given to
other factors such as their age or comorbidities.
Assessing people with type 2 diabetes for the presence of
obesity as a relevant measure (step 1)
Whiletheinsulinogenicindex(II)orC-peptideindexremain
useful as measures of insulin-secretory capacity, as does Homeo-
static Model Assessment – Insulin Resistance (HOMA-IR) to
evaluate insulin resistance in assessing people with diabetes for
insulin de?ciency or insulin resistance as part of the core pathol-
ogy, type 2 diabetes mellitus is such a common disease that
assessing all affected individuals using these indices is hardly fea-
sible in clinical practice. Given that one of the important aims of
the proposed algorithm is to promote the proper use of
Consensus statement on the
algorithm for pharmacotherapy in
T2DM patients
A ranked listing of antidiabetic medications (priorities) was proposed
after weighing the strength of available evidence for these
medications and their prescribing patterns in clinical practice in Japan.
With the accumulation of evidence for/clinical experience in diabetes
pharmacotherapy, the proposed algorithm is expected to evolve over
time thus continuing to contribute to improved diabetes management.
Given the differences in diabetes pathology
between Japanese and Westerners, a different
treatment strategy has been proposed in Japan,
where the antidiabetic medication prescribing
patterns also differ from those in the West.
Diabetes
pathology
Antidiabetic medication
prescribing patterns in
Japan
Evidence of additional
medication benefits
for comorbidities
Figure 1 | Working concept of an algorithm for pharmacotherapy in type 2 diabetes mellitus.
4 J Diabetes Investig Vol. C15C15 No. C15C15 C15C15C15 2022 a 2022 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
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antidiabetic medications among non-experts, the presence or
absence of obesity was adopted as the single most important clin-
ical measure to allow the core pathology of diabetes to be
detected to some extent. Thus, it is recommended that patients
are assessed for obesity using the de?nition of obesity in Japan,
body mass index (BMI) 25 kg/m
2
or more
30
, in choosing medi-
cations for type 2 diabetes mellitus. Given that the extent of obe-
sity (BMI) and insulin resistance are shown to be positively
correlated, insulin resistance is assumed to have a greater
contribution to type 2 diabetes mellitus in highly obese patients,
thus prompting the choice of medications to address the pathol-
ogyinquestion.Thecaveatisthatvisceralfataccumulationis
often noted in Japanese and Asian individuals with a BMI lower
than that in obese Westerners and that insulin resistance may be
implicated due to visceral fat accumulation in some of these
patients, they are usually categorized by BMI as being non-
obese
4,31,32
. Despite this caveat, however, it is assumed that
patients can be accurately assessed for excessive visceral fat
Figure 2 | Proposed algorithm for pharmacotherapy in type 2 diabetes mellitus.
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accumulation by assessing them for BMI and waist circumfer-
ence at the same time. Note here that excessive visceral fat accu-
mulation may be suspected in men with a waist circumference of
85 cm or greater as well as in women with a waist circumference
of 90 cm or greater. Now, candidate medications for patients
with obesity include non-insulin secretagogues, e.g., biguanides,
SGLT2 inhibitors, and thiazolidinediones, as well as insulin secre-
tagogues, e.g., GLP-1 receptor agonists with potential for weight-
reducing effects and imeglimin, for which obesity/insulin resis-
tance is a good indication, given its insulin-sensitizing properties.
In most non-obese individuals with type 2 diabetes mellitus
in whom insulin insuf?ciency is assumed to constitute the core
pathology, consideration should be given in medication selec-
tion to insulin secretagogues as the mainstay of treatment. Of
these, DPP-4 inhibitors remain the most frequently prescribed
for people with type 2 diabetes in Japan, particularly most fre-
quently in elderly patients, probably re?ecting the high expecta-
tions for their safety in the elderly
25
. DPP-4 inhibitors are also
shown in some reports to exert far greater glucose-lowering
ef?cacy in Asians than in other races
33,34
,suggestingthatnon-
obese patients with type 2 diabetes likely represent a good indi-
cation for this medication class, given its safety and ef?cacy.
Again, while numerous studies conducted to date consistently
suggest a low cardiovascular risk with DPP-4 inhibitors as a
class
35–37
, some of these medications are also reported to be
associated with an increased risk of heart failure, thus calling
for their judicious use in patients at high risk of heart failure
38
.
Of the insulin secretagogues, sulfonylureas (SUs) are also of
interest, in that they are non-glucose-dependent insulin secreta-
gogues and are associated with a high risk of hypoglycemia
39
,
while glinides and a-glucosidase inhibitors also represent good
medication candidates for patients exhibiting marked postpran-
dial hyperglycemia. Metformin is shown to exert comparable
HbA1c-lowering ef?cacy in both non-obese and obese Japanese
patients with type 2 diabetes mellitus and thus represents an
option for non-obese people with type 2 diabetes
40,41
. Note here
that non-obese patients include lean patients (BMI <18.5 kg/
m
2
) who are mainly elderly; thus, caution should be exercised
in using antidiabetic medications with weight-reducing proper-
ties, i.e., GLP-1 receptor agonists and SGLT2 inhibitors, in lean
patients
16
, as it may be associated with an increased risk of
geriatric syndrome, e.g., sarcopenia and frailty.
Giving due consideration to ensuring safety (step 2)
Note that the most desirable attribute required of antidiabetic
medications is their ability to ‘lower blood glucose safely’.Thus,
the proposed algorithm has included a summary of their glu-
cose-lowering potency relative to their ef?cacy and safety and
risk of hypoglycemia, as well as precautions (particularly con-
traindications) for their use in patients with organ derangement
(e.g., renal impairment, hepatic disorder [particularly cirrhosis],
cardiovascular disorder, and heart failure) in Table 1,withrun-
ning commentary on areas where caution should be exercised
in their use: (1) the use in elderly patients of sulfonylureas and
glinides, both of which are associated with a high risk of hypo-
glycemia; (2) safety precautions in medication selection in
patients with renal impairment, a highly common comorbidity
in people with type 2 diabetes; and (3) medications contraindi-
cated in patients with heart failure.
According to a network meta-analysis of the HbA1c-lowering
ef?cacy of antidiabetic medications, GLP-1 receptor agonists are
shown to be the most potent of all medications in lowering
HbA1c, followed by metformin, pioglitazone, and sulfonylureas
42
.
It is also shown that metformin lowers glucose dose-dependently
and exerts highly potent glucose-lowering effects at its high doses
and that the thiazolidinedione lowers glucose through its insulin-
sensitizing effects on adipose tissue and skeletal muscle and thus
isshowntobemoreeffectiveinobesepatients.
Safety against hypoglycemia risk remains the most relevant of
all safety requirements for antidiabetic medications. As single
agents, antidiabetic medications other than the non-glucose
dependent sulfonylureas and glinides are generally associated
with a low risk of hypoglycemia, while sulfonylureas are among
the agents associated with a high risk of hypoglycemia. Indeed,
according to a report from the JDS Committee on Survey of Sev-
ere Hypoglycemia Associated with Diabetes Treatment, patients
treated with sulfonylureas accounted for about 30% of all patients
treated with any antidiabetic medications (or about 85% of all
patients treated with medications other than insulin therapy)
who required emergency transportation for severe hypo-
glycemia
39
.A?nding of particular interest from this survey is
that elderly patients accounted for a large proportion of those
thus transported for severe hypoglycemia, suggesting that caution
should be exercised in the use of sulfonylureas in elderly patients.
The impact of antidiabetic medications on body weight is
also particularly relevant to the correction of obesity and the
prevention of geriatric syndrome, two major issues referred to
above. In this regard, SGLT2 inhibitors are shown to be associ-
ated with a weight reduction of 2 kg compared with placebo
16
,
suggesting their suitability for use in obese people with type 2
diabetes. GLP-1 receptor agonists are also shown to have
weight-reducing effects and are thus deemed suitable for use in
obese people with type 2 diabetes, with the reduction in body
weight reported to be 2 kg on average in patients treated with
these medications compared with those treated with placebo
16
.
Of these, samaglutide was evaluated for its ef?cacy in Japanese
patients with type 2 diabetes mellitus in a recently reported
study, which demonstrated that the medication was associated
with a signi?cant reduction in body weight (ranging from 2 to
3 kg) at high doses
43,44
.Again,a-glucosidase inhibitors are
shown to be associated with a greater weight reduction in obese
Japanese people with type 2 diabetes than miglitol
45
.Con-
versely, many studies reported a weight gain of about 2 kg in
patients treated with sulfonylureas than that in patients treated
with placebo, while pioglitazone was shown to be associated
withaweightgainof1–4kg
46
and likely edema as well.
Caution needs to be exercised in the use of multiple antidia-
betic medications in patients with diabetes complicated by renal
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impairment.Giventhatmostnon-glucose-dependentinsulin
secretagogues (e.g., sulfonylureas and glinides) are renally
excreted, their use is thought likely to be associated with
increased risk of hypoglycemia, and sulfonylureas and nateglin-
ide are both contraindicated for use in those with renal impair-
ment
39
, while, as a glinide with biliary excretion, repaglinide is
shown to be relatively safer for use in patients with renal
impairment than other glinides. Metformin is shown to be
associated with an increased risk of lactic acidosis in patients
with renal dysfunction and is thus contraindicated in those
with eGFR <30 mL/min/1.73 m
2
butisrecommendedforuse
at a daily maximum dose of 750 and 1,500 mg in those with
eGFR <45 mL/min/1.73 m
2
and ≥45 mL/min/1.73 m
2
, respec-
tively
28
. Pioglitazone is available for use overseas even in renally
impaired patients but is contraindicated for use in severely ren-
ally impaired patients in Japan. As their glucose-lowering ef?-
cacy is shown to be diminished in renally impaired patients,
SGLT2 inhibitors raise concern over their failure to achieve
adequate glucose lowering in severely renally impaired patients.
Severe hepatic disorder constitutes a contraindication for
biguanides, sulfonylureas, and thiazolidinediones (despite being a
relative indication for insulin therapy). Of all patients with car-
diovascular disease (CVD), those with hemodynamically unstable
disease and heart failure are a contraindication for biguanides,
while metformin is no longer contraindicated in patients with
heart failure (while still contraindicated in patients with hemody-
namically unstable, acute heart failure) in Western countries, fol-
lowing reports of reductions in the need for hospitalization due
to heart failure and in mortality risk with metformin
47–49
.While
patients with stage C or higher symptomatic heart failure are
deemed a contraindication, and those with stage A and B an indi-
cation, for thiazolidinediones, consideration should be given in
the latter to their dose adjustment, salt restriction, and concomi-
tant use of diuretics for associated ?uid retention.
While not mentioned in Table 1, it is important that patients
receiving SGLT2 inhibitors be closely monitored for euglycemic
diabetic ketoacidosis. SGLT2 inhibitors are expected to increase
urinary glucose excretion and to lower blood glucose and insu-
lin, leading to an increased glucagon/insulin ratio and an
increased hepatic glycogenesis/lipolysis in adipose tissue, thus
resulting in increased usage of lipids for energy metabolism.
Therefore, SGLT2 inhibitors are associated with the risk of
Table 1 | A summary of the characteristics of antidiabetic medications for safe glycemic control: a comparison of glucose-lowering potency,
hypoglycemia risk, contraindications, adherence rates and medication costs (a ranked listing of medications initially prescribed by frequency)
Area of interest DPP-4 inhibitors Biguanides SGLT2 inhibitors Sulfonylureas
α-glucosidase
inhibitors
Thiazolidinediones Glinides
GLP-1RA
Imeglimin
Glucose-lowering
potency
High
(dose-dependent)
Intermediate High Ameliorate
postprandial
hyperglycemia
Intermediate
(highly e?ecg415ve in
obese pag415ents)
Ameliorate
postprandial
hyperglycemia
High Intermediate
Single-agent
hypoglycemia risk
Low Low Low High Low Low Intermediate Low Low
E?ect on body
weight
Neutral Neutral to weight-
reducing
Weight-reducing Weight-increasing Neutral Weight-increasing Weight-increasing Weight-reducing Neutral
Renal impairment Dose reducg415on
required for some
agents
Dose reducg415on
required in renal
impairment;
Contraindicated in
severe renal
impairment
No e?ecg415ve
expected in
severe renal
impairment
Caug415on required
(for hypoglycemia)
Contraindicated in
severe renal
impairment
Caug415on required (for
hypoglycemia)
Exenag415de
contraindicated in
severe renal
impairment
Not recommended in
pag415ents with eGFR <
45 mL/min/1.73 m
2
Hepag415c dysfuncg415on
Vildaglipg415n is
contraindicated in
severe liver
dysfuncg415on
Contraindicated in
severe hepag415c
dysfuncg415on
Contraindicated in
severe hepag415c
dysfuncg415on
Contraindicated in
severe hepag415c
dysfuncg415on
Caug415on required (for
hypoglycemia)
No clinical trials
conducted in pag415ents
with severe hepag415c
dysfuncg415on
Cardiovascular
disorder
Contraindicated in
hemodynamically
unstable disease,
e.g., myocardial
infarcg415on
Extra caug415on
required
(for the risk of
severe
hypoglycemia)
Heart failure
Some agents
associated with
increased risk of HF
Contraindicated Contraindicated
Adherence rate High
(parg415cularly with
once weekly dosing)
Intermediate
(due to
gastrointesg415nal
symptoms)
Intermediate
(due to micturig415on,
genital infecg415on)
Intermediate
(due to weight gain,
hypoglycemia)
Low
(due to route of
administrag415on,
gastrointesg415nal
symptoms)
Intermediate
(due to edema,
weight gain)
Low
(due to route of
administrag415on,
hypoglycemia)
Intermediate
(due to injecg415ons,
route of
administrag415on,
gastrointesg415nal
symptoms)
Intermediate
(due to
gastrointesg415nal
symptoms)
Medicag415on cost Intermediate Low Intermediate/High Low Intermediate Low Intermediate High Intermediate
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ketoacidosis even in patients with normoglycemia due to an
acuteincreaseinketonebodiesonthebasisofinsulininsuf?-
ciency or during their sick days.
Weighing the additional medication bene?ts for comorbidities
(step 3)
Given that numerous large-scale clinical trials conducted mainly
overseas have shown the ef?cacy of SGLT2 inhibitors and GLP-1
receptor agonists against chronic kidney (particularly overt
nephropathy), cardiovascular disease, and heart failure, the pro-
posed algorithm included cardiovascular disease, heart failure,
and chronic kidney disease (particularly overt nephropathy) as
target diseases of secondary interest for which antidiabetic medi-
cations may be seen to offer additional bene?ts. While it should
be noted that, unfortunately, the algorithm draws mainly on the
evidence available from overseas due to the paucity of data from
Japan on this issue, these comorbidities appear to be a valid indi-
cation for the use of SGLT2 inhibitors and GLP-1 receptor ago-
nists, with the caveat that the reduction seen in cardiovascular
events in these trials may be accounted for in part by that in
HbA1c with these agents
50
, suggesting that their organ-protective
effects may not be completely independent of their glucose-low-
ering effects and that further studies are awaited to elucidate the
mechanisms involved.
Weighing the additional bene?t of antidiabetic medications for
cardiovascular disease
Large-scale clinical trials of SGLT2 inhibitors (i.e., EMPA-REG,
CANVAS, and DECLARE TIMI 58) have been conducted in
people with type 2 diabetes having cardiovascular disease or
high-risk patients with type 2 diabetes with major adverse car-
diovascular events (MACE) (a composite of cardiovascular
death, non-fatal myocardial infarction (MI), and non-fatal
ischemic stroke) as the primary endpoint and demonstrated a
signi?cant reduction in MACE with these agents
51–53
with this
?nding also con?rmed by independent meta-analyses of these
trials
54,55
. Likewise, of the GLP-1 receptor agonists available,
those of human origin have been shown in several large-scale
clinical trials (i.e., LEADER, SUSTAIN6, and Harmony) to pro-
duce a signi?cant reduction in MACE
56–58
with this outcome
also con?rmed in a meta-analysis
54
. Thus, while it should be
noted that there is a paucity of data from large-scale trials in
Japanese patients and that Japanese people with diabetes are at
lower risk of cardiovascular disease than their Western counter-
parts, the evidence available overseas is so numerous and of
such high quality that SGLT2 inhibitors and GLP-1 receptor
agonists were included as highly recommended options in the
order listed for their additional bene?t for cardiovascular dis-
ease in the proposed algorithm.
Weighing the additional bene?t of antidiabetic medications for
heart failure
Assessing and treating people with type 2 diabetes mellitus for
heartfailureisofvitalimportance,giventhateven
asymptomatic people with type 2 diabetes mellitus are deemed
to be in a state called ‘pre-HF’, i.e., at high risk of heart failure.
In this regard, SGLT2 inhibitors (i.e., empagli?ozin, canagli?o-
zin, and dapagli?ozin) are shown in clinical trials investigating
their cardiovascular safety to be useful in preventing heart fail-
ure
51–53
, with a similar ?nding shown in a subset analysis of
Asian subjects
59
. Also of interest is a study that compared the
real-world evidence for SGLT2 inhibitors vs DPP-4 inhibitors
in global populations including Japanese and Koreans, which
also con?rmed the usefulness of SGLT2 inhibitors in preventing
heart failure
60
. Furthermore, SGLT2 inhibitors are shown in a
clinical trial in heart failure patients with or without type 2 dia-
betes mellitus exhibiting heart failure with reduced ejection
fraction (HFrEF) to produce a signi?cant reduction in heart
failure aggravation and cardiovascular death
61,62
with this out-
come con?rmed in a meta-analysis
63
.SGLT2inhibitorsarealso
shown in heart failure patients with or without type 2 diabetes
mellitus exhibiting heart failure with preserved EF (HFpEF) to
produce a signi?cant reduction in heart failure aggravation and
cardiovascular death
64,65
. Given this evidence, therefore, SGLT2
inhibitors were included as medications of ?rst choice in people
with type 2 diabetes having heart failure.
In contrast, GLP-1 receptor agonists are not consistently
shown to be useful in preventing heart failure in clinical studies
evaluating their cardiovascular safety but are nevertheless shown
to be useful as a class in preventing heart failure in a meta-
analysis
66
. However, their usefulness in a Japanese population
remains unclear at the time of this review. Again, the FIGHT
trial evaluated the safety of liraglutide in patients with acute
heart failure exhibiting dLVEF and demonstrated that, contrary
to expectations, treatment with liraglutide led to an increased
risk of heart failure in those with type 2 diabetes mellitus
67
,
suggesting the need to further investigate the useful of GLP-1
receptor agonists for each heart failure pathology or stage as
well as their respective mechanisms of action.
Weighing the additional bene?t of antidiabetic medications for
CKD (particularly overt nephropathy)
In sub-analyses of data from people with type 2 diabetes melli-
tus at high risk of cardiovascular disease participating in cardio-
vascular safety trials, SGLT2 inhibitors (i.e., empagli?ozin,
canagli?ozin, and dapagli?ozin) are shown to be useful in
reducing the composite renal events
51–53
. Of note, reanalysis of
the canagli?ozin trial data using a rigorous composite endpoint
(doubling of serum creatinine, end-stage renal failure, and renal
death) showed a signi?cant reduction in the composite renal
endpoint, as well as in renal dysfunction and albuminuria, with
the medication
68
. Also of interest are the ?ndings from large-
scale clinical trials evaluating the usefulness of SGLT2 inhibitors
(i.e., DAPA-CKD and CREDENCE)
69,70
. While the DAPA-
CKD and CREDENCE trials involved different patient popula-
tions (chronic kidney disease patients with or without type 2
diabetes mellitus of whom those without type 2 diabetes melli-
tus accounted for 32.5% [eGFR, 25–75 mL/min/1.73 m
2
;
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urinary albumin/creatinine ratio (ACR), 200–5,000 mg/g] and
patients with type 2 diabetes mellitus with chronic kidney dis-
ease exhibiting albuminuria [eGFR, ≥30/<90 mL/min/1.73 m
2
;
urinary ACR, >300–5,000 mg/g], respectively), both studies
showed a signi?cant reduction in the composite renal endpoint.
Interestingly, dapagli?ozin was examined for its renoprotective
effect by primary cause of chronic kidney disease in an explora-
tory analysis of the DAPA-CKD study data, which revealed
that despite there being no interaction between its renoprotec-
tive effect and any primary cause of chronic kidney disease, the
medication offered renoprotection for patients with diabetic
nephropathy
71
. Given that most subjects in the DAPA-CKD
and CREDENCE trials were shown to have overt albuminuria
(urinary ACR, ≥300 mg/g), at present, it appears that the evi-
dence of renoprotection with SGLT2 inhibitors remains nearly
limited to people with type 2 diabetes mellitus having overt
nephropathy. In this light, the proposed algorithm noted that
SGLT2 inhibitors should be considered as medications of ?rst
choice in patients with albuminuria (particularly overt
nephropathy), regardless of their glucose-lowering effects, while
not only SGLT2 inhibitors but GLP-1 receptor agonists, as
noted below, should be considered in patients without albumin-
uria.Again,itshouldalsobenotednotonlythattherenopro-
tective effect of SGLT2 inhibitors remains unclear in highly
renally impaired patients (eGFR, 25 mL/min/1.73 m
2
)andbut
that they cannot be expected to be useful as antidiabetic medi-
cations in these patients.
Of the GLP-1 receptor agonists currently available, liraglutide
is shown to inhibit the onset of persistent overt albuminuria
thereby reducing the occurrence of a composite renal endpoint
in a subset analysis of people with type 2 diabetes mellitus at
high risk of cardiovascular disease treated with the medica-
tion
72
. Again, semaglutide is shown to reduce a composite renal
endpoint in people with type 2 diabetes mellitus at high risk of
cardiovascular disease
73
, and duraglutide to inhibit the deterio-
ration of eGFR thereby signi?cantly reducing albuminuria in
people with type 2 diabetes mellitus exhibiting an eGFR ≥30/
<60 mL/min/1.73 m
274
. As GLP-1 receptor agonists are also
reported to reduce a composite cardiovascular endpoint (car-
diovascular death, non-fatal MI, and non-fatal cerebral infarc-
tion [CI]) in people with type 2 diabetes mellitus having renal
dysfunction (eGFR, <60 mL/min/1.73 m
2
)
75
, GLP-1 receptor
agonists were recommended as medications of second choice in
people with type 2 diabetes mellitus having albuminuria but
SGLT2 inhibitors or GLP-1 receptor agonists were recom-
mended as medications worth considering in people with type
2 diabetes mellitus without albuminuria in the proposed algo-
rithm.
Choosing medications with relevant patient background
characteristics of interest in mind (step 4)
The proposed algorithm included a summary of relevant
patient background characteristics of interest against which to
choose medications as well as the medical costs involved
(Figure 2,Table1).Giventhatmedicationadherenceinpeople
with type 2 diabetes mellitus is shown not only to impact their
glycemic control but to be associated with their cardiovascular
disease morbidity, mortality, and hospitalization risk, paying
attention to maintaining their medication adherence represents
an extremely important part of diabetes clinical practice. The
medical cost burden should be weighted for each patient, as it
includes not only the medication costs but associated healthcare
costs.
Individuals with chronic disease, such as diabetes mellitus,
must recognize that they need to be on long-term pharma-
cotherapy for the disease while adhering to the dosage and
usage of the medication(s) prescribed. Indeed, a decline in
adherence to these medications not only diminishes their
antidiabetic ef?cacy but increases the risk of hypoglycemia
through inappropriate intensi?cation of therapy and contributes
to polypharmacy. Unfortunately, however, the adherence rate is
shown to be only moderately good at 68.8% in patients newly
prescribed antidiabetic medications and at 78.1% in all patients
receiving these medications
76
. According to a meta-analysis of
eight observational studies in people with type 2 diabetes melli-
tus, the relative risks for all-cause mortality and hospitalization
are shown to be 0.72 (95% con?dence interval [CI], 0.62–0.82)
and 0.90 (0.87–0.94) in those in the high adherence (80% or
higher) group compared with the low adherence (<80%) group,
suggesting that low adherence is associated with an increased
cardiovascular disease risk
77
. Studies overseas also reported that
there was a signi?cant correlation between medication adher-
ence and changes in HbA1c in people with type 2 diabetes
mellitus, i.e., that a 10% increase in adherence translates into a
0.15% decrease in HbA1c
78,79
, and similar results were shown
in a questionnaire survey conducted in 1,022 patients with type
2 diabetes mellitus in Japan, i.e., that the more frequent the
dosing and the older the patient, the lower the adherence and
that there was a signi?cant difference in adherence between
those receiving, and those not receiving, their medications as
one package
80
. Of note, a systematic review and meta-analysis
of medication adherence in people with type 2 diabetes mellitus
has become available
81
. In this review, a comparison of adher-
ence to metformin, sulfonylureas and thiazolidinediones showed
that medication adherence is signi?cantly higher with sulfony-
lureas and thiazolidinediones than with metformin, higher with
thiazolidinediones than with sulfonylureas, and higher with
DPP-4 inhibitors than with thiazolidinediones or sulfonylureas.
Of note here also is a retrospective study conducted to evaluate
the need for intensi?cation of therapy after treatment with
biguanides or DPP-4 inhibitors in medication-na€?ve Japanese
patients with type 2 diabetes, which suggested that DPP-4 inhi-
bitors are superior to biguanides
82
.Again,whileglinidesanda-
glucosidase inhibitors, which need to be taken before meals, are
assumed to be associated with lower adherence rates than sul-
fonylureas, biguanides, or thiazolidinediones
83
,thismaybe
remedied by implementing appropriate measures, e.g., ensuring
that all other medications are also taken before meals
80
.Thus,
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based on the evidence summarized above, the proposed algo-
rithm included a summary of adherence rates for the available
antidiabetic medications in a separate table to help in medica-
tion selection. In an increasingly aging society such as Japan, it
is deemed important that efforts be focused on minimizing
dosing frequency as well as on maintaining or improving medi-
cation adherence through appropriate measures, e.g., provision
of medications in one package or the use of combination
medications.
Medical expenditure is ever increasing with the aging of the
population
84
. A survey on medical expenditure for lifestyle-re-
lated diseases in 2019 by the National Federation of Health
Insurance Societies showed that, of the 10 lifestyle-related dis-
eases including cerebrovascular disease, ischemic heart disease
and dialysis, diabetes mellitus imposes a huge economic burden
on affected individuals, accounting for the third largest share in
hospitalization costs, the largest share in non-hospitalization
costs, and the second largest share next to dialysis in daily
healthcare costs
85
. As high medical expenditure is associated
with a decline in adherence to medications
86
,itisalsolikelyto
be associated with a decline in their ef?cacy. Thus, considera-
tion needs to be given to the choice of antidiabetic medication
(s), as they vary widely in their prices in Japan and expensive
choices impose an increased burden on the patients and the
patient’s burden is not limited to medication costs. Of note
here is a survey conducted using the National Database of
Health Insurance Claims and Speci?c Health Check-ups to
investigate total medical expenditures incurred by Japanese peo-
ple with type 2 diabetes mellitus in 1 year following their initial
antidiabetic prescription (adjusted for age, sex, comorbidities,
healthcare institutional attributes, and other relevant factors),
which showed that, of all antidiabetic medications, biguanides
represented the lowest 1 year expenditure, followed by thiazo-
lidinediones and a-glucosidase inhibitors, while GLP-1 receptor
agonists represented the highest
25
. An estimation of the eco-
nomic burden associated with the use of antidiabetic medica-
tions is given in a separate table in terms of their prices and
associated total medical expenditure. To help reduce each
patient’s economic burden, therefore, consideration should be
given to using generics, switching to biguanides, or switching
from multiple single agents to combination medications.
PERIODIC ASSESSMENT OF TREATMENT EFFICACY
AND THE NEED FOR ADJUSTMENTS IN
PHARMACOTHERAPY
It is proposed in the present algorithm that each medication
regimen be reviewed for possible revision every 3 months after
its initiation to avoid delays in addressing the needs of patients
requiring intensi?cation of therapy and that attention be
focused on promoting medical nutrition therapy tailored to
address their diabetes pathology and nephropathy, exercise
therapy, and lifestyle modi?cation in each patient, while revert-
ing to step 1, as required, to add further medications, increase
their medication doses or consider alternative medications.
It should be noted that if left untreated, hyperglycemia
increases the subsequent risk of diabetic microangiopathy,
macroangiopathy or death in people with diabetes
87,88
and that
inappropriate glycemic control results at least in part from
delays in initiation or intensi?cation of therapy (i.e., clinical
inertia)
89
. Indeed, it is reported in a US study that antidiabetic
therapy was not appropriately initiated and intensi?ed within
6 months of consultation in 37% and 18% of people with dia-
betes requiring initiation and intensi?cation of therapy, respec-
tively
90
, and it is also reported in another study that
antidiabetic therapy was not intensi?ed within 6 months of
consultation in 44% of people with type 2 diabetes mellitus
having HbA1c 9% or higher
91
. Thus, while clinical inertia
occurs often in clinical practice, pharmacotherapy needs to be
immediately adjusted in patients who have failed to achieve
their respective HbA1c control goals. In this regard, while it is
recommended by the ADA that any medication regimen be
reviewed for ef?cacy as well as for revision every 3–6 months
19
,
it is recommended in the current algorithm that any regimen
in place be reviewed for revision in a 3 month cycle, re?ecting
the usual frequency of hospital visits by people with diabetes in
Japan, with a focus also on promoting medical nutrition ther-
apy tailored to address the diabetes pathology and nephropathy,
as well as exercise therapy and lifestyle modi?cation, in each
patient.
ACKNOWLEDGMENTS
The authors would like to acknowledge that the current con-
sensus statement has been compiled with reference to the opin-
ion and views of executive board members and organizers of
the Japan Diabetes Society as well as to public comments pro-
vided by the Japanese Circulation Society and the Japanese
Society of Nephology. The authors would also like to extend
their deep gratitude to all the experts who contributed to the
development of the current statement.
DISCLOSURE
Y.O. reports subsidies or donations from Novo Nordisk Pharma
Co., Ltd, Kyowa Kirin Co., Ltd, Mitsubishi Tanabe Pharma Co.,
Ltd, Takeda Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd,
Teijin Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, and
Sumitomo Pharma Co., Ltd. D.Y. reports honoraria from Novo
Nordisk Pharma Co., Ltd, Ono Pharmaceutical Co., Ltd,
research funding from Terumo Co., Ltd, and endowed depart-
ments by Novo Nordisk Pharma Co., Ltd, Nippon Boehringer
Ingelheim Co., Ltd, Ono Pharmaceutical Co., Ltd, Taisho Phar-
maceutical Co., Ltd, and Arkray. R.N. reports honoraria from
Sano? Co., Ltd, Medtronic Co., Ltd, Nippon Boehringer Ingel-
heim Co., Ltd, Takeda Pharmaceutical Co., Ltd, Kissei Pharma-
ceutical Co., Ltd, Novartis Pharma Co., Ltd, Eli Lilly Japan Co.,
Ltd, Novo Nordisk Pharma Co., MSD, Astellas Pharma Inc.,
and Abbott and subsidies or donations from Taisho Pharmaceu-
tical Co., Ltd, Ono Pharmaceutical Co., Ltd, Takeda Pharmaceu-
tical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, and
10 J Diabetes Investig Vol. C15C15 No. C15C15 C15C15C15 2022 a 2022 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
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Abbott. N.H. reports research funding from Ono Pharmaceuti-
cal Co., Ltd, Mitsubishi Tanabe Pharma Co., Ltd, and Japan
Diabetes Foundation. H.K. reports honoraria from Novo Nor-
disk Pharma Co., Ltd, Sano? K.K., Sumitomo Pharma Co., Ltd,
Nippon Boehringer Ingelheim Co.,Ltd,EliLilyJapanK.K.,
Daiichi Sankyo Co., Ltd, Ono Pharmaceutical Co., Ltd, Kissei
Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Co., Ltd,
Kowa Co., Ltd, Novartis Pharma Co., Ltd, MSD, Sanwa Kagaku
Kenkyusho Co., Ltd, research funding from Kissei Pharmaceuti-
cal Co., Ltd, Ono Pharmaceutical Co., Ltd, Eli Lilly Japan K.K.,
subsidies or donations from MSD, Ono Pharmaceutical Co.,
Ltd, Sumitomo Pharma Co., Ltd, Takeda Pharmaceutical Co.,
Ltd, Mitsubishi Tanabe Pharma Co., Ltd, Japan Tobacco Inc.,
Novo Nordisk Pharma Co., Ltd, travel fees from Ono Pharma-
ceutical Co., Ltd, Sanwa Kagaku Kenkyusho Co., Ltd, Kowa Co.,
Ltd, Terumo Co., Ltd, and Abott. R.S. reports honoraria from
Mitsubishi Tanabe Pharma Co., Ltd, Eli Lilly Japan K.K., Novo
Nordisk Pharma Co., Ltd, Ono Pharmaceutical Co., Ltd, Sumit-
omo Pharma Co., Ltd, Sano? Co., Ltd, Astellas Pharma Inc.,
DaiichiSankyoCo.,Ltd,KowaCo.,Ltd,SanwaKagakuKen-
kyusho Co., Ltd, Takeda Pharmaceutical Co., Ltd, Nippon Boeh-
ringer Ingelheim Co., Ltd, Taisho Pharmaceutical Co., Ltd,
Novartis Pharma Co., Ltd, research funding from Sumitomo
Pharma Co., Ltd, subsidies or donations from Nippon Boehrin-
ger Ingelheim Co., Ltd, Mitsubishi Tanabe Pharma Co., Ltd,
LifeScanJapanCo.,Ltd,andOnoPharmaceuticalCo.,Ltd.T.Y.
reports honoraria from MSD, Ono Pharmaceutical Co., Ltd,
Takeda Pharmaceutical Co., Ltd, Daiichi Sankyo Co., Ltd, Novo
Nordisk Pharma Co., Ltd, Sumitomo Pharma Co., Ltd, Teijin
Health Care Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd,
research funding from Astra Zeneca, Kowa Pharmaceutical Co.,
Ltd, MSD, Nippon Boehringer Ingelheim Co., Ltd, Aero
Switchtherapeutics Inc., Minophagen Pharmaceutical, Co., Ltd,
Mitsubishi Corporation Life Sciences Ltd, NIPRO Co., Ltd, sub-
sidies or donations from Novo Nordisk Pharma Co., Ltd, Mit-
subishi Tanabe Pharma Co., Ltd, Taisho Pharmaceutical Co.,
Ltd, Kyowa Kirin Co., Ltd, Takeda Pharmaceutical Co., Ltd,
Ono Pharmaceutical Co., Ltd, Astellas Pharma Inc., Sano? Co.,
Ltd, Sumitomo Pharma Co., Ltd, Kowa Pharmaceutical Co.,
Ltd, Takeda Science Foundation, endowed departments by
Takeda Pharmaceutical Co., Ltd, Ono Pharmaceutical Co., Ltd,
Novo Nordisk Pharma Co., Ltd, Mitsubishi Tanabe Pharma
Co., Ltd, MSD, Nippon Boehringer Ingelheim Co., Ltd, Kowa
Pharmaceutical Co., Ltd, NTT DOCOMO Inc., and Asahi
Mutual Life Insurance Co., Ltd. No other potential con?icts of
interest relevant to this article were reported.
Approval of the research protocol: N/A.
Informed consent: N/A.
Registry and the registration no. of the study/trial: N/A.
Animal studies: N/A.
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